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Sample records for variant predicts esrd

  1. The PPAR gamma 2 Pro12Ala variant predicts ESRD and mortality in patients with type 1 diabetes and diabetic nephropathy

    DEFF Research Database (Denmark)

    Jorsal, A; Tarnow, L; Lajer, M

    2008-01-01

    The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma 2 gene is suggested to associate with diabetic nephropathy and cardiovascular disease in type 2 diabetes. The aim of this study was to investigate the polymorphism in relation to diabetic nephropathy, end-stage renal...... frequencies (p=0.25). Cox regression analysis revealed a covariate-adjusted hazard ratio (HR) for all-cause mortality in patients with the Ala/Ala genotype of 2.44 (1.23-4.84). The Pro12Ala polymorphism did not predict CVD events. However, the Ala/Ala genotype predicts ESRD (covariate-adjusted HR 2.60 (1.......11-6.07)). Furthermore, Carriers of the Ala-allele had a higher rate of decline in GFR (p=0.040). In conclusion, the Pro12Ala polymorphism is not associated with type 1 diabetic nephropathy. The Ala-allele is associated with enhanced decline in GFR and predicts ESRD and all-cause mortality in patients with nephropathy....

  2. Quantifying exposure to calcium and phosphate in ESRD; predictive of atherosclerosis on top of arteriosclerosis?

    NARCIS (Netherlands)

    Jaarsveld, van B.C.; Graaf, van der Y.; Vos, P.F.; Soedamah-Muthu, S.S.

    2010-01-01

    Background: Long-term exposure to hypercalcaemia and hyperphosphataemia leads to media calcification and predicts mortality in patients with end-stage renal disease (ESRD). It is debatable whether this exposure is only a risk factor for arteriosclerosis, or also for superimposed atherosclerosis.

  3. Predictive power of sequential measures of albuminuria for progression to ESRD or death in Pima Indians with type 2 diabetes.

    Science.gov (United States)

    Pavkov, Meda E; Knowler, William C; Hanson, Robert L; Bennett, Peter H; Nelson, Robert G

    2008-05-01

    To determine whether historic albuminuria measurements provide additional predictive value for diabetic end-stage renal disease (ESRD) and natural mortality over the most recent measurement, ie, whether "regression" from high albuminuria has a different prognosis than stability at the lower level. Observational longitudinal study. Pima Indians 15 years or older with type 2 diabetes and at least 2 consecutive measurements of urinary albumin-creatinine ratio (ACR) within 6 years. Sequential measurements of urinary ACR. Proportional hazards analyses were used to estimate the risk of ESRD and natural death associated with the first and second ACR measurement. The ability of these highly correlated variables to predict outcome was compared with receiver operating characteristic curves calculated by means of the generalized c statistic. In 983 subjects, 136 developed ESRD and 180 died of natural causes during a maximum follow-up of 12.6 years. Each doubling in the second ACR was associated with a 1.71-fold greater incidence of ESRD (95% confidence interval, 1.54 to 1.89) and 1.16-fold greater natural mortality (95% confidence interval, 1.07 to 1.27) adjusted for age, sex, diabetes duration, and antihypertensive medication. The addition of the first ACR measurement to the model did not add to the predictive value for ESRD or mortality. In pairwise comparisons of c statistics, the second ACR was a significantly better predictor of ESRD than the first ACR. The predictive value of ACR measurements is decreased to the extent that its precision is based on a single measure. The predictive power of the latest ACR for ESRD and natural mortality in patients with diabetes is not enhanced by knowledge of the preceding ACR. Therefore, ACR changes over time, ie, regression or progression, add minimal predictive value beyond the latest measurement in the series.

  4. [Penultimate pulse wave velocity, better than baseline pulse wave velocity, predicted mortality in Italian ESRD cohort study - a case for daily hemodialysis for ESRD patients with accelerated pulse wave velocity changes].

    Science.gov (United States)

    Onuigbo, Macaulay; Onuigbo, Nnonyelum; Bellasi, Antonio; Russo, Domenico; Di Iorio, Biagio Raffaele

    2013-01-01

    .5, NS). Repeat PWV values increased in the 106 patients who died from 9.43 +/- 3.75 to 12.11 +/- 4.18 (ppatients who died from SD, death occurred 24 hours ATLD in 20 and >48 hours ATLD in 17. Of the 47 patients who died from AMI, 6 died 24 hours ATLD and 23 died >48 hours ATLD. Of the 14 ESRD patients in the cohort that died from hyperkalemia, 3 died 24 hours ATLD, and 7 died >48 hours ATLD. CAC data scatter did not allow for adequate statistical subgroup analysis but overall, baseline CAC values were higher in the AMI/SD dead patients vs surviving patients. This is the first report to show a scalable and direct relationship between translational follow up PWV changes after six months versus observed cardiovascular mortality in an ESRD cohort. We have shown, for the first time, that penultimate PWV, better than baseline PWV, predicted cardiovascular mortality in this ESRD cohort. Moreover, higher proportions of the ESRD deaths from AMI, SD and hyperkalemia occurred during the long inter-dialytic (weekend) period when ESRD patients went for 3 days without hemodialysis. We propose that PWV be monitored among all new ESRD patients, and be repeated after six months of initiation of chronic hemodialysis. Our group had earlier demonstrated in 2012 that daily dialysis reduced PWV in chronic hemodialysis patients. From these study findings, we have proposed that ESRD patients who exhibit elevated initial PWV values, or more so, ESRD patients who demonstrate accelerated PWV values after six months on maintenance chronic hemodialysis should be converted to daily hemodialysis protocol. Furthermore, such patients may require more intense cardiovascular analysis by cardiologists. Further research into new preventative or therapeutic options in this area of ESRD care is warranted.

  5. ESRD Payment System

    Data.gov (United States)

    U.S. Department of Health & Human Services — Medicare payment to ESRD facilities for outpatient maintenance dialysis services furnished to Medicare beneficiaries with End-Stage Renal Disease (ESRD) is based on...

  6. Sickle Cell Trait and the Risk of ESRD in Blacks.

    Science.gov (United States)

    Naik, Rakhi P; Irvin, Marguerite R; Judd, Suzanne; Gutiérrez, Orlando M; Zakai, Neil A; Derebail, Vimal K; Peralta, Carmen; Lewis, Michael R; Zhi, Degui; Arnett, Donna; McClellan, William; Wilson, James G; Reiner, Alexander P; Kopp, Jeffrey B; Winkler, Cheryl A; Cushman, Mary

    2017-07-01

    Blacks, compared with whites, have an increased risk of progression to end-stage renal disease (ESRD). Emerging evidence suggests that, in addition to APOL1 high-risk genotypes, hemoglobin variants, including sickle cell trait (SCT) and hemoglobin C trait, have a role in kidney disease in blacks. However, the association between these hemoglobin traits and ESRD remains unknown. In a large population-based cohort, the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, we evaluated 9909 self-reported blacks (739 with SCT and 243 with hemoglobin C trait). Incident ESRD occurred in 40 of 739 (5.4%) individuals with SCT, six of 243 (2.5%) individuals with hemoglobin C trait, and 234 of 8927 (2.6%) noncarriers. The incidence rate for ESRD was 8.5 per 1000 person-years for participants with SCT and 4.0 per 1000 person-years for noncarriers. Compared with individuals without SCT, individuals with SCT had a hazard ratio for ESRD of 2.03 (95% confidence interval, 1.44 to 2.84). Hemoglobin C trait did not associate with prevalent CKD or ESRD. The incidence rate for ESRD among participants with APOL1 high-risk genotypes was 6.6 per 1000 person-years, with a hazard ratio for ESRD of 1.77 (95% confidence interval, 1.31 to 2.38) for participants with, compared with those without, APOL1 high-risk genotypes. In this cohort, SCT strongly associated with risk of progression to ESRD in blacks, and this degree of risk for ESRD was similar to that conferred by APOL1 high-risk genotypes. These results may have important public policy implications for genetic counseling of SCT carriers. Copyright © 2017 by the American Society of Nephrology.

  7. variant formula for predicting peak expiratory flow rate in pregnant ...

    African Journals Online (AJOL)

    DR. AMINU

    Accepted: November, 2009. VARIANT FORMULA FOR PREDICTING PEAK EXPIRATORY FLOW RATE IN. PREGNANT WOMEN IN KURA LOCAL GOVERNMENT AREA, KANO STATE,. NIGERIA. A. I. Salisu. Department of Human Physiology, Faculty of Medicine, Bayero University, Kano salisahmedibrahim@yahoo.co.uk;.

  8. Serious Illness Conversations in ESRD.

    Science.gov (United States)

    Mandel, Ernest I; Bernacki, Rachelle E; Block, Susan D

    2017-05-08

    Dialysis-dependent ESRD is a serious illness with high disease burden, morbidity, and mortality. Mortality in the first year on dialysis for individuals over age 75 years old approaches 40%, and even those with better prognoses face multiple hospitalizations and declining functional status. In the last month of life, patients on dialysis over age 65 years old experience higher rates of hospitalization, intensive care unit admission, procedures, and death in hospital than patients with cancer or heart failure, while using hospice services less. This high intensity of care is often inconsistent with the wishes of patients on dialysis but persists due to failure to explore or discuss patient goals, values, and preferences in the context of their serious illness. Fewer than 10% of patients on dialysis report having had a conversation about goals, values, and preferences with their nephrologist, although nearly 90% report wanting this conversation. Many nephrologists shy away from these conversations, because they do not wish to upset their patients, feel that there is too much uncertainty in their ability to predict prognosis, are insecure in their skills at broaching the topic, or have difficulty incorporating the conversations into their clinical workflow. In multiple studies, timely discussions about serious illness care goals, however, have been associated with enhanced goal-consistent care, improved quality of life, and positive family outcomes without an increase in patient distress or anxiety. In this special feature article, we will ( 1 ) identify the barriers to serious illness conversations in the dialysis population, ( 2 ) review best practices in and specific approaches to conducting serious illness conversations, and ( 3 ) offer solutions to overcome barriers as well as practical advice, including specific language and tools, to implement serious illness conversations in the dialysis population. Copyright © 2017 by the American Society of Nephrology.

  9. 42 CFR 405.2110 - Designation of ESRD networks.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 2 2010-10-01 2010-10-01 false Designation of ESRD networks. 405.2110 Section 405... End-Stage Renal Disease (ESRD) Services § 405.2110 Designation of ESRD networks. CMS designated ESRD networks in which the approved ESRD facilities collectively provide the necessary care for ESRD patients...

  10. Predicting functional decline in behavioural variant frontotemporal dementia

    Science.gov (United States)

    Whitwell, Jennifer L.; Weigand, Stephen D.; Senjem, Matthew L.; Boeve, Bradley F.; Knopman, David S.; Smith, Glenn E.; Ivnik, Robert J.; Jack, Clifford R.; Petersen, Ronald C.

    2011-01-01

    Behavioural variant frontotemporal dementia is characterized by a change in comportment. It is associated with considerable functional decline over the course of the illness albeit with sometimes dramatic variability among patients. It is unknown whether any baseline features, or combination of features, could predict rate of functional decline in behavioural variant frontotemporal dementia. The aim of this study was to investigate the effects of different baseline clinical, neuropsychological, neuropsychiatric, genetic and anatomic predictors on the rate of functional decline as measured by the Clinical Dementia Rating Sum of Boxes scale. We identified 86 subjects with behavioural variant frontotemporal dementia that had multiple serial Clinical Dementia Rating Sum of Boxes assessments (mean 4, range 2–18). Atlas-based parcellation was used to generate volumes for specific regions of interest at baseline. Volumes were utilized to classify subjects into different anatomical subtypes using the advanced statistical technique of cluster analysis and were assessed as predictor variables. Composite scores were generated for the neuropsychological domains of executive, language, memory and visuospatial function. Behaviours from the brief questionnaire form of the Neuropsychiatric Inventory were assessed. Linear mixed-effects regression modelling was used to determine which baseline features predict rate of future functional decline. Rates of functional decline differed across the anatomical subtypes of behavioural variant frontotemporal dementia, with faster rates observed in the frontal dominant and frontotemporal subtypes. In addition, subjects with poorer performance on neuropsychological tests of executive, language and visuospatial function, less disinhibition, agitation/aggression and night-time behaviours at presentation, and smaller medial, lateral and orbital frontal lobe volumes showed faster rates of decline. In many instances, the effect of the predictor

  11. ESRD QIP - Vascular Access - Payment Year 2017

    Data.gov (United States)

    U.S. Department of Health & Human Services — Payment Year 2015 ESRD QIP data by facility: % hemodialysis patients using an arteriovenous fistula, % hemodialysis patients using an intravenous catheter

  12. ESRD QIP - Vascular Access - Payment Year 2015

    Data.gov (United States)

    U.S. Department of Health & Human Services — Payment Year 2015 ESRD QIP data by facility: % hemodialysis patients using an arteriovenous fistula, % hemodialysis patients using an intravenous catheter

  13. Predicting the pathogenicity of novel variants in mitochondrial tRNA with MitoTIP.

    Directory of Open Access Journals (Sweden)

    Sanjay Sonney

    2017-12-01

    Full Text Available Novel or rare variants in mitochondrial tRNA sequences may be observed after mitochondrial DNA analysis. Determining whether these variants are pathogenic is critical, but confirmation of the effect of a variant on mitochondrial function can be challenging. We have used available databases of benign and pathogenic variants, alignment between diverse tRNAs, structural information and comparative genomics to predict the impact of all possible single-base variants and deletions. The Mitochondrial tRNA Informatics Predictor (MitoTIP is available through MITOMAP at www.mitomap.org. The source code for MitoTIP is available at www.github.com/sonneysa/MitoTIP.

  14. Combined effects of thrombosis pathway gene variants predict cardiovascular events.

    Directory of Open Access Journals (Sweden)

    Kirsi Auro

    2007-07-01

    Full Text Available The genetic background of complex diseases is proposed to consist of several low-penetrance risk loci. Addressing this complexity likely requires both large sample size and simultaneous analysis of different predisposing variants. We investigated the role of four thrombosis genes: coagulation factor V (F5, intercellular adhesion molecule 1 (ICAM1, protein C (PROC, and thrombomodulin (THBD in cardiovascular diseases. Single allelic gene variants and their pair-wise combinations were analyzed in two independently sampled population cohorts from Finland. From among 14,140 FINRISK participants (FINRISK-92, n = 5,999 and FINRISK-97, n = 8,141, we selected for genotyping a sample of 2,222, including 528 incident cardiovascular disease (CVD cases and random subcohorts totaling 786. To cover all known common haplotypes (>10%, 54 single nucleotide polymorphisms (SNPs were genotyped. Classification-tree analysis identified 11 SNPs that were further analyzed in Cox's proportional hazard model as single variants and pair-wise combinations. Multiple testing was controlled by use of two independent cohorts and with false-discovery rate. Several CVD risk variants were identified: In women, the combination of F5 rs7542281 x THBD rs1042580, together with three single F5 SNPs, was associated with CVD events. Among men, PROC rs1041296, when combined with either ICAM1 rs5030341 or F5 rs2269648, was associated with total mortality. As a single variant, PROC rs1401296, together with the F5 Leiden mutation, was associated with ischemic stroke events. Our strategy to combine the classification-tree analysis with more traditional genetic models was successful in identifying SNPs-acting either in combination or as single variants--predisposing to CVD, and produced consistent results in two independent cohorts. These results suggest that variants in these four thrombosis genes contribute to arterial cardiovascular events at population level.

  15. ESRD QIP - Dialysis Adequacy - Payment Year 2017

    Data.gov (United States)

    U.S. Department of Health & Human Services — ESRD QIP data by facility: % of hemodialysis patient-months with spKt/V >= 1.2; % of peritoneal patient-months with Kt/V >= 1.7 Kt/V (dialytic + residual)...

  16. ESRD QIP - Dialysis Adequacy - Payment Year 2015

    Data.gov (United States)

    U.S. Department of Health & Human Services — ESRD QIP data by facility: % of hemodialysis patient-months with spKt/V >= 1.2; % of peritoneal patient-months with Kt/V >= 1.7 Kt/V (dialytic + residual)...

  17. End-Stage Renal Disease (ESRD) Quality Initiative

    Data.gov (United States)

    U.S. Department of Health & Human Services — The End Stage Renal Disease (ESRD) Quality Initiative promotes ongoing CMS strategies to improve the quality of care provided to ESRD patients. This initiative...

  18. ESRD QIP - Standardized Readmission Ratio - Payment Year 2017

    Data.gov (United States)

    U.S. Department of Health & Human Services — ESRD QIP – Standardized Readmission Ratio – Payment Year 2017 Lists standardized readmission data used by ESRD QIP to assess dialysis facility performance.

  19. 42 CFR 405.2112 - ESRD network organizations.

    Science.gov (United States)

    2010-10-01

    ... End-Stage Renal Disease (ESRD) Services § 405.2112 ESRD network organizations. CMS will designate an administrative governing body (network organization) for each network. The functions of a network organization... 42 Public Health 2 2010-10-01 2010-10-01 false ESRD network organizations. 405.2112 Section 405...

  20. Impact of predicted protein-truncating genetic variants on the human transcriptome

    Science.gov (United States)

    Rivas, Manuel A.; Pirinen, Matti; Conrad, Donald F.; Lek, Monkol; Tsang, Emily K.; Karczewski, Konrad J.; Maller, Julian B.; Kukurba, Kimberly R.; DeLuca, David; Fromer, Menachem; Ferreira, Pedro G.; Smith, Kevin S.; Zhang, Rui; Zhao, Fengmei; Banks, Eric; Poplin, Ryan; Ruderfer, Douglas; Purcell, Shaun M.; Tukiainen, Taru; Minikel, Eric V.; Stenson, Peter D.; Cooper, David N.; Huang, Katharine H.; Sullivan, Timothy J.; Nedzel, Jared; Bustamante, Carlos D.; Li, Jin Billy; Daly, Mark J.; Guigo, Roderic; Donnelly, Peter; Ardlie, Kristin; Sammeth, Michael; Dermitzakis, Emmanouil; McCarthy, Mark I.; Montgomery, Stephen B.; Lappalainen, Tuuli; MacArthur, Daniel G.

    2015-01-01

    Accurate prediction of the functional impact of genetic variation is critical for clinical genome interpretation. We systematically characterized the transcriptome effects of protein-truncating variants (PTVs), a class of variants expected to have profound impacts on gene function, using data from the Genotype-Tissue Expression (GTEx) and Geuvadis projects. We quantitate tissue-specific and positional effects on nonsense-mediated transcript decay, and present an improved predictive model for this decay. We directly measure the impact of variants both proximal and distal to splice junctions. Furthermore, we find that robustness to heterozygous gene inactivation is not due to dosage compensation. Our results illustrate the value of transcriptome data in the functional interpretation of genetic variants. PMID:25954003

  1. Increased burden of de novo predicted deleterious variants in complex congenital diaphragmatic hernia

    Science.gov (United States)

    Yu, Lan; Sawle, Ashley D.; Wynn, Julia; Aspelund, Gudrun; Stolar, Charles J.; Arkovitz, Marc S.; Potoka, Douglas; Azarow, Kenneth S.; Mychaliska, George B.; Shen, Yufeng; Chung, Wendy K.

    2015-01-01

    Congenital diaphragmatic hernia (CDH) is a serious birth defect that accounts for 8% of all major birth anomalies. Approximately 40% of cases occur in association with other anomalies. As sporadic complex CDH likely has a significant impact on reproductive fitness, we hypothesized that de novo variants would account for the etiology in a significant fraction of cases. We performed exome sequencing in 39 CDH trios and compared the frequency of de novo variants with 787 unaffected controls from the Simons Simplex Collection. We found no significant difference in overall frequency of de novo variants between cases and controls. However, among genes that are highly expressed during diaphragm development, there was a significant burden of likely gene disrupting (LGD) and predicted deleterious missense variants in cases (fold enrichment = 3.2, P-value = 0.003), and these genes are more likely to be haploinsufficient (P-value = 0.01) than the ones with benign missense or synonymous de novo variants in cases. After accounting for the frequency of de novo variants in the control population, we estimate that 15% of sporadic complex CDH patients are attributable to de novo LGD or deleterious missense variants. We identified several genes with predicted deleterious de novo variants that fall into common categories of genes related to transcription factors and cell migration that we believe are related to the pathogenesis of CDH. These data provide supportive evidence for novel genes in the pathogenesis of CDH associated with other anomalies and suggest that de novo variants play a significant role in complex CDH cases. PMID:26034137

  2. Increased burden of de novo predicted deleterious variants in complex congenital diaphragmatic hernia.

    Science.gov (United States)

    Yu, Lan; Sawle, Ashley D; Wynn, Julia; Aspelund, Gudrun; Stolar, Charles J; Arkovitz, Marc S; Potoka, Douglas; Azarow, Kenneth S; Mychaliska, George B; Shen, Yufeng; Chung, Wendy K

    2015-08-15

    Congenital diaphragmatic hernia (CDH) is a serious birth defect that accounts for 8% of all major birth anomalies. Approximately 40% of cases occur in association with other anomalies. As sporadic complex CDH likely has a significant impact on reproductive fitness, we hypothesized that de novo variants would account for the etiology in a significant fraction of cases. We performed exome sequencing in 39 CDH trios and compared the frequency of de novo variants with 787 unaffected controls from the Simons Simplex Collection. We found no significant difference in overall frequency of de novo variants between cases and controls. However, among genes that are highly expressed during diaphragm development, there was a significant burden of likely gene disrupting (LGD) and predicted deleterious missense variants in cases (fold enrichment = 3.2, P-value = 0.003), and these genes are more likely to be haploinsufficient (P-value = 0.01) than the ones with benign missense or synonymous de novo variants in cases. After accounting for the frequency of de novo variants in the control population, we estimate that 15% of sporadic complex CDH patients are attributable to de novo LGD or deleterious missense variants. We identified several genes with predicted deleterious de novo variants that fall into common categories of genes related to transcription factors and cell migration that we believe are related to the pathogenesis of CDH. These data provide supportive evidence for novel genes in the pathogenesis of CDH associated with other anomalies and suggest that de novo variants play a significant role in complex CDH cases. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. Structure Prediction and Analysis of Neuraminidase Sequence Variants

    Science.gov (United States)

    Thayer, Kelly M.

    2016-01-01

    Analyzing protein structure has become an integral aspect of understanding systems of biochemical import. The laboratory experiment endeavors to introduce protein folding to ascertain structures of proteins for which the structure is unavailable, as well as to critically evaluate the quality of the prediction obtained. The model system used is the…

  4. Regulatory element-based prediction identifies new susceptibility regulatory variants for osteoporosis.

    Science.gov (United States)

    Yao, Shi; Guo, Yan; Dong, Shan-Shan; Hao, Ruo-Han; Chen, Xiao-Feng; Chen, Yi-Xiao; Chen, Jia-Bin; Tian, Qing; Deng, Hong-Wen; Yang, Tie-Lin

    2017-08-01

    Despite genome-wide association studies (GWASs) have identified many susceptibility genes for osteoporosis, it still leaves a large part of missing heritability to be discovered. Integrating regulatory information and GWASs could offer new insights into the biological link between the susceptibility SNPs and osteoporosis. We generated five machine learning classifiers with osteoporosis-associated variants and regulatory features data. We gained the optimal classifier and predicted genome-wide SNPs to discover susceptibility regulatory variants. We further utilized Genetic Factors for Osteoporosis Consortium (GEFOS) and three in-house GWASs samples to validate the associations for predicted positive SNPs. The random forest classifier performed best among all machine learning methods with the F1 score of 0.8871. Using the optimized model, we predicted 37,584 candidate SNPs for osteoporosis. According to the meta-analysis results, a list of regulatory variants was significantly associated with osteoporosis after multiple testing corrections and contributed to the expression of known osteoporosis-associated protein-coding genes. In summary, combining GWASs and regulatory elements through machine learning could provide additional information for understanding the mechanism of osteoporosis. The regulatory variants we predicted will provide novel targets for etiology research and treatment of osteoporosis.

  5. dbWGFP: a database and web server of human whole-genome single nucleotide variants and their functional predictions

    OpenAIRE

    Wu, Jiaxin; Wu, Mengmeng; Li, Lianshuo; Liu, Zhuo; Zeng, Wanwen; Jiang, Rui

    2016-01-01

    The recent advancement of the next generation sequencing technology has enabled the fast and low-cost detection of all genetic variants spreading across the entire human genome, making the application of whole-genome sequencing a tendency in the study of disease-causing genetic variants. Nevertheless, there still lacks a repository that collects predictions of functionally damaging effects of human genetic variants, though it has been well recognized that such predictions play a central role ...

  6. Predicting the Functional Impact of KCNQ1 Variants of Unknown Significance.

    Science.gov (United States)

    Li, Bian; Mendenhall, Jeffrey L; Kroncke, Brett M; Taylor, Keenan C; Huang, Hui; Smith, Derek K; Vanoye, Carlos G; Blume, Jeffrey D; George, Alfred L; Sanders, Charles R; Meiler, Jens

    2017-10-01

    An emerging standard-of-care for long-QT syndrome uses clinical genetic testing to identify genetic variants of the KCNQ1 potassium channel. However, interpreting results from genetic testing is confounded by the presence of variants of unknown significance for which there is inadequate evidence of pathogenicity. In this study, we curated from the literature a high-quality set of 107 functionally characterized KCNQ1 variants. Based on this data set, we completed a detailed quantitative analysis on the sequence conservation patterns of subdomains of KCNQ1 and the distribution of pathogenic variants therein. We found that conserved subdomains generally are critical for channel function and are enriched with dysfunctional variants. Using this experimentally validated data set, we trained a neural network, designated Q1VarPred, specifically for predicting the functional impact of KCNQ1 variants of unknown significance. The estimated predictive performance of Q1VarPred in terms of Matthew's correlation coefficient and area under the receiver operating characteristic curve were 0.581 and 0.884, respectively, superior to the performance of 8 previous methods tested in parallel. Q1VarPred is publicly available as a web server at http://meilerlab.org/q1varpred. Although a plethora of tools are available for making pathogenicity predictions over a genome-wide scale, previous tools fail to perform in a robust manner when applied to KCNQ1. The contrasting and favorable results for Q1VarPred suggest a promising approach, where a machine-learning algorithm is tailored to a specific protein target and trained with a functionally validated data set to calibrate informatics tools. © 2017 American Heart Association, Inc.

  7. Cyclooxygenase 2 promotes parathyroid hyperplasia in ESRD.

    Science.gov (United States)

    Zhang, Qian; Qiu, Junsi; Li, Haiming; Lu, Yanwen; Wang, Xiaoyun; Yang, Junwei; Wang, Shaoqing; Zhang, Liyin; Gu, Yong; Hao, Chuan-Ming; Chen, Jing

    2011-04-01

    Hyperplasia of the PTG underlies the secondary hyperparathyroidism (SHPT) observed in CKD, but the mechanism underlying this hyperplasia is incompletely understood. Because aberrant cyclooxygenase 2 (COX2) expression promotes epithelial cell proliferation, we examined the effects of COX2 on the parathyroid gland in uremia. In patients with ESRD who underwent parathyroidectomy, clusters of cells within the parathyroid glands had increased COX2 expression. Some COX2-positive cells exhibited two nuclei, consistent with proliferation. Furthermore, nearly 78% of COX2-positive cells expressed proliferating cell nuclear antigen (PCNA). In the 5/6-nephrectomy rat model, rats fed a high-phosphate diet had significantly higher serum PTH levels and larger parathyroid glands than sham-operated rats. Compared with controls, the parathyroid glands of uremic rats exhibited more PCNA-positive cells and greater COX2 expression in the chief cells. Treatment with COX2 inhibitor celecoxib significantly reduced PCNA expression, attenuated serum PTH levels, and reduced the size of the glands. In conclusion, COX2 promotes the pathogenesis of hyperparathyroidism in ESRD, suggesting that inhibiting the COX2 pathway could be a potential therapeutic target. Copyright © 2011 by the American Society of Nephrology

  8. Model-based prediction of human hair color using DNA variants.

    Science.gov (United States)

    Branicki, Wojciech; Liu, Fan; van Duijn, Kate; Draus-Barini, Jolanta; Pośpiech, Ewelina; Walsh, Susan; Kupiec, Tomasz; Wojas-Pelc, Anna; Kayser, Manfred

    2011-04-01

    Predicting complex human phenotypes from genotypes is the central concept of widely advocated personalized medicine, but so far has rarely led to high accuracies limiting practical applications. One notable exception, although less relevant for medical but important for forensic purposes, is human eye color, for which it has been recently demonstrated that highly accurate prediction is feasible from a small number of DNA variants. Here, we demonstrate that human hair color is predictable from DNA variants with similarly high accuracies. We analyzed in Polish Europeans with single-observer hair color grading 45 single nucleotide polymorphisms (SNPs) from 12 genes previously associated with human hair color variation. We found that a model based on a subset of 13 single or compound genetic markers from 11 genes predicted red hair color with over 0.9, black hair color with almost 0.9, as well as blond, and brown hair color with over 0.8 prevalence-adjusted accuracy expressed by the area under the receiver characteristic operating curves (AUC). The identified genetic predictors also differentiate reasonably well between similar hair colors, such as between red and blond-red, as well as between blond and dark-blond, highlighting the value of the identified DNA variants for accurate hair color prediction.

  9. A sequence-based method to predict the impact of regulatory variants using random forest.

    Science.gov (United States)

    Liu, Qiao; Gan, Mingxin; Jiang, Rui

    2017-03-14

    Most disease-associated variants identified by genome-wide association studies (GWAS) exist in noncoding regions. In spite of the common agreement that such variants may disrupt biological functions of their hosting regulatory elements, it remains a great challenge to characterize the risk of a genetic variant within the implicated genome sequence. Therefore, it is essential to develop an effective computational model that is not only capable of predicting the potential risk of a genetic variant but also valid in interpreting how the function of the genome is affected with the occurrence of the variant. We developed a method named kmerForest that used a random forest classifier with k-mer counts to predict accessible chromatin regions purely based on DNA sequences. We demonstrated that our method outperforms existing methods in distinguishing known accessible chromatin regions from random genomic sequences. Furthermore, the performance of our method can further be improved with the incorporation of sequence conservation features. Based on this model, we assessed importance of the k-mer features by a series of permutation experiments, and we characterized the risk of a single nucleotide polymorphism (SNP) on the function of the genome using the difference between the importance of the k-mer features affected by the occurrence of the SNP. We conducted a series of experiments and showed that our model can well discriminate between pathogenic and normal SNPs. Particularly, our model correctly prioritized SNPs that are proved to be enriched for the binding sites of FOXA1 in breast cancer cell lines from previous studies. We presented a novel method to interpret functional genetic variants purely base on DNA sequences. The proposed k-mer based score offers an effective means of measuring the impact of SNPs on the function of the genome, and thus shedding light on the identification of genetic risk factors underlying complex traits and diseases.

  10. Novel Associations between Common Breast Cancer Susceptibility Variants and Risk-Predicting Mammographic Density Measures

    Science.gov (United States)

    Stone, Jennifer; Thompson, Deborah J.; dos-Santos-Silva, Isabel; Scott, Christopher; Tamimi, Rulla M.; Lindstrom, Sara; Kraft, Peter; Hazra, Aditi; Li, Jingmei; Eriksson, Louise; Czene, Kamila; Hall, Per; Jensen, Matt; Cunningham, Julie; Olson, Janet E.; Purrington, Kristen; Couch, Fergus J.; Brown, Judith; Leyland, Jean; Warren, Ruth M. L.; Luben, Robert N.; Khaw, Kay-Tee; Smith, Paula; Wareham, Nicholas J.; Jud, Sebastian M.; Heusinger, Katharina; Beckmann, Matthias W.; Douglas, Julie A.; Shah, Kaanan P.; Chan, Heang-Ping; Helvie, Mark A.; Le Marchand, Loic; Kolonel, Laurence N.; Woolcott, Christy; Maskarinec, Gertraud; Haiman, Christopher; Giles, Graham G.; Baglietto, Laura; Krishnan, Kavitha; Southey, Melissa C.; Apicella, Carmel; Andrulis, Irene L.; Knight, Julia A.; Ursin, Giske; Grenaker Alnaes, Grethe I.; Kristensen, Vessela N.; Borresen-Dale, Anne-Lise; Gram, Inger Torhild; Bolla, Manjeet K.; Wang, Qin; Michailidou, Kyriaki; Dennis, Joe; Simard, Jacques; Paroah, Paul; Dunning, Alison M.; Easton, Douglas F.; Fasching, Peter A.; Pankratz, V. Shane; Hopper, John; Vachon, Celine M.

    2015-01-01

    Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute non-dense area adjusted for study, age and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210 (ESR1) and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all p breast cancer susceptibility variants, associations were found between rs1432679 (EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and non-dense areas, and between rs17356907 (NTN4) and adjusted absolute non-dense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18% of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiological pathways implicated in how mammographic density predicts breast cancer risk. PMID:25862352

  11. Many amino acid substitution variants identified in DNA repair genes during human population screenings are predicted to impact protein function

    Energy Technology Data Exchange (ETDEWEB)

    Xi, T; Jones, I M; Mohrenweiser, H W

    2003-11-03

    Over 520 different amino acid substitution variants have been previously identified in the systematic screening of 91 human DNA repair genes for sequence variation. Two algorithms were employed to predict the impact of these amino acid substitutions on protein activity. Sorting Intolerant From Tolerant (SIFT) classified 226 of 508 variants (44%) as ''Intolerant''. Polymorphism Phenotyping (PolyPhen) classed 165 of 489 amino acid substitutions (34%) as ''Probably or Possibly Damaging''. Another 9-15% of the variants were classed as ''Potentially Intolerant or Damaging''. The results from the two algorithms are highly associated, with concordance in predicted impact observed for {approx}62% of the variants. Twenty one to thirty one percent of the variant proteins are predicted to exhibit reduced activity by both algorithms. These variants occur at slightly lower individual allele frequency than do the variants classified as ''Tolerant'' or ''Benign''. Both algorithms correctly predicted the impact of 26 functionally characterized amino acid substitutions in the APE1 protein on biochemical activity, with one exception. It is concluded that a substantial fraction of the missense variants observed in the general human population are functionally relevant. These variants are expected to be the molecular genetic and biochemical basis for the associations of reduced DNA repair capacity phenotypes with elevated cancer risk.

  12. Survival after dialysis discontinuation and hospice enrollment for ESRD.

    Science.gov (United States)

    O'Connor, Nina R; Dougherty, Meredith; Harris, Pamela S; Casarett, David J

    2013-12-01

    Textbooks report that patients with ESRD survive for 7-10 days after discontinuation of dialysis. Studies describing actual survival are limited, however, and research has not defined patient characteristics that may be associated with longer or shorter survival times. The goals of this study were to determine the mean life expectancy of patients admitted to hospice after discontinuation of dialysis, and to identify independent predictors of survival time. Data for demographics, clinical characteristics, and survival were obtained from 10 hospices for patients with ESRD who discontinued dialysis before hospice admission. Data were collected for patients admitted between January 1, 2008 and May 15, 2012. All hospices were members of the Coalition of Hospices Organized to Investigate Comparative Effectiveness network, which obtains de-identified data from an electronic medical record. Of 1947 patients who discontinued dialysis, the mean survival after hospice enrollment was 7.4 days (range, 0-40 days). Patients who discontinued dialysis had significantly shorter survival compared with other patients (n=124,673) with nonrenal hospice diagnoses (mean survival 54.4 days; hazard ratio, 2.96; 95% confidence interval, 2.82 to 3.09; P<0.001). A Cox proportional hazards model identified seven independent predictors of earlier mortality after dialysis discontinuation, including male sex, referral from a hospital, lower functional status (Palliative Performance Scale score), and the presence of peripheral edema. Patients who discontinue dialysis have significantly shorter survival than other hospice patients. Individual survival time varies greatly, but several variables can be used to predict survival and tailor a patient's care plan based on estimated prognosis.

  13. Thrombophilia and arteriovenous fistula survival in ESRD.

    Science.gov (United States)

    Salmela, Birgitta; Hartman, Jari; Peltonen, Seija; Albäck, Anders; Lassila, Riitta

    2013-06-01

    The role of thrombophilia in failing arteriovenous fistula (AVF) among patients with ESRD undergoing hemodialysis is not established. This study aimed to assess whether AVF primary patency is associated with thrombophilia and coagulation abnormalities. This observational study screened 219 patients between 2002 and 2004 for thrombophilia before AVF surgery. Thrombophilia included factor V Leiden and prothrombin G20210A mutations, protein C and antithrombin activities, and protein S. Coagulation abnormalities included high factor VIII:C, homocysteine, fibrinogen, and d-dimer levels; presence of antiphospholipid antibodies; and short thrombin time. We reviewed patient charts for comorbid conditions, AVF maturation and interventions, kidney transplantation, and patient survival (mean follow-up duration, 3.6 [range, 2.3-5.8] years). Primary patency from the AVF placement and functional primary patency from the first AVF cannulation were analyzed with Kaplan-Meier and Cox proportional hazards models. Thrombophilia was present in 9% of the patients, and coagulation abnormalities occurred in 77%. One-year primary patency was 68%; 46% of the AVF failures occurred before the initiation of hemodialysis. Female sex (hazard ratio [HR], 2.6; 95% confidence interval [CI], 1.7-4.1) and thrombophilia (HR, 2.2; 95% CI, 1.2-4.2) were independent risk factors for loss of primary patency. Thrombophilia mutations or low antithrombin level (HR, 3.8), female sex (HR, 2.5), and diabetes (HR, 1.9) were associated with shortened functional primary patency of AVF. Against the background of frequent coagulation abnormalities, thrombophilia and female sex predispose patients with ESRD to access failure, mostly due to thrombosis or stenosis.

  14. Prediction of breast cancer risk based on common genetic variants in women of East Asian ancestry.

    Science.gov (United States)

    Wen, Wanqing; Shu, Xiao-Ou; Guo, Xingyi; Cai, Qiuyin; Long, Jirong; Bolla, Manjeet K; Michailidou, Kyriaki; Dennis, Joe; Wang, Qin; Gao, Yu-Tang; Zheng, Ying; Dunning, Alison M; García-Closas, Montserrat; Brennan, Paul; Chen, Shou-Tung; Choi, Ji-Yeob; Hartman, Mikael; Ito, Hidemi; Lophatananon, Artitaya; Matsuo, Keitaro; Miao, Hui; Muir, Kenneth; Sangrajrang, Suleeporn; Shen, Chen-Yang; Teo, Soo H; Tseng, Chiu-Chen; Wu, Anna H; Yip, Cheng Har; Simard, Jacques; Pharoah, Paul D P; Hall, Per; Kang, Daehee; Xiang, Yongbing; Easton, Douglas F; Zheng, Wei

    2016-12-08

    Approximately 100 common breast cancer susceptibility alleles have been identified in genome-wide association studies (GWAS). The utility of these variants in breast cancer risk prediction models has not been evaluated adequately in women of Asian ancestry. We evaluated 88 breast cancer risk variants that were identified previously by GWAS in 11,760 cases and 11,612 controls of Asian ancestry. SNPs confirmed to be associated with breast cancer risk in Asian women were used to construct a polygenic risk score (PRS). The relative and absolute risks of breast cancer by the PRS percentiles were estimated based on the PRS distribution, and were used to stratify women into different levels of breast cancer risk. We confirmed significant associations with breast cancer risk for SNPs in 44 of the 78 previously reported loci at P women in the middle quintile of the PRS, women in the top 1% group had a 2.70-fold elevated risk of breast cancer (95% CI: 2.15-3.40). The risk prediction model with the PRS had an area under the receiver operating characteristic curve of 0.606. The lifetime risk of breast cancer for Shanghai Chinese women in the lowest and highest 1% of the PRS was 1.35% and 10.06%, respectively. Approximately one-half of GWAS-identified breast cancer risk variants can be directly replicated in East Asian women. Collectively, common genetic variants are important predictors for breast cancer risk. Using common genetic variants for breast cancer could help identify women at high risk of breast cancer.

  15. Noncoding Variants Functional Prioritization Methods Based on Predicted Regulatory Factor Binding Sites.

    Science.gov (United States)

    Fu, Haoyue; Zhang, Xiangde

    2017-08-01

    With the advent of the post genomic era, the research for the genetic mechanism of the diseases has found to be increasingly depended on the studies of the genes, the gene-networks and gene-protein interaction networks. To explore gene expression and regulation, the researchers have carried out many studies on transcription factors and their binding sites (TFBSs). Based on the large amount of transcription factor binding sites predicting values in the deep learning models, further computation and analysis have been done to reveal the relationship between the gene mutation and the occurrence of the disease. It has been demonstrated that based on the deep learning methods, the performances of the prediction for the functions of the noncoding variants are outperforming than those of the conventional methods. The research on the prediction for functions of Single Nucleotide Polymorphisms (SNPs) is expected to uncover the mechanism of the gene mutation affection on traits and diseases of human beings. We reviewed the conventional TFBSs identification methods from different perspectives. As for the deep learning methods to predict the TFBSs, we discussed the related problems, such as the raw data preprocessing, the structure design of the deep convolution neural network (CNN) and the model performance measure et al. And then we summarized the techniques that usually used in finding out the functional noncoding variants from de novo sequence. Along with the rapid development of the high-throughout assays, more and more sample data and chromatin features would be conducive to improve the prediction accuracy of the deep convolution neural network for TFBSs identification. Meanwhile, getting more insights into the deep CNN framework itself has been proved useful for both the promotion on model performance and the development for more suitable design to sample data. Based on the feature values predicted by the deep CNN model, the prioritization model for functional noncoding

  16. CHRNA5 risk variant predicts delayed smoking cessation and earlier lung cancer diagnosis--a meta-analysis

    NARCIS (Netherlands)

    Chen, L.S.; Hung, R.J.; Baker, T.; Horton, A.; Culverhouse, R.; Saccone, N.; Cheng, I.; Deng, B.; Han, Y.; Hansen, H.M.; Horsman, J.; Kim, C.; Lutz, S.; Rosenberger, A.; Aben, K.K.H.; Andrew, A.S.; Breslau, N.; Chang, S.C.; Dieffenbach, A.K.; Dienemann, H.; Frederiksen, B.; Han, J.; Hatsukami, D.K.; Johnson, E.O.; Pande, M.; Wrensch, M.R.; McLaughlin, J.; Skaug, V.; Heijden, H.F. van der; Wampfler, J.; Wenzlaff, A.; Woll, P.; Zienolddiny, S.; Bickeboller, H.; Brenner, H.; Duell, E.J.; Haugen, A.; Heinrich, J.; Hokanson, J.E.; Hunter, D.J.; Kiemeney, B.; Lazarus, P.; Marchand, L. Le; Liu, G.; Mayordomo, J.; Risch, A.; Schwartz, A.G.; Teare, D.; Wu, X.; Wiencke, J.K.; Yang, P.; Zhang, Z.F.; Spitz, M.R.; Kraft, P.; Amos, C.I.; Bierut, L.J.

    2015-01-01

    BACKGROUND: Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis. METHODS:

  17. Predicting the impact of non-coding variants on DNA methylation.

    Science.gov (United States)

    Zeng, Haoyang; Gifford, David K

    2017-06-20

    DNA methylation plays a crucial role in the establishment of tissue-specific gene expression and the regulation of key biological processes. However, our present inability to predict the effect of genome sequence variation on DNA methylation precludes a comprehensive assessment of the consequences of non-coding variation. We introduce CpGenie, a sequence-based framework that learns a regulatory code of DNA methylation using a deep convolutional neural network and uses this network to predict the impact of sequence variation on proximal CpG site DNA methylation. CpGenie produces allele-specific DNA methylation prediction with single-nucleotide sensitivity that enables accurate prediction of methylation quantitative trait loci (meQTL). We demonstrate that CpGenie prioritizes validated GWAS SNPs, and contributes to the prediction of functional non-coding variants, including expression quantitative trait loci (eQTL) and disease-associated mutations. CpGenie is publicly available to assist in identifying and interpreting regulatory non-coding variants. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  18. The Value of Online Algorithms to Predict T-Cell Ligands Created by Genetic Variants.

    Science.gov (United States)

    van der Lee, Dyantha I; Pont, Margot J; Falkenburg, J H Frederik; Griffioen, Marieke

    2016-01-01

    Allogeneic stem cell transplantation can be a curative treatment for hematological malignancies. After HLA-matched allogeneic stem cell transplantation, beneficial anti-tumor immunity as well as detrimental side-effects can develop due to donor-derived T-cells recognizing polymorphic peptides that are presented by HLA on patient cells. Polymorphic peptides on patient cells that are recognized by specific T-cells are called minor histocompatibility antigens (MiHA), while the respective peptides in donor cells are allelic variants. MiHA can be identified by reverse strategies in which large sets of peptides are screened for T-cell recognition. In these strategies, selection of peptides by prediction algorithms may be relevant to increase the efficiency of MiHA discovery. We investigated the value of online prediction algorithms for MiHA discovery and determined the in silico characteristics of 68 autosomal HLA class I-restricted MiHA that have been identified as natural ligands by forward strategies in which T-cells from in vivo immune responses after allogeneic stem cell transplantation are used to identify the antigen. Our analysis showed that HLA class I binding was accurately predicted for 87% of MiHA of which a relatively large proportion of peptides had strong binding affinity (56%). Weak binding affinity was also predicted for a considerable number of antigens (31%) and the remaining 13% of MiHA were not predicted as HLA class I binding peptides. Besides prediction for HLA class I binding, none of the other online algorithms significantly contributed to MiHA characterization. Furthermore, we demonstrated that the majority of MiHA do not differ from their allelic variants in in silico characteristics, suggesting that allelic variants can potentially be processed and presented on the cell surface. In conclusion, our analyses revealed the in silico characteristics of 68 HLA class I-restricted MiHA and explored the value of online algorithms to predict T

  19. ESRD QIP - Complete QIP Data - Payment Year 2017

    Data.gov (United States)

    U.S. Department of Health & Human Services — The data set includes the number of eligible patients by clinical measure; % patients with Hemoglobin > 12; ESRD QIP data by facility: % of hemodialysis...

  20. ESRD QIP - Complete QIP Data - Payment Year 2015

    Data.gov (United States)

    U.S. Department of Health & Human Services — The data set includes the number of eligible patients by clinical measure; % patients with Hemoglobin > 12; ESRD QIP data by facility: % of hemodialysis...

  1. Exceptions to the rule: case studies in the prediction of pathogenicity for genetic variants in hereditary cancer genes.

    Science.gov (United States)

    Rosenthal, E T; Bowles, K R; Pruss, D; van Kan, A; Vail, P J; McElroy, H; Wenstrup, R J

    2015-12-01

    Based on current consensus guidelines and standard practice, many genetic variants detected in clinical testing are classified as disease causing based on their predicted impact on the normal expression or function of the gene in the absence of additional data. However, our laboratory has identified a subset of such variants in hereditary cancer genes for which compelling contradictory evidence emerged after the initial evaluation following the first observation of the variant. Three representative examples of variants in BRCA1, BRCA2 and MSH2 that are predicted to disrupt splicing, prematurely truncate the protein, or remove the start codon were evaluated for pathogenicity by analyzing clinical data with multiple classification algorithms. Available clinical data for all three variants contradicts the expected pathogenic classification. These variants illustrate potential pitfalls associated with standard approaches to variant classification as well as the challenges associated with monitoring data, updating classifications, and reporting potentially contradictory interpretations to the clinicians responsible for translating test outcomes to appropriate clinical action. It is important to address these challenges now as the model for clinical testing moves toward the use of large multi-gene panels and whole exome/genome analysis, which will dramatically increase the number of genetic variants identified. © 2015 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. A Variant of Peptide Transporter 2 Predicts the Severity of Porphyria-Associated Kidney Disease.

    Science.gov (United States)

    Tchernitchko, Dimitri; Tavernier, Quentin; Lamoril, Jérôme; Schmitt, Caroline; Talbi, Neila; Lyoumi, Said; Robreau, Anne-Marie; Karim, Zoubida; Gouya, Laurent; Thervet, Eric; Karras, Alexandre; Puy, Hervé; Pallet, Nicolas

    2017-06-01

    CKD occurs in most patients with acute intermittent porphyria (AIP). During AIP, δ-aminolevulinic acid (ALA) accumulates and promotes tubular cell death and tubulointerstitial damage. The human peptide transporter 2 (PEPT2) expressed by proximal tubular cells mediates the reabsorption of ALA, and variants of PEPT2 have different affinities for ALA. We tested the hypothesis that PEPT2 genotypes affect the severity and prognosis of porphyria-associated kidney disease. We analyzed data from 122 individuals with AIP who were followed from 2003 to 2013 and genotyped for PEPT2 At last follow-up, carriers of the PEPT2*1*1 genotype (higher affinity variant) exhibited worse renal function than carriers of the lower affinity variants PEPT2*1/*2 and PEPT2*2/*2 (mean±SD eGFR: 54.4±19.1, 66.6±23.8, and 78.1±19.9 ml/min per 1.73 m(2), respectively). Change in eGFR (mean±SD) over the 10-year period was -11.0±3.3, -2.4±1.9, and 3.4±2.6 ml/min per 1.73 m(2) for PEPT2*1/*1, PEPT2*1*2, and PEPT*2*2*2 carriers, respectively. At the end of follow-up, 68% of PEPT2*1*1 carriers had an eGFR1 ml/min per 1.73 m(2) (odds ratio, 3.64; 95% confidence interval, 1.37 to 9.91). Thus, a gene variant is predictive of the severity of a chronic complication of AIP. The therapeutic value of PEPT2 inhibitors in preventing porphyria-associated kidney disease warrants investigation. Copyright © 2017 by the American Society of Nephrology.

  3. Preeclampsia and ESRD: The Role of Shared Risk Factors.

    Science.gov (United States)

    Kattah, Andrea G; Scantlebury, Dawn C; Agarwal, Sanket; Mielke, Michelle M; Rocca, Walter A; Weaver, Amy L; Vaughan, Lisa E; Miller, Virginia M; Weissgerber, Tracey L; White, Wendy; Garovic, Vesna D

    2017-04-01

    Several registry-based studies, using diagnostic codes, have suggested that preeclampsia is a risk factor for end-stage renal disease (ESRD). However, because the 2 diseases share risk factors, the true nature of their association remains uncertain. Our goals were to conduct a population-based study to determine the magnitude of the association between preeclampsia and ESRD and evaluate the role of shared risk factors. Population-based nested case-control study. The US Renal Data System was used to identify women with ESRD from a cohort of 34,581 women who gave birth in 1976 to 2010 in Olmsted County, MN. 44 cases of ESRD were identified and each one was matched to 2 controls based on year of birth (±1 year), age at first pregnancy (±2 years), and parity (±1 or ≥4). Preeclamptic pregnancy, confirmed by medical record review. ESRD. Prepregnancy serum creatinine and urine protein measurements were recorded. Comorbid conditions existing prior to pregnancy were abstracted from medical records and included kidney disease, obesity, diabetes, and hypertension. There was evidence of kidney disease prior to the first pregnancy in 9 of 44 (21%) cases and 1 of 88 (preeclampsia and ESRD; however, obesity is a previously unexplored confounder. Pre-existing kidney disease was common, but not consistently coded or diagnosed. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  4. A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

    DEFF Research Database (Denmark)

    Bergman, Jorieke E H; Janssen, Nicole; van der Sloot, Almer M

    2012-01-01

    CHARGE syndrome is characterized by the variable occurrence of multisensory impairment, congenital anomalies, and developmental delay, and is caused by heterozygous mutations in the CHD7 gene. Correct interpretation of CHD7 variants is essential for genetic counseling. This is particularly...... difficult for missense variants because most variants in the CHD7 gene are private and a functional assay is not yet available. We have therefore developed a novel classification system to predict the pathogenic effects of CHD7 missense variants that can be used in a diagnostic setting. Our classification...... system combines the results from two computational algorithms (PolyPhen-2 and Align-GVGD) and the prediction of a newly developed structural model of the chromo- and helicase domains of CHD7 with segregation and phenotypic data. The combination of different variables will lead to a more confident...

  5. Missense variants in CFTR nucleotide-binding domains predict quantitative phenotypes associated with cystic fibrosis disease severity.

    Science.gov (United States)

    Masica, David L; Sosnay, Patrick R; Raraigh, Karen S; Cutting, Garry R; Karchin, Rachel

    2015-04-01

    Predicting the impact of genetic variation on human health remains an important and difficult challenge. Often, algorithmic classifiers are tasked with predicting binary traits (e.g. positive or negative for a disease) from missense variation. Though useful, this arrangement is limiting and contrived, because human diseases often comprise a spectrum of severities, rather than a discrete partitioning of patient populations. Furthermore, labeling variants as causal or benign can be error prone, which is problematic for training supervised learning algorithms (the so-called garbage in, garbage out phenomenon). We explore the potential value of training classifiers using continuous-valued quantitative measurements, rather than binary traits. Using 20 variants from cystic fibrosis transmembrane conductance regulator (CFTR) nucleotide-binding domains and six quantitative measures of cystic fibrosis (CF) severity, we trained classifiers to predict CF severity from CFTR variants. Employing cross validation, classifier prediction and measured clinical/functional values were significantly correlated for four of six quantitative traits (correlation P-values from 1.35 × 10(-4) to 4.15 × 10(-3)). Classifiers were also able to stratify variants by three clinically relevant risk categories with 85-100% accuracy, depending on which of the six quantitative traits was used for training. Finally, we characterized 11 additional CFTR variants using clinical sweat chloride testing, two functional assays, or all three diagnostics, and validated our classifier using blind prediction. Predictions were within the measured sweat chloride range for seven of eight variants, and captured the differential impact of specific variants on the two functional assays. This work demonstrates a promising and novel framework for assessing the impact of genetic variation. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. Data mining of high density genomic variant data for prediction of Alzheimer's disease risk

    Directory of Open Access Journals (Sweden)

    Briones Natalia

    2012-01-01

    Full Text Available Abstract Background The discovery of genetic associations is an important factor in the understanding of human illness to derive disease pathways. Identifying multiple interacting genetic mutations associated with disease remains challenging in studying the etiology of complex diseases. And although recently new single nucleotide polymorphisms (SNPs at genes implicated in immune response, cholesterol/lipid metabolism, and cell membrane processes have been confirmed by genome-wide association studies (GWAS to be associated with late-onset Alzheimer's disease (LOAD, a percentage of AD heritability continues to be unexplained. We try to find other genetic variants that may influence LOAD risk utilizing data mining methods. Methods Two different approaches were devised to select SNPs associated with LOAD in a publicly available GWAS data set consisting of three cohorts. In both approaches, single-locus analysis (logistic regression was conducted to filter the data with a less conservative p-value than the Bonferroni threshold; this resulted in a subset of SNPs used next in multi-locus analysis (random forest (RF. In the second approach, we took into account prior biological knowledge, and performed sample stratification and linkage disequilibrium (LD in addition to logistic regression analysis to preselect loci to input into the RF classifier construction step. Results The first approach gave 199 SNPs mostly associated with genes in calcium signaling, cell adhesion, endocytosis, immune response, and synaptic function. These SNPs together with APOE and GAB2 SNPs formed a predictive subset for LOAD status with an average error of 9.8% using 10-fold cross validation (CV in RF modeling. Nineteen variants in LD with ST5, TRPC1, ATG10, ANO3, NDUFA12, and NISCH respectively, genes linked directly or indirectly with neurobiology, were identified with the second approach. These variants were part of a model that included APOE and GAB2 SNPs to predict LOAD

  7. Data mining of high density genomic variant data for prediction of Alzheimer's disease risk.

    Science.gov (United States)

    Briones, Natalia; Dinu, Valentin

    2012-01-25

    The discovery of genetic associations is an important factor in the understanding of human illness to derive disease pathways. Identifying multiple interacting genetic mutations associated with disease remains challenging in studying the etiology of complex diseases. And although recently new single nucleotide polymorphisms (SNPs) at genes implicated in immune response, cholesterol/lipid metabolism, and cell membrane processes have been confirmed by genome-wide association studies (GWAS) to be associated with late-onset Alzheimer's disease (LOAD), a percentage of AD heritability continues to be unexplained. We try to find other genetic variants that may influence LOAD risk utilizing data mining methods. Two different approaches were devised to select SNPs associated with LOAD in a publicly available GWAS data set consisting of three cohorts. In both approaches, single-locus analysis (logistic regression) was conducted to filter the data with a less conservative p-value than the Bonferroni threshold; this resulted in a subset of SNPs used next in multi-locus analysis (random forest (RF)). In the second approach, we took into account prior biological knowledge, and performed sample stratification and linkage disequilibrium (LD) in addition to logistic regression analysis to preselect loci to input into the RF classifier construction step. The first approach gave 199 SNPs mostly associated with genes in calcium signaling, cell adhesion, endocytosis, immune response, and synaptic function. These SNPs together with APOE and GAB2 SNPs formed a predictive subset for LOAD status with an average error of 9.8% using 10-fold cross validation (CV) in RF modeling. Nineteen variants in LD with ST5, TRPC1, ATG10, ANO3, NDUFA12, and NISCH respectively, genes linked directly or indirectly with neurobiology, were identified with the second approach. These variants were part of a model that included APOE and GAB2 SNPs to predict LOAD risk which produced a 10-fold CV average error of

  8. Using self-organizing maps to determine observation threshold limit predictions in highly variant data

    Science.gov (United States)

    Paganoni, C.A.; Chang, K.C.; Robblee, M.B.

    2006-01-01

    A significant data quality challenge for highly variant systems surrounds the limited ability to quantify operationally reasonable limits on the data elements being collected and provide reasonable threshold predictions. In many instances, the number of influences that drive a resulting value or operational range is too large to enable physical sampling for each influencer, or is too complicated to accurately model in an explicit simulation. An alternative method to determine reasonable observation thresholds is to employ an automation algorithm that would emulate a human analyst visually inspecting data for limits. Using the visualization technique of self-organizing maps (SOM) on data having poorly understood relationships, a methodology for determining threshold limits was developed. To illustrate this approach, analysis of environmental influences that drive the abundance of a target indicator species (the pink shrimp, Farfantepenaeus duorarum) provided a real example of applicability. The relationship between salinity and temperature and abundance of F. duorarum is well documented, but the effect of changes in water quality upstream on pink shrimp abundance is not well understood. The highly variant nature surrounding catch of a specific number of organisms in the wild, and the data available from up-stream hydrology measures for salinity and temperature, made this an ideal candidate for the approach to provide a determination about the influence of changes in hydrology on populations of organisms.

  9. Imbalance-Aware Machine Learning for Predicting Rare and Common Disease-Associated Non-Coding Variants.

    Science.gov (United States)

    Schubach, Max; Re, Matteo; Robinson, Peter N; Valentini, Giorgio

    2017-06-07

    Disease and trait-associated variants represent a tiny minority of all known genetic variation, and therefore there is necessarily an imbalance between the small set of available disease-associated and the much larger set of non-deleterious genomic variation, especially in non-coding regulatory regions of human genome. Machine Learning (ML) methods for predicting disease-associated non-coding variants are faced with a chicken and egg problem - such variants cannot be easily found without ML, but ML cannot begin to be effective until a sufficient number of instances have been found. Most of state-of-the-art ML-based methods do not adopt specific imbalance-aware learning techniques to deal with imbalanced data that naturally arise in several genome-wide variant scoring problems, thus resulting in a significant reduction of sensitivity and precision. We present a novel method that adopts imbalance-aware learning strategies based on resampling techniques and a hyper-ensemble approach that outperforms state-of-the-art methods in two different contexts: the prediction of non-coding variants associated with Mendelian and with complex diseases. We show that imbalance-aware ML is a key issue for the design of robust and accurate prediction algorithms and we provide a method and an easy-to-use software tool that can be effectively applied to this challenging prediction task.

  10. Predicting the Pathogenic Potential of BRCA1 and BRCA2 Gene Variants Identified in Clinical Genetic Testing

    Directory of Open Access Journals (Sweden)

    Clare Brookes

    2015-05-01

    Full Text Available Objectives: Missense variants are very commonly detected when screening for mutations in the BRCA1 and BRCA2 genes. Pathogenic mutations in the BRCA1 and BRCA2 genes lead to an increased risk of developing breast, ovarian, prostate and/or pancreatic cancer. This study aimed to assess the predictive capability of in silico programmes and mutation databases in assisting diagnostic laboratories to determine the pathogenicity of sequence-detectable mutations. Methods: Between July 2011 and April 2013, an analysis was undertaken of 13 missense BRCA gene variants that had been detected in patients referred to the Genetic Health Services New Zealand (Northern Hub for BRCA gene analysis. The analysis involved the use of 13 in silico protein prediction programmes, two in silico transcript analysis programmes and the examination of three BRCA gene databases. Results: In most of the variants, the analysis showed different in silico interpretations. This illustrates the interpretation challenges faced by diagnostic laboratories. Conclusion: Unfortunately, when using online mutation databases and carrying out in silico analyses, there is significant discordance in the classification of some missense variants in the BRCA genes. This discordance leads to complexities in interpreting and reporting these variants in a clinical context. The authors have developed a simple procedure for analysing variants; however, those of unknown significance largely remain unknown. As a consequence, the clinical value of some reports may be negligible.

  11. Genetic variants demonstrating flip-flop phenomenon and breast cancer risk prediction among women of African ancestry.

    Science.gov (United States)

    Wang, Shengfeng; Qian, Frank; Zheng, Yonglan; Ogundiran, Temidayo; Ojengbede, Oladosu; Zheng, Wei; Blot, William; Nathanson, Katherine L; Hennis, Anselm; Nemesure, Barbara; Ambs, Stefan; Olopade, Olufunmilayo I; Huo, Dezheng

    2018-01-04

    Few studies have evaluated the performance of existing breast cancer risk prediction models among women of African ancestry. In replication studies of genetic variants, a change in direction of the risk association is a common phenomenon. Termed flip-flop, it means that a variant is risk factor in one population but protective in another, affecting the performance of risk prediction models. We used data from the genome-wide association study (GWAS) of breast cancer in the African diaspora (The Root consortium), which included 3686 participants of African ancestry from Nigeria, USA, and Barbados. Polygenic risk scores (PRSs) were constructed from the published odds ratios (ORs) of four sets of susceptibility loci for breast cancer. Discrimination capacity was measured using the area under the receiver operating characteristic curve (AUC). Flip-flop phenomenon was observed among 30~40% of variants across studies. Using the 34 variants with consistent directionality among previous studies, we constructed a PRS with AUC of 0.531 (95% confidence interval [CI]: 0.512-0.550), which is similar to the PRS using 93 variants and ORs from European ancestry populations (AUC = 0.525, 95% CI: 0.506-0.544). Additionally, we found the 34-variant PRS has good discriminative accuracy in women with family history of breast cancer (AUC = 0.586, 95% CI: 0.532-0.640). We found that PRS based on variants identified from prior GWASs conducted in women of European and Asian ancestries did not provide a comparable degree of risk stratification for women of African ancestry. Further large-scale fine-mapping studies in African ancestry populations are desirable to discover population-specific genetic risk variants.

  12. A method of predicting changes in human gene splicing induced by genetic variants in context of cis-acting elements.

    Science.gov (United States)

    Churbanov, Alexander; Vorechovský, Igor; Hicks, Chindo

    2010-01-12

    Polymorphic variants and mutations disrupting canonical splicing isoforms are among the leading causes of human hereditary disorders. While there is a substantial evidence of aberrant splicing causing Mendelian diseases, the implication of such events in multi-genic disorders is yet to be well understood. We have developed a new tool (SpliceScan II) for predicting the effects of genetic variants on splicing and cis-regulatory elements. The novel Bayesian non-canonical 5'GC splice site (SS) sensor used in our tool allows inference on non-canonical exons. Our tool performed favorably when compared with the existing methods in the context of genes linked to the Autism Spectrum Disorder (ASD). SpliceScan II was able to predict more aberrant splicing isoforms triggered by the mutations, as documented in DBASS5 and DBASS3 aberrant splicing databases, than other existing methods. Detrimental effects behind some of the polymorphic variations previously associated with Alzheimer's and breast cancer could be explained by changes in predicted splicing patterns. We have developed SpliceScan II, an effective and sensitive tool for predicting the detrimental effects of genomic variants on splicing leading to Mendelian and complex hereditary disorders. The method could potentially be used to screen resequenced patient DNA to identify de novo mutations and polymorphic variants that could contribute to a genetic disorder.

  13. A method of predicting changes in human gene splicing induced by genetic variants in context of cis-acting elements

    Directory of Open Access Journals (Sweden)

    Hicks Chindo

    2010-01-01

    Full Text Available Abstract Background Polymorphic variants and mutations disrupting canonical splicing isoforms are among the leading causes of human hereditary disorders. While there is a substantial evidence of aberrant splicing causing Mendelian diseases, the implication of such events in multi-genic disorders is yet to be well understood. We have developed a new tool (SpliceScan II for predicting the effects of genetic variants on splicing and cis-regulatory elements. The novel Bayesian non-canonical 5'GC splice site (SS sensor used in our tool allows inference on non-canonical exons. Results Our tool performed favorably when compared with the existing methods in the context of genes linked to the Autism Spectrum Disorder (ASD. SpliceScan II was able to predict more aberrant splicing isoforms triggered by the mutations, as documented in DBASS5 and DBASS3 aberrant splicing databases, than other existing methods. Detrimental effects behind some of the polymorphic variations previously associated with Alzheimer's and breast cancer could be explained by changes in predicted splicing patterns. Conclusions We have developed SpliceScan II, an effective and sensitive tool for predicting the detrimental effects of genomic variants on splicing leading to Mendelian and complex hereditary disorders. The method could potentially be used to screen resequenced patient DNA to identify de novo mutations and polymorphic variants that could contribute to a genetic disorder.

  14. Evaluation of the predictive capacity of DNA variants associated with straight hair in Europeans.

    Science.gov (United States)

    Pośpiech, Ewelina; Karłowska-Pik, Joanna; Marcińska, Magdalena; Abidi, Sarah; Andersen, Jeppe Dyrberg; Berge, Margreet van den; Carracedo, Ángel; Eduardoff, Mayra; Freire-Aradas, Ana; Morling, Niels; Sijen, Titia; Skowron, Małgorzata; Söchtig, Jens; Syndercombe-Court, Denise; Weiler, Natalie; Schneider, Peter M; Ballard, David; Børsting, Claus; Parson, Walther; Phillips, Chris; Branicki, Wojciech

    2015-11-01

    DNA-based prediction of hair morphology, defined as straight, curly or wavy hair, could contribute to an improved description of an unknown offender and allow more accurate forensic reconstructions of physical appearance in the field of forensic DNA phenotyping. Differences in scalp hair morphology are significant at the worldwide scale and within Europe. The only genome-wide association study made to date revealed the Trichohyalin gene (TCHH) to be significantly associated with hair morphology in Europeans and reported weaker associations for WNT10A and FRAS1 genes. We conducted a study that centered on six SNPs located in these three genes with a sample of 528 individuals from Poland. The predictive capacity of the candidate DNA variants was evaluated using logistic regression; classification and regression trees; and neural networks, by applying a 10-fold cross validation procedure. Additionally, an independent test set of 142 males from six European populations was used to verify performance of the developed prediction models. Our study confirmed association of rs11803731 (TCHH), rs7349332 (WNT10A) and rs1268789 (FRAS1) SNPs with hair morphology. The combined genotype risk score for straight hair had an odds ratio of 2.7 and these predictors explained ∼ 8.2% of the total variance. The selected three SNPs were found to predict straight hair with a high sensitivity but low specificity when a 10-fold cross validation procedure was applied and the best results were obtained using the neural networks approach (AUC=0.688, sensitivity=91.2%, specificity=23.0%). Application of the neural networks model with 65% probability threshold on an additional test set gave high sensitivity (81.4%) and improved specificity (50.0%) with a total of 78.7% correct calls, but a high non-classification rate (66.9%). The combined TTGGGG SNP genotype for rs11803731, rs7349332, rs1268789 (European frequency=4.5%) of all six straight hair-associated alleles was identified as the best

  15. 42 CFR 417.423 - Special rules: ESRD and hospice patients.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 3 2010-10-01 2010-10-01 false Special rules: ESRD and hospice patients. 417.423... Special rules: ESRD and hospice patients. (a) ESRD patients. (1) A Medicare beneficiary who has been... not disenroll the beneficiary except as provided in § 417.460. (b) Hospice patients. A Medicare...

  16. Preoperative RAS Mutational Analysis Is of Great Value in Predicting Follicular Variant of Papillary Thyroid Carcinoma

    Directory of Open Access Journals (Sweden)

    Tae Sook Hwang

    2015-01-01

    Full Text Available Follicular variant of papillary thyroid carcinoma (FVPTC, particularly the encapsulated subtype, often causes a diagnostic dilemma. We reconfirmed the molecular profiles in a large number of FVPTCs and investigated the efficacy of the preoperative mutational analysis in indeterminate thyroid nodules. BRAF V600E/K601E and RAS mutational analysis was performed on 187 FVPTCs. Of these, 132 (70.6% had a point mutation in one of the BRAF V600E (n=57, BRAF K601E (n=11, or RAS (n=64 genes. All mutations were mutually exclusive. The most common RAS mutations were at NRAS codon 61. FNA aspirates from 564 indeterminate nodules were prospectively tested for BRAF and RAS mutation and the surgical outcome was correlated with the mutational status. Fifty-seven and 47 cases were positive for BRAF and RAS mutation, respectively. Twenty-seven RAS-positive patients underwent surgery and all except one patient had FVPTC. The PPV and accuracy of RAS mutational analysis for predicting FVPTC were 96% and 84%, respectively. BRAF or RAS mutations were present in more than two-thirds of FVPTCs and these were mutually exclusive. BRAF mutational analysis followed by N, H, and KRAS codon 61 mutational analysis in indeterminate thyroid nodules would streamline the management of patients with malignancies, mostly FVPTC.

  17. Genetic variants in the integrin signaling pathway genes predict cutaneous melanoma survival.

    Science.gov (United States)

    Li, Hongyu; Wang, Yanru; Liu, Hongliang; Shi, Qiong; Xu, Yinghui; Wu, Wenting; Zhu, Dakai; Amos, Christopher I; Fang, Shenying; Lee, Jeffrey E; Han, Jiali; Wei, Qingyi

    2017-03-15

    To identify genetic variants involved in prognosis of cutaneous melanoma (CM), we investigated associations of single nucleotide polymorphisms (SNPs) of genes in the integrin signaling pathway with CM survival by re-analyzing a published genome-wide association study (GWAS) from The University of Texas M.D. Anderson Cancer Center (MDACC) and then validated significant SNPs in another GWAS from Harvard University. In the MDACC study, 1,148 SNPs were significantly associated with CM-specific survival (CMSS) (p ≤ 0.050 and false-positive report probability ≤ 0.20), and nine SNPs were validated in the Harvard study (p ≤ 0.050). Among these, three independent SNPs (i.e., DOCK1 rs11018104 T > A, rs35748949 C > T and PAK2 rs1718404 C > T) showed a predictive role in CMSS, with an effect-allele attributed adjusted hazards ratio [adjHR of 1.50 (95% confidence interval (CI) = 1.18-1.90, p = 7.46E-04), 1.53 (1.18-1.97, 1.18E-03) and 0.58 (0.45-0.76, 5.60E-05), respectively]. Haplotype analysis revealed that a haplotype carrying two risk alleles A-T in DOCK1 was associated with the poorest survival in both MDACC (adjHR = 1.73, 95% CI = 1.19-2.50, p = 0.004) and Harvard (adjHR = 1.95, 95% CI = 1.14-3.33, p = 0.010) studies. In addition, patients with an increasing number of unfavorable genotypes (NUGs) for these three SNPs had a poorer survival. Incorporating NUGs with clinical variables showed a significantly improved ability to classify CMSS (AUC increased from 86.8% to 88.6%, p = 0.031). Genetic variants in the integrin signaling pathway may independently or jointly modulate the survival of CM patients. Further large, prospective studies are needed to validate these findings. © 2016 UICC.

  18. FunSAV: predicting the functional effect of single amino acid variants using a two-stage random forest model.

    Directory of Open Access Journals (Sweden)

    Mingjun Wang

    Full Text Available Single amino acid variants (SAVs are the most abundant form of known genetic variations associated with human disease. Successful prediction of the functional impact of SAVs from sequences can thus lead to an improved understanding of the underlying mechanisms of why a SAV may be associated with certain disease. In this work, we constructed a high-quality structural dataset that contained 679 high-quality protein structures with 2,048 SAVs by collecting the human genetic variant data from multiple resources and dividing them into two categories, i.e., disease-associated and neutral variants. We built a two-stage random forest (RF model, termed as FunSAV, to predict the functional effect of SAVs by combining sequence, structure and residue-contact network features with other additional features that were not explored in previous studies. Importantly, a two-step feature selection procedure was proposed to select the most important and informative features that contribute to the prediction of disease association of SAVs. In cross-validation experiments on the benchmark dataset, FunSAV achieved a good prediction performance with the area under the curve (AUC of 0.882, which is competitive with and in some cases better than other existing tools including SIFT, SNAP, Polyphen2, PANTHER, nsSNPAnalyzer and PhD-SNP. The sourcecodes of FunSAV and the datasets can be downloaded at http://sunflower.kuicr.kyoto-u.ac.jp/sjn/FunSAV.

  19. Working-memory endophenotype and dyslexia-associated genetic variant predict dyslexia phenotype.

    Science.gov (United States)

    Männel, Claudia; Meyer, Lars; Wilcke, Arndt; Boltze, Johannes; Kirsten, Holger; Friederici, Angela D

    2015-10-01

    Developmental dyslexia, a severe impairment of literacy acquisition, is known to have a neurological basis and a strong genetic background. However, effects of individual genetic variations on dyslexia-associated deficits are only moderate and call for the assessment of the genotype's impact on mediating neuro-endophenotypes by the imaging genetics approach. Using voxel-based morphometry (VBM) in German participants with and without dyslexia, we investigated gray matter changes and their association with impaired phonological processing, such as reduced verbal working memory. These endophenotypical alterations were, together with dyslexia-associated genetic variations, examined on their suitability as potential predictors of dyslexia. We identified two gray matter clusters in the left posterior temporal cortex related to verbal working memory capacity. Regional cluster differences correlated with genetic risk variants in TNFRSF1B. High-genetic-risk participants exhibit a structural predominance of auditory-association areas relative to auditory-sensory areas, which may partly compensate for deficient early auditory-sensory processing stages of verbal working memory. The reverse regional predominance observed in low-genetic-risk participants may in turn reflect reliance on these early auditory-sensory processing stages. Logistic regression analysis further supported that regional gray matter differences and genetic risk interact in the prediction of individuals' diagnostic status: With increasing genetic risk, the working-memory related structural predominance of auditory-association areas relative to auditory-sensory areas classifies participants with dyslexia versus control participants. Focusing on phonological deficits in dyslexia, our findings suggest endophenotypical changes in the left posterior temporal cortex could comprise novel pathomechanisms for verbal working memory-related processes translating TNFRSF1B genotype into the dyslexia phenotype. Copyright

  20. Conveying uncertainty in prognosis to patients with ESRD.

    Science.gov (United States)

    Parvez, Sanah; Abdel-Kader, Khaled; Song, Mi-Kyung; Unruh, Mark

    2015-01-01

    Prognosis is a component of medical practice imbued with uncertainty. In nephrology, where mortality rates of elderly patients on dialysis are comparable to those of cancer patients, the implications of prognosis are unavoidable. Yet while most patients with end-stage renal disease (ESRD) desire to hear their prognosis, many nephrologists balk at this prospect in part owing to the uncertainty inherent in prognostic estimates. In this review, the concept of 'uncertainty' in clinical practice is considered from physician and patient perspectives. From the training perspective, providers learn that uncertainty is inescapable in medicine and develop strategies to manage its presence, including the avoidance of communicating uncertainty to their patients. This presages infrequent discussions of prognosis, which in turn influence patient preferences for treatments that have little therapeutic benefits. A general approach to conveying prognostic uncertainty to ESRD patients includes confronting our own emotional reaction to uncertainty, learning how to effectively communicate uncertainty to our patients, and using an effective interdisciplinary team approach to demonstrate an ongoing commitment to our patients despite the presence of prognostic uncertainty. Uncertainty in prognosis is inevitable. Once providers learn to incorporate it into their discussions of prognosis and collaborate with their ESRD patients, such discussions can foster trust and reduce anxiety for both sides. © 2015 S. Karger AG, Basel.

  1. Marijuana and Cannabinoids in ESRD and Earlier Stages of CKD.

    Science.gov (United States)

    Rein, Joshua L; Wyatt, Christina M

    2017-08-12

    Marijuana is the most commonly used recreational drug in the United States, and legal recreational and medicinal use has gained public acceptance during the last decade. Twenty-nine US states have established medical marijuana programs, 8 of which have also legalized recreational marijuana, and Canada is expected to legalize recreational marijuana in 2018. Advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) are chronic conditions with significant associated morbidity and mortality. Patients experience substantial symptom burden that is frequently undertreated due to adverse medication side effects. This article reviews the available evidence for the use of medical marijuana to manage chronic pain, nausea/vomiting, anorexia/cachexia, and pruritus, all of which are frequently reported by patients with advanced CKD or ESRD. Potential adverse health effects of medical and recreational marijuana use are also discussed. Regardless of personal, social, and political beliefs, marijuana use is becoming mainstream, and nephrologists should be aware of the potential impact on our patient population. Further research is warranted to investigate the renal endocannabinoid system, the impact of marijuana use on kidney disease outcomes, and the risks and benefits of medical marijuana use on symptoms of advanced CKD and ESRD. Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  2. Variants in KCNJ11 and BAD do not predict response to ketogenic dietary therapies for epilepsy.

    Science.gov (United States)

    Schoeler, Natasha E; Leu, Costin; White, Jon; Plagnol, Vincent; Ellard, Sian; Matarin, Mar; Yellen, Gary; Thiele, Elizabeth A; Mackay, Mark; McMahon, Jacinta M; Scheffer, Ingrid E; Sander, Josemir W; Cross, J Helen; Sisodiya, Sanjay M

    2015-12-01

    In the absence of specific metabolic disorders, predictors of response to ketogenic dietary therapies (KDT) are unknown. We aimed to determine whether variants in established candidate genes KCNJ11 and BAD influence response to KDT. We sequenced KCNJ11 and BAD in individuals without previously-known glucose transporter type 1 deficiency syndrome or other metabolic disorders, who received KDT for epilepsy. Hospital records were used to obtain demographic and clinical data. Two response phenotypes were used: ≥ 50% seizure reduction and seizure-freedom at 3-month follow-up. Case/control association tests were conducted with KCNJ11 and BAD variants with minor allele frequency (MAF)>0.01, using PLINK. Response to KDT in individuals with variants with MAF0.01. Eight variants in KCNJ11 and seven in BAD (of which three were previously-unreported) had MAFepilepsy. We can exclude, with 80% power, association from variants with a MAF of >0.05 and effect size >3. A larger sample size is needed to detect associations from rare variants or those with smaller effect sizes. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Functional analysis of rare variants in mismatch repair proteins augments results from computation-based predictive methods.

    Science.gov (United States)

    Arora, Sanjeevani; Huwe, Peter J; Sikder, Rahmat; Shah, Manali; Browne, Amanda J; Lesh, Randy; Nicolas, Emmanuelle; Deshpande, Sanat; Hall, Michael J; Dunbrack, Roland L; Golemis, Erica A

    2017-07-03

    The cancer-predisposing Lynch Syndrome (LS) arises from germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1, MSH2, MSH6, and PMS2. A major challenge for clinical diagnosis of LS is the frequent identification of variants of uncertain significance (VUS) in these genes, as it is often difficult to determine variant pathogenicity, particularly for missense variants. Generic programs such as SIFT and PolyPhen-2, and MMR gene-specific programs such as PON-MMR and MAPP-MMR, are often used to predict deleterious or neutral effects of VUS in MMR genes. We evaluated the performance of multiple predictive programs in the context of functional biologic data for 15 VUS in MLH1, MSH2, and PMS2. Using cell line models, we characterized VUS predicted to range from neutral to pathogenic on mRNA and protein expression, basal cellular viability, viability following treatment with a panel of DNA-damaging agents, and functionality in DNA damage response (DDR) signaling, benchmarking to wild-type MMR proteins. Our results suggest that the MMR gene-specific classifiers do not always align with the experimental phenotypes related to DDR. Our study highlights the importance of complementary experimental and computational assessment to develop future predictors for the assessment of VUS.

  4. Evidence of differential effects of vitamin D receptor variants on epithelial ovarian cancer risk by predicted vitamin D status

    Directory of Open Access Journals (Sweden)

    Jennifer ePrescott

    2014-10-01

    Full Text Available Introduction: Experimental studies suggest vitamin D inhibits ovarian carcinogenesis. Yet, epidemiologic studies of ovarian cancer risk and lifestyle correlates of vitamin D status, plasma 25-hydroxyvitamin D [25(OHD], or vitamin D receptor (VDR variants have been inconsistent. Objective: To evaluate VDR genetic associations by high vs. low predicted 25(OHD, scores derived from known determinants of plasma 25(OHD. To assess ovarian cancer associations with variants identified in genome-wide association studies (GWAS of plasma 25(OHD. Methods: We genotyped up to 7 VDR and 8 25(OHD GWAS variants in the Nurses’ Health Studies (562 cases, 1,553 controls and New England Case-Control study (1,821 cases, 1,870 controls. We estimated haplotype scores using expectation-maximization-based algorithms. We used unconditional logistic regression to calculate odds ratios (ORs and 95% confidence intervals (CI. We combined study results using DerSimonian and Laird meta-analysis. Results: Ovarian cancer risk increased per A allele of rs7975232 (VDR; OR=1.12, 95% CI=1.01-1.25 among all women. When stratified by predicted 25(OHD, ovarian cancer was associated with rs731236 (VDR; per C allele OR=1.31 and rs7975232 (OR=1.38 among women with high predicted 25(OHD, but not among women with low levels (P≤0.009. We also observed heterogeneity by predicted 25(OHD for the ovarian cancer association with VDR 3’ end haplotypes (P=0.009. Of 25(OHD-associated GWAS loci, rs7041 was associated with reduced ovarian cancer risk (per T allele OR=0.92, 95% CI=0.85-0.99, which did not differ by predicted 25(OHD status. Conclusion: Our study suggests an influence of VDR 3’ end variants on ovarian cancer risk may be observed in women with high predicted 25(OHD, which remained even after taking multiple comparisons into consideration. Future studies are needed to confirm our results and explore further the relation between vitamin D exposure, genetic variants, and ovarian cancer

  5. ACE I/D and MMP-7 A-181G variants and the risk of end stage renal disease.

    Science.gov (United States)

    Rahimi, Zohreh; Abdi, Hamed; Tanhapoor, Maryam; Rahimi, Ziba; Vaisi-Raygani, Asad; Nomani, Hamid

    2017-03-01

    The variants of angiotensin converting enzyme (ACE) and matrix metalloproteinases (MMPs) genes might be involved in the pathogenesis of end stage renal disease (ESRD) and hypertension. We studied the ACE insertion/deletion (I/D) and MMP-7 A-181G variants in 99 unrelated ESRD patients and 117 individuals without renal complications from Western Iran with Kurdish ethnic background. The frequency of ACE I/D variants was not significantly different between ESRD patients and controls. However, the presence of ACE D allele increased the risk of hypertension in ESRD patients by 2.14-fold (P=0.036). The MMP-7 -181 AG genotype increased the risk of ESRD by 2.04 times (P=0.026). The present study indicated the absence of an association between the ACE I/D polymorphism with the risk of ESRD. However, the ACE D allele increased the risk of hypertension in ESRD patients. Also, the present study suggests a role for MMP-7 AG genotype in the pathogenesis of ESRD.

  6. CHRNA5 Risk Variant Predicts Delayed Smoking Cessation and Earlier Lung Cancer Diagnosis—A Meta-Analysis

    Science.gov (United States)

    Hung, Rayjean J.; Baker, Timothy; Horton, Amy; Culverhouse, Rob; Saccone, Nancy; Cheng, Iona; Deng, Bo; Han, Younghun; Hansen, Helen M.; Horsman, Janet; Kim, Claire; Lutz, Sharon; Rosenberger, Albert; Aben, Katja K.; Andrew, Angeline S.; Breslau, Naomi; Chang, Shen-Chih; Dieffenbach, Aida Karina; Dienemann, Hendrik; Frederiksen, Brittni; Han, Jiali; Hatsukami, Dorothy K.; Johnson, Eric O.; Pande, Mala; Wrensch, Margaret R.; McLaughlin, John; Skaug, Vidar; van der Heijden, Henricus F.; Wampfler, Jason; Wenzlaff, Angela; Woll, Penella; Zienolddiny, Shanbeh; Bickeböller, Heike; Brenner, Hermann; Duell, Eric J.; Haugen, Aage; Heinrich, Joachim; Hokanson, John E.; Hunter, David J.; Kiemeney, Lambertus A.; Lazarus, Philip; Le Marchand, Loic; Liu, Geoffrey; Mayordomo, Jose; Risch, Angela; Schwartz, Ann G.; Teare, Dawn; Wu, Xifeng; Wiencke, John K.; Yang, Ping; Zhang, Zuo-Feng; Spitz, Margaret R.; Kraft, Peter; Amos, Christopher I.; Bierut, Laura J.

    2015-01-01

    Background: Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis. Methods: Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided. Results: The rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10–5). Conclusion: These data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk. PMID:25873736

  7. Maternal Neutralization-Resistant Virus Variants Do Not Predict Infant HIV Infection Risk.

    Science.gov (United States)

    Milligan, Caitlin; Omenda, Maxwel M; Chohan, Vrasha; Odem-Davis, Katherine; Richardson, Barbra A; Nduati, Ruth; Overbaugh, Julie

    2016-02-02

    Mother-to-child transmission (MTCT) of HIV provides a setting for studying immune correlates of protection. Neutralizing antibodies (NAbs) are suggested to contribute to a viral bottleneck during MTCT, but their role in blocking transmission is unclear, as studies comparing the NAb sensitivities of maternal viruses have yielded disparate results. We sought to determine whether transmitting mothers differ from nontransmitting mothers in the ability to neutralize individual autologous virus variants present at transmission. Ten transmitting and 10 nontransmitting HIV-infected mothers at high risk of MTCT were included in this study. Full-length HIV envelope genes (n = 100) were cloned from peripheral blood mononuclear cells obtained near transmission from transmitting mothers and at similar time points from nontransmitting mothers. Envelope clones were tested as pseudoviruses against contemporaneous, autologous maternal plasma in neutralization assays. The association between transmission and the log2 50% inhibitory concentration (IC50) for multiple virus variants per mother was estimated by using logistic regression with clustered standard errors. t tests were used to compare proportions of neutralization-resistant viruses. Overall, transmitting mothers had a median IC50 of 317 (interquartile range [IQR], 202 to 521), and nontransmitting mothers had a median IC50 of 243 (IQR, 95 to 594). Transmission risk was not significantly associated with autologous NAb activity (odds ratio, 1.25; P = 0.3). Compared to nontransmitting mothers, transmitting mothers had similar numbers of or fewer neutralization-resistant virus variants, depending on the IC50 neutralization resistance cutoff. In conclusion, HIV-infected mothers harbor mostly neutralization-sensitive viruses, although resistant variants were detected in both transmitting and nontransmitting mothers. These results suggest that MTCT during the breastfeeding period is not driven solely by the presence of maternal

  8. Loss Frequency and Awareness Predict Performance on a Preschool Variant of the Iowa Gambling Task

    Science.gov (United States)

    Garon, Nancy; Longard, Julie; Craig, Bethany; Kent, Kiera

    2015-01-01

    The current study investigated the effect of frequency of loss and awareness on the ability to make advantageous decisions in preschoolers using a child variant of the Iowa Gambling Task (Bechara, Damasio, Damasio, & Anderson, 1994). Preschoolers (N = 50) were randomly assigned to either a low loss frequency (0.1) or a high loss frequency…

  9. motifbreakR: an R/Bioconductor package for predicting variant effects at transcription factor binding sites.

    Science.gov (United States)

    Coetzee, Simon G; Coetzee, Gerhard A; Hazelett, Dennis J

    2015-12-01

    Functional annotation represents a key step toward the understanding and interpretation of germline and somatic variation as revealed by genome-wide association studies (GWAS) and The Cancer Genome Atlas (TCGA), respectively. GWAS have revealed numerous genetic risk variants residing in non-coding DNA associated with complex diseases. For sequences that lie within enhancers or promoters of transcription, it is not straightforward to assess the effects of variants on likely transcription factor binding sites. Consequently we introduce motifbreakR, which allows the biologist to judge whether the sequence surrounding a polymorphism or mutation is a good match, and how much information is gained or lost in one allele of the polymorphism or mutation relative to the other. MotifbreakR is flexible, giving a choice of algorithms for interrogation of genomes with motifs from many public sources that users can choose from. MotifbreakR can predict effects for novel or previously described variants in public databases, making it suitable for tasks beyond the scope of its original design. Lastly, it can be used to interrogate any genome curated within bioconductor. https://github.com/Simon-Coetzee/MotifBreakR, www.bioconductor.org. dennis.hazelett@cshs.org. © The Author 2015. Published by Oxford University Press.

  10. Novel Non-Histocompatibility Antigen Mismatched Variants Improve the Ability to Predict Antibody-Mediated Rejection Risk in Kidney Transplant

    Directory of Open Access Journals (Sweden)

    Silvia Pineda

    2017-12-01

    Full Text Available Transplant rejection is the critical clinical end-point limiting indefinite survival after histocompatibility antigen (HLA mismatched organ transplantation. The predominant cause of late graft loss is antibody-mediated rejection (AMR, a process whereby injury to the organ is caused by donor-specific antibodies, which bind to HLA and non-HLA (nHLA antigens. AMR is incompletely diagnosed as donor/recipient (D/R matching is only limited to the HLA locus and critical nHLA immunogenic antigens remain to be identified. We have developed an integrative computational approach leveraging D/R exome sequencing and gene expression to predict clinical post-transplant outcome. We performed a rigorous statistical analysis of 28 highly annotated D/R kidney transplant pairs with biopsy-confirmed clinical outcomes of rejection [either AMR or T-cell-mediated rejection (CMR] and no-rejection (NoRej, identifying a significantly higher number of mismatched nHLA variants in AMR (ANOVA—p-value = 0.02. Using Fisher’s exact test, we identified 123 variants associated mainly with risk of AMR (p-value < 0.001. In addition, we applied a machine-learning technique to circumvent the issue of statistical power and we found a subset of 65 variants using random forest, that are predictive of post-tx AMR showing a very low error rate. These variants are functionally relevant to the rejection process in the kidney and AMR as they relate to genes and/or expression quantitative trait loci (eQTLs that are enriched in genes expressed in kidney and vascular endothelium and underlie the immunobiology of graft rejection. In addition to current D/R HLA mismatch evaluation, additional mismatch nHLA D/R variants will enhance the stratification of post-tx AMR risk even before engraftment of the organ. This innovative study design is applicable in all solid organ transplants, where the impact of mitigating AMR on graft survival may be greater, with considerable benefits on

  11. Integrating multiple genomic data to predict disease-causing nonsynonymous single nucleotide variants in exome sequencing studies.

    Directory of Open Access Journals (Sweden)

    Jiaxin Wu

    2014-03-01

    Full Text Available Exome sequencing has been widely used in detecting pathogenic nonsynonymous single nucleotide variants (SNVs for human inherited diseases. However, traditional statistical genetics methods are ineffective in analyzing exome sequencing data, due to such facts as the large number of sequenced variants, the presence of non-negligible fraction of pathogenic rare variants or de novo mutations, and the limited size of affected and normal populations. Indeed, prevalent applications of exome sequencing have been appealing for an effective computational method for identifying causative nonsynonymous SNVs from a large number of sequenced variants. Here, we propose a bioinformatics approach called SPRING (Snv PRioritization via the INtegration of Genomic data for identifying pathogenic nonsynonymous SNVs for a given query disease. Based on six functional effect scores calculated by existing methods (SIFT, PolyPhen2, LRT, MutationTaster, GERP and PhyloP and five association scores derived from a variety of genomic data sources (gene ontology, protein-protein interactions, protein sequences, protein domain annotations and gene pathway annotations, SPRING calculates the statistical significance that an SNV is causative for a query disease and hence provides a means of prioritizing candidate SNVs. With a series of comprehensive validation experiments, we demonstrate that SPRING is valid for diseases whose genetic bases are either partly known or completely unknown and effective for diseases with a variety of inheritance styles. In applications of our method to real exome sequencing data sets, we show the capability of SPRING in detecting causative de novo mutations for autism, epileptic encephalopathies and intellectual disability. We further provide an online service, the standalone software and genome-wide predictions of causative SNVs for 5,080 diseases at http://bioinfo.au.tsinghua.edu.cn/spring.

  12. CHRNA5 risk variant predicts delayed smoking cessation and earlier lung cancer diagnosis--a meta-analysis.

    Science.gov (United States)

    Chen, Li-Shiun; Hung, Rayjean J; Baker, Timothy; Horton, Amy; Culverhouse, Rob; Saccone, Nancy; Cheng, Iona; Deng, Bo; Han, Younghun; Hansen, Helen M; Horsman, Janet; Kim, Claire; Lutz, Sharon; Rosenberger, Albert; Aben, Katja K; Andrew, Angeline S; Breslau, Naomi; Chang, Shen-Chih; Dieffenbach, Aida Karina; Dienemann, Hendrik; Frederiksen, Brittni; Han, Jiali; Hatsukami, Dorothy K; Johnson, Eric O; Pande, Mala; Wrensch, Margaret R; McLaughlin, John; Skaug, Vidar; van der Heijden, Henricus F; Wampfler, Jason; Wenzlaff, Angela; Woll, Penella; Zienolddiny, Shanbeh; Bickeböller, Heike; Brenner, Hermann; Duell, Eric J; Haugen, Aage; Heinrich, Joachim; Hokanson, John E; Hunter, David J; Kiemeney, Lambertus A; Lazarus, Philip; Le Marchand, Loic; Liu, Geoffrey; Mayordomo, Jose; Risch, Angela; Schwartz, Ann G; Teare, Dawn; Wu, Xifeng; Wiencke, John K; Yang, Ping; Zhang, Zuo-Feng; Spitz, Margaret R; Kraft, Peter; Amos, Christopher I; Bierut, Laura J

    2015-05-01

    Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis. Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided. The rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10(-5)). These data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. A Common Variant in the SETD7 Gene Predicts Serum Lycopene Concentrations.

    Science.gov (United States)

    D'Adamo, Christopher R; D'Urso, Antonietta; Ryan, Kathleen A; Yerges-Armstrong, Laura M; Semba, Richard D; Steinle, Nanette I; Mitchell, Braxton D; Shuldiner, Alan R; McArdle, Patrick F

    2016-02-06

    Dietary intake and higher serum concentrations of lycopene have been associated with lower incidence of prostate cancer and other chronic diseases. Identifying determinants of serum lycopene concentrations may thus have important public health implications. Prior studies have suggested that serum lycopene concentrations are under partial genetic control. The goal of this research was to identify genetic predictors of serum lycopene concentrations using the genome-wide association study (GWAS) approach among a sample of 441 Old Order Amish adults that consumed a controlled diet. Linear regression models were utilized to evaluate associations between genetic variants and serum concentrations of lycopene. Variant rs7680948 on chromosome 4, located in the intron region of the SETD7 gene, was significantly associated with serum lycopene concentrations (p = 3.41 × 10(-9)). Our findings also provided nominal support for the association previously noted between SCARB1 and serum lycopene concentrations, although with a different SNP (rs11057841) in the region. This study identified a novel locus associated with serum lycopene concentrations and our results raise a number of intriguing possibilities regarding the nature of the relationship between SETD7 and lycopene, both of which have been independently associated with prostate cancer. Further investigation into this relationship might help provide greater mechanistic understanding of these associations.

  14. A Common Variant in the SETD7 Gene Predicts Serum Lycopene Concentrations

    Directory of Open Access Journals (Sweden)

    Christopher R. D’Adamo

    2016-02-01

    Full Text Available Dietary intake and higher serum concentrations of lycopene have been associated with lower incidence of prostate cancer and other chronic diseases. Identifying determinants of serum lycopene concentrations may thus have important public health implications. Prior studies have suggested that serum lycopene concentrations are under partial genetic control. The goal of this research was to identify genetic predictors of serum lycopene concentrations using the genome-wide association study (GWAS approach among a sample of 441 Old Order Amish adults that consumed a controlled diet. Linear regression models were utilized to evaluate associations between genetic variants and serum concentrations of lycopene. Variant rs7680948 on chromosome 4, located in the intron region of the SETD7 gene, was significantly associated with serum lycopene concentrations (p = 3.41 × 10−9. Our findings also provided nominal support for the association previously noted between SCARB1 and serum lycopene concentrations, although with a different SNP (rs11057841 in the region. This study identified a novel locus associated with serum lycopene concentrations and our results raise a number of intriguing possibilities regarding the nature of the relationship between SETD7 and lycopene, both of which have been independently associated with prostate cancer. Further investigation into this relationship might help provide greater mechanistic understanding of these associations.

  15. IMHOTEP—a composite score integrating popular tools for predicting the functional consequences of non-synonymous sequence variants

    Science.gov (United States)

    Knecht, Carolin; Mort, Matthew; Junge, Olaf; Cooper, David N.; Krawczak, Michael

    2017-01-01

    Abstract The in silico prediction of the functional consequences of mutations is an important goal of human pathogenetics. However, bioinformatic tools that classify mutations according to their functionality employ different algorithms so that predictions may vary markedly between tools. We therefore integrated nine popular prediction tools (PolyPhen-2, SNPs&GO, MutPred, SIFT, MutationTaster2, Mutation Assessor and FATHMM as well as conservation-based Grantham Score and PhyloP) into a single predictor. The optimal combination of these tools was selected by means of a wide range of statistical modeling techniques, drawing upon 10 029 disease-causing single nucleotide variants (SNVs) from Human Gene Mutation Database and 10 002 putatively ‘benign’ non-synonymous SNVs from UCSC. Predictive performance was found to be markedly improved by model-based integration, whilst maximum predictive capability was obtained with either random forest, decision tree or logistic regression analysis. A combination of PolyPhen-2, SNPs&GO, MutPred, MutationTaster2 and FATHMM was found to perform as well as all tools combined. Comparison of our approach with other integrative approaches such as Condel, CoVEC, CAROL, CADD, MetaSVM and MetaLR using an independent validation dataset, revealed the superiority of our newly proposed integrative approach. An online implementation of this approach, IMHOTEP (‘Integrating Molecular Heuristics and Other Tools for Effect Prediction’), is provided at http://www.uni-kiel.de/medinfo/cgi-bin/predictor/. PMID:28180317

  16. Long-Term Risk of Cancer in Survivors of Pediatric ESRD

    NARCIS (Netherlands)

    Ploos van Amstel, Sophie; Vogelzang, Judith L.; Starink, Marcus V.; Jager, Kitty J.; Groothoff, Jaap W.

    2015-01-01

    ESRD is associated with an increased risk of malignancies. We analyzed the incidence of cancer in patients with pediatric ESRD after long-term follow-up. All Dutch patients born before 1979 who were transplanted at age <15 years old in 1972-1992 were followed until 2010. We explored type and

  17. Copeptin Levels Associate with Cardiovascular Events in Patients with ESRD and Type 2 Diabetes Mellitus

    Science.gov (United States)

    Fenske, Wiebke; Wanner, Christoph; Allolio, Bruno; Drechsler, Christiane; Blouin, Katja; Lilienthal, Jürgen

    2011-01-01

    In ESRD, the neurohormone arginine vasopressin (AVP) may act primarily through V1a and V1b receptors, which promote vasoconstriction, myocardial hypertrophy, and release of adrenocorticotropic hormone. The preanalytical instability of AVP limits the investigation of whether this hormone associates with cardiovascular events, but the stable glycopeptide copeptin may serve as a surrogate because it is co-secreted with AVP from the posterior pituitary. Here, we studied whether copeptin predicts cardiovascular risk and mortality in ESRD. We measured copeptin at baseline in 1241 hemodialysis patients with type 2 diabetes participating in the German Diabetes and Dialysis Study. The median copeptin level was 81 pmol/L (interquartile range, 81 to 122 pmol/L). In Cox regression analyses, compared with patients with copeptin levels in the lowest quartile (≤51 pmol/L), patients with copeptin levels in the highest quartile (>122 pmol/L) had a 3.5-fold increased risk for stroke (HR, 3.48; 95% CI: 1.71 to 7.09), a 73% higher risk for sudden death (HR, 1.73; 95% CI: 1.01 to 2.95), a 42% higher risk for combined cardiovascular events (HR, 1.42; 95% CI: 1.06 to 1.90), and a 48% higher risk for all-cause mortality (HR, 1.48; 95% CI: 1.15 to 1.90). In contrast, we did not detect significant associations between copeptin levels and risks for myocardial infarction or death caused by congestive heart failure. In conclusion, copeptin levels strongly associate with stroke, sudden death, combined cardiovascular events, and mortality in hemodialysis patients with type 2 diabetes. Whether vasopressin receptor antagonists will improve these outcomes requires further studies. PMID:21415158

  18. Evaluation of DNA variants associated with androgenetic alopecia and their potential to predict male pattern baldness.

    Science.gov (United States)

    Marcińska, Magdalena; Pośpiech, Ewelina; Abidi, Sarah; Andersen, Jeppe Dyrberg; van den Berge, Margreet; Carracedo, Ángel; Eduardoff, Mayra; Marczakiewicz-Lustig, Anna; Morling, Niels; Sijen, Titia; Skowron, Małgorzata; Söchtig, Jens; Syndercombe-Court, Denise; Weiler, Natalie; Schneider, Peter M; Ballard, David; Børsting, Claus; Parson, Walther; Phillips, Chris; Branicki, Wojciech

    2015-01-01

    Androgenetic alopecia, known in men as male pattern baldness (MPB), is a very conspicuous condition that is particularly frequent among European men and thus contributes markedly to variation in physical appearance traits amongst Europeans. Recent studies have revealed multiple genes and polymorphisms to be associated with susceptibility to MPB. In this study, 50 candidate SNPs for androgenetic alopecia were analyzed in order to verify their potential to predict MPB. Significant associations were confirmed for 29 SNPs from chromosomes X, 1, 5, 7, 18 and 20. A simple 5-SNP prediction model and an extended 20-SNP model were developed based on a discovery panel of 305 males from various European populations fitting one of two distinct phenotype categories. The first category consisted of men below 50 years of age with significant baldness and the second; men aged 50 years or older lacking baldness. The simple model comprised the five best predictors: rs5919324 near AR, rs1998076 in the 20p11 region, rs929626 in EBF1, rs12565727 in TARDBP and rs756853 in HDAC9. The extended prediction model added 15 SNPs from five genomic regions that improved overall prevalence-adjusted predictive accuracy measured by area under the receiver characteristic operating curve (AUC). Both models were evaluated for predictive accuracy using a test set of 300 males reflecting the general European population. Applying a 65% probability threshold, high prediction sensitivity of 87.1% but low specificity of 42.4% was obtained in men aged <50 years. In men aged ≥50, prediction sensitivity was slightly lower at 67.7% while specificity reached 90%. Overall, the AUC=0.761 calculated for men at or above 50 years of age indicates these SNPs offer considerable potential for the application of genetic tests to predict MPB patterns, adding a highly informative predictive system to the emerging field of forensic analysis of externally visible characteristics.

  19. Evaluation of DNA variants associated with androgenetic alopecia and their potential to predict male pattern baldness.

    Directory of Open Access Journals (Sweden)

    Magdalena Marcińska

    Full Text Available Androgenetic alopecia, known in men as male pattern baldness (MPB, is a very conspicuous condition that is particularly frequent among European men and thus contributes markedly to variation in physical appearance traits amongst Europeans. Recent studies have revealed multiple genes and polymorphisms to be associated with susceptibility to MPB. In this study, 50 candidate SNPs for androgenetic alopecia were analyzed in order to verify their potential to predict MPB. Significant associations were confirmed for 29 SNPs from chromosomes X, 1, 5, 7, 18 and 20. A simple 5-SNP prediction model and an extended 20-SNP model were developed based on a discovery panel of 305 males from various European populations fitting one of two distinct phenotype categories. The first category consisted of men below 50 years of age with significant baldness and the second; men aged 50 years or older lacking baldness. The simple model comprised the five best predictors: rs5919324 near AR, rs1998076 in the 20p11 region, rs929626 in EBF1, rs12565727 in TARDBP and rs756853 in HDAC9. The extended prediction model added 15 SNPs from five genomic regions that improved overall prevalence-adjusted predictive accuracy measured by area under the receiver characteristic operating curve (AUC. Both models were evaluated for predictive accuracy using a test set of 300 males reflecting the general European population. Applying a 65% probability threshold, high prediction sensitivity of 87.1% but low specificity of 42.4% was obtained in men aged <50 years. In men aged ≥50, prediction sensitivity was slightly lower at 67.7% while specificity reached 90%. Overall, the AUC=0.761 calculated for men at or above 50 years of age indicates these SNPs offer considerable potential for the application of genetic tests to predict MPB patterns, adding a highly informative predictive system to the emerging field of forensic analysis of externally visible characteristics.

  20. Genetic variants of PDGF signaling pathway genes predict cutaneous melanoma survival.

    Science.gov (United States)

    Li, Hong; Wang, Yanru; Liu, Hongliang; Shi, Qiong; Li, Hongyu; Wu, Wenting; Zhu, Dakai; Amos, Christopher I; Fang, Shenying; Lee, Jeffrey E; Li, Yi; Han, Jiali; Wei, Qingyi

    2017-09-26

    To investigate whether genetic variants of platelet-derived growth factor (PDGF) signaling pathway genes are associated with survival of cutaneous melanoma (CM) patients, we assessed associations of single-nucleotide polymorphisms in PDGF pathway with melanoma-specific survival in 858 CM patients of M.D. Anderson Cancer Center (MDACC). Additional data of 409 cases from Harvard University were also included for further analysis. We identified 13 SNPs in four genes (COL6A3, NCK2, COL5A1 and PRKCD) with a nominal P Harvard datasets, there were two SNPs associated with poor survival of CM patients: rs6707820 C>T in NCK2 (HR = 1.87, 95% CI = 1.35-2.59, Pmeta= 1.53E-5); and rs2306574 T>C in PRKCD (HR = 1.73, 95% CI = 1.33-2.24, Pmeta= 4.56E-6). Moreover, CM patients in MDACC with combined risk genotypes of these two loci had markedly poorer survival (HR = 2.47, 95% CI = 1.58-3.84, P T in NCK2 and rs2306574 T>C in PRKCD of the PDGF signaling pathway may be biomarkers for melanoma survival.

  1. Genetic variants in 3'-UTRs of methylenetetrahydrofolate reductase (MTHFR) predict colorectal cancer susceptibility in Koreans.

    Science.gov (United States)

    Jeon, Young Joo; Kim, Jong Woo; Park, Hye Mi; Kim, Jung O; Jang, Hyo Geun; Oh, Jisu; Hwang, Seong Gyu; Kwon, Sung Won; Oh, Doyeun; Kim, Nam Keun

    2015-06-05

    Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) play important roles in tumor development, progression, and metastasis. Moreover, recent studies have reported that a number of 3'-UTR polymorphisms potentially bind to specific microRNAs in a variety of cancers. The aim of this study was to investigate the association of four MTHFR polymorphisms, 2572C>A [rs4846049], 4869C>G [rs1537514], 5488C>T [rs3737967], and 6685T>C [rs4846048] with colorectal cancer (CRC) in Koreans. A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of MTHFR 3'-UTR polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis or TaqMan allelic discrimination assay. We found that MTHFR 2572C>A, 4869C>G, and 5488C>T genotypes were substantially associated with CRC susceptibility. Of the potentially susceptible polymorphisms, MTHFR 2572C>A was associated with increased homocysteine and decreased folate levels in the plasma based on MTHFR 677CC. Our study provides the evidences for 3'-UTR variants in MTHFR gene as potential biomarkers for use in CRC prevention.

  2. Predictive and Prognostic Implications of Variant Philadelphia Translocations in CML: Experience From a Tertiary Oncology Center in Southern India.

    Science.gov (United States)

    Kanakasetty, Govind Babu; Kuntejowdahalli, Lakshmaiah; Thanky, Aditi Harsh; Dasappa, Lokanatha; Jacob, Linu Abraham; Mallekavu, Suresh Babu; Kumari, Prasanna

    2017-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by Philadelphia (Ph) chromosome with classical t(9;22)(q34;q11) seen in up to 90% of cases. However 5% to 10% of patients who present with variant Ph translocations (vPh) have been an area of research for their significance in predicting response to various therapies including tyrosine kinase inhibitors as well as prognosticating survival outcomes for many years involving varied patient populations, with conflicting results. We retrospectively analyzed our data from January 2002 to December 2014. Patients with vPh in chronic phase of CML (CML-CP) were analyzed with respect to their demographic parameters, response to imatinib therapy, and survival and their data were compared with data of patients with classical Ph translocation (cPh). Of 615 patients diagnosed with CML-CP, 72 patients (11.7%) showed vPh. Most common chromosomes involved in these translocations were 14 (13.9%), 11 (12.5%), 19 (9.7%), and 7 (8.3%). Rates of complete hematological response, complete cytogenetic response, and major molecular response were not statistically different between the groups. At 5 years, event-free survival, failure-free survival, progression-free survival, and overall survival were 60% versus 67.9%, 62.7% versus 69.7%, 84.7% versus 92.1%, and 87.5% versus 92.4%, respectively, in vPh and cPh. The differences in survival were statistically not significant. To our knowledge, this is the largest series of variant translocations in CML-CP, pertaining to the Indian population. Our data suggest that the presence of vPh in CML has no significant effect in predicting response to imatinib as well as in prognosticating survival. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. HLA class I and class II associations with ESRD in Saudi Arabian population.

    Directory of Open Access Journals (Sweden)

    Nuha Mahmoud Hamdi

    Full Text Available Chronic renal failure (CRF leads in the majority of instances to end stage renal disease (ESRD requiring renal replacement therapy. Our interest was to evaluate the possible associations of HLA class I and class II antigens with ESRD independent of other factors, in Saudi Arabia population.A retrospective study to determine the HLA class I and class II polymorphisms and their association with ESRD, was performed on 350 patients with ESRD, and 105 healthy unrelated control. Patients and control groups were typed by SSOP lumenix techniques. The alleles positively associated to the ESRD were: HLA-B*15, B*18, B*49 - DRB1*03, negatively associated alleles were A*26, HLA-B*39, B*50. The haplotypes positively associated with ESRD were: HLA-A*01-DRB1*13 and HLA-A*30-DRBI*03. The negatively associated haplotypes were: HLA-A*02-B*39, A*02-B*50, A*24-B*35, A*24-B*58, A*24-DRB1*16, A*68-DRB1*04, A*02-DQB1*03, A*29-DQB1*02, A*29-DOB1*05 and B*27-DRB1*07 and the last one is the most significant protective haplotypes.The high Relative Risk (RR observed and its statistical correlation reflect the strength of the described association between HLA antigens and ESRD.

  4. HLA Class I and Class II Associations with ESRD in Saudi Arabian Population

    Science.gov (United States)

    Hamdi, Nuha Mahmoud; Al-Hababi, Fadel Hassan; Eid, Amr Ekhlas

    2014-01-01

    Background Chronic renal failure (CRF) leads in the majority of instances to end stage renal disease (ESRD) requiring renal replacement therapy. Our interest was to evaluate the possible associations of HLA class I and class II antigens with ESRD independent of other factors, in Saudi Arabia population. Methodology A retrospective study to determine the HLA class I and class II polymorphisms and their association with ESRD, was performed on 350 patients with ESRD, and 105 healthy unrelated control. Patients and control groups were typed by SSOP lumenix techniques. The alleles positively associated to the ESRD were: HLA-B*15, B*18, B*49 - DRB1*03, negatively associated alleles were A*26, HLA-B*39, B*50. The haplotypes positively associated with ESRD were: HLA-A*01-DRB1*13 and HLA-A*30-DRBI*03. The negatively associated haplotypes were: HLA-A*02-B*39, A*02-B*50, A*24-B*35, A*24-B*58, A*24-DRB1*16, A*68-DRB1*04, A*02-DQB1*03, A*29-DQB1*02, A*29-DOB1*05 and B*27-DRB1*07 and the last one is the most significant protective haplotypes. Conclusion The high Relative Risk (RR) observed and its statistical correlation reflect the strength of the described association between HLA antigens and ESRD. PMID:25380295

  5. Evaluation of the predictive capacity of DNA variants associated with straight hair in Europeans

    DEFF Research Database (Denmark)

    Pośpiech, Ewelina; Karłowska-Pik, Joanna; Marcińska, Magdalena

    2015-01-01

    pattern baldness revealed a suggestive association with hair morphology for rs4679955 on 3q25.1. The study results reported provide the starting point for the development of a predictive test for hair morphology in Europeans. More studies are now needed to discover additional determinants of hair...

  6. Model-based prediction of human hair color using DNA variants

    NARCIS (Netherlands)

    W. Branicki (Wojciech); F. Liu (Fan); K. van Duijn (Kate); J. Draus-Barini (Jolanta); E. Pośpiech (Ewelina); S. Walsh (Susan); T. Kupiec (Tomasz); A. Wojas-Pelc (Anna); M.H. Kayser (Manfred)

    2011-01-01

    textabstractPredicting complex human phenotypes from genotypes is the central concept of widely advocated personalized medicine, but so far has rarely led to high accuracies limiting practical applications. One notable exception, although less relevant for medical but important for forensic

  7. Prediction and characterization of variant electron diffraction patterns for {gamma}{double_prime} and {delta} precipitates in an Inconel 718 alloy

    Energy Technology Data Exchange (ETDEWEB)

    Rong, Y.; Chen, S.; Hu, G. [Shanghai Jiao Tong Univ. (China). School of Materials Science and Engineering; Gao, M.; Wei, R.P. [Lehigh Univ., Bethlehem, PA (United States). Dept. of Mechanical Engineering and Mechanics

    1999-09-01

    A universal theoretical method has been developed in this article to predict and characterize electron diffraction patterns (EDPs) which contain various variants of precipitate(s) with a matrix. The plane and direction transition matrices for three {gamma}{double_prime}-phase variants and 12 {delta}-phase variants precipitated from a {gamma} matrix in the Inconel 718 alloy were deduced, from which the EDPs for seven low-index zones of {gamma} matrix containing {gamma}{double_prime} precipitates were predicted by plotting and were found to be consistent with transmission electron microscopy (TEM) observations, showing that some of the results reported by Quist et al. should be corrected. Meanwhile, three variants of {delta} phase, precipitated from any one of four {l_brace}111{r_brace} matrices in 12 possible orientational variants, were also predicted and confirmed by EDPs. Different from Paulonis` conclusion, the theoretical calculations indicated that the {l_brace}1/2 1 0{r_brace}-type superlattice reflections in the <100> zone of the {gamma} matrix permitted detection of both {gamma}{double_prime}- and {sigma}-phase precipitates, but not of {gamma}{double_prime}-phase precipitates. Therefore, the precipitates shown in dark-field images using these superlattice reflections cannot be unambiguously determined to be {gamma}{double_prime} phase. A unique approach for identification of {gamma}{double_prime} precipitates in the alloy has been proposed.

  8. Genetic variants and their interactions in the prediction of increased pre-clinical carotid atherosclerosis: the cardiovascular risk in young Finns study.

    Science.gov (United States)

    Okser, Sebastian; Lehtimäki, Terho; Elo, Laura L; Mononen, Nina; Peltonen, Nina; Kähönen, Mika; Juonala, Markus; Fan, Yue-Mei; Hernesniemi, Jussi A; Laitinen, Tomi; Lyytikäinen, Leo-Pekka; Rontu, Riikka; Eklund, Carita; Hutri-Kähönen, Nina; Taittonen, Leena; Hurme, Mikko; Viikari, Jorma S A; Raitakari, Olli T; Aittokallio, Tero

    2010-09-30

    The relative contribution of genetic risk factors to the progression of subclinical atherosclerosis is poorly understood. It is likely that multiple variants are implicated in the development of atherosclerosis, but the subtle genotypic and phenotypic differences are beyond the reach of the conventional case-control designs and the statistical significance testing procedures being used in most association studies. Our objective here was to investigate whether an alternative approach--in which common disorders are treated as quantitative phenotypes that are continuously distributed over a population--can reveal predictive insights into the early atherosclerosis, as assessed using ultrasound imaging-based quantitative measurement of carotid artery intima-media thickness (IMT). Using our population-based follow-up study of atherosclerosis precursors as a basis for sampling subjects with gradually increasing IMT levels, we searched for such subsets of genetic variants and their interactions that are the most predictive of the various risk classes, rather than using exclusively those variants meeting a stringent level of statistical significance. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive value of the variants, and cross-validation was used to assess how well the predictive models will generalize to other subsets of subjects. By means of our predictive modeling framework with machine learning-based SNP selection, we could improve the prediction of the extreme classes of atherosclerosis risk and progression over a 6-year period (average AUC 0.844 and 0.761), compared to that of using conventional cardiovascular risk factors alone (average AUC 0.741 and 0.629), or when combined with the statistically significant variants (average AUC 0.762 and 0.651). The predictive accuracy remained relatively high in an independent validation set of subjects (average decrease of 0.043). These results demonstrate that the modeling

  9. Evaluation of DNA Variants Associated with Androgenetic Alopecia and Their Potential to Predict Male Pattern Baldness

    DEFF Research Database (Denmark)

    Marcińska, Magdalena; Pośpiech, Ewelina; Abidi, Sarah

    2015-01-01

    Androgenetic alopecia, known in men as male pattern baldness (MPB), is a very conspicuous condition that is particularly frequent among European men and thus contributes markedly to variation in physical appearance traits amongst Europeans. Recent studies have revealed multiple genes and polymorp......Androgenetic alopecia, known in men as male pattern baldness (MPB), is a very conspicuous condition that is particularly frequent among European men and thus contributes markedly to variation in physical appearance traits amongst Europeans. Recent studies have revealed multiple genes...... and polymorphisms to be associated with susceptibility to MPB. In this study, 50 candidate SNPs for androgenetic alopecia were analyzed in order to verify their potential to predict MPB. Significant associations were confirmed for 29 SNPs from chromosomes X, 1, 5, 7, 18 and 20. A simple 5-SNP prediction model...

  10. PPARα gene variants as predicted performance-enhancing polymorphisms in professional Italian soccer players

    Directory of Open Access Journals (Sweden)

    Proia P

    2014-12-01

    demonstrated an association of intron 7 G allele as well as the GG genotype in endurance athletes. Our result suggests that this is the case also in professional soccer players. Keywords: PCR-RFLP, gene variants, endurance athlete, G allele

  11. Rs895819 in MIR27A improves the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine-associated toxicity.

    Science.gov (United States)

    Meulendijks, Didier; Henricks, Linda M; Amstutz, Ursula; Froehlich, Tanja K; Largiadèr, Carlo R; Beijnen, Jos H; de Boer, Anthonius; Deenen, Maarten J; Cats, Annemieke; Schellens, Jan H M

    2016-06-01

    The objective of this study was to determine whether genotyping of MIR27A polymorphisms rs895819A>G and rs11671784C>T can be used to improve the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine-associated toxicity (FP-toxicity). Patients treated previously in a prospective study with fluoropyrimidine-based chemotherapy were genotyped for rs895819 and rs11671784, and DPYD c.2846A>T, c.1679T>G, c.1129-5923C>G and c.1601G>A. The predictive value of MIR27A variants for early-onset grade ≥3 FP-toxicity, alone or in combination with DPYD variants, was tested in multivariable logistic regression models. Random-effects meta-analysis was performed, including previously published data. A total of 1,592 patients were included. Allele frequencies of rs895819 and rs11671784 were 0.331 and 0.020, respectively. In DPYD wild-type patients, MIR27A variants did not affect risk of FP-toxicity (OR 1.3 for ≥1 variant MIR27A allele vs. none, 95% CI: 0.87-1.82, p = 0.228). In contrast, in patients carrying DPYD variants, the presence of ≥1 rs895819 variant allele was associated with increased risk of FP-toxicity (OR 4.9, 95% CI: 1.24-19.7, p = 0.023). Rs11671784 was not associated with FP-toxicity (OR 2.9, 95% CI: 0.47-18.0, p = 0.253). Patients carrying a DPYD variant and rs895819 were at increased risk of FP-toxicity compared to patients wild type for rs895819 and DPYD (OR 2.4, 95% CI: 1.27-4.37, p = 0.007), while patients with a DPYD variant but without a MIR27A variant were not (OR 0.3 95% CI: 0.06-1.17, p = 0.081). In meta-analysis, rs895819 remained significantly associated with FP-toxicity in DPYD variant allele carriers, OR 5.4 (95% CI: 1.83-15.7, p = 0.002). This study demonstrates the clinical validity of combined MIR27A/DPYD screening to identify patients at risk of severe FP-toxicity. © 2016 UICC.

  12. Healthy Dietary Patterns and Risk of Mortality and ESRD in CKD: A Meta-Analysis of Cohort Studies.

    Science.gov (United States)

    Kelly, Jaimon T; Palmer, Suetonia C; Wai, Shu Ning; Ruospo, Marinella; Carrero, Juan-Jesus; Campbell, Katrina L; Strippoli, Giovanni F M

    2017-02-07

    Patients with CKD are advised to follow dietary recommendations that restrict individual nutrients. Emerging evidence indicates overall eating patterns may better predict clinical outcomes, however, current data on dietary patterns in kidney disease are limited. This systematic review aimed to evaluate the association between dietary patterns and mortality or ESRD among adults with CKD. Medline, Embase, and reference lists were systematically searched up to November 24, 2015 by two independent review authors. Eligible studies were longitudinal cohort studies reporting the association of dietary patterns with mortality, cardiovascular events, or ESRD. A total of seven studies involving 15,285 participants were included. Healthy dietary patterns were generally higher in fruit and vegetables, fish, legumes, cereals, whole grains, and fiber, and lower in red meat, salt, and refined sugars. In six studies, healthy dietary patterns were consistently associated with lower mortality (3983 events; adjusted relative risk, 0.73; 95% confidence interval, 0.63 to 0.83; risk difference of 46 fewer (29-63 fewer) events per 1000 people over 5 years). There was no statistically significant association between healthy dietary patterns and risk of ESRD (1027 events; adjusted relative risk, 1.04; 95% confidence interval, 0.68 to 1.40). Healthy dietary patterns are associated with lower mortality in people with kidney disease. Interventions to support adherence to increased fruit and vegetable, fish, legume, whole grain, and fiber intake, and reduced red meat, sodium, and refined sugar intake could be effective tools to lower mortality in people with kidney disease. Copyright © 2017 by the American Society of Nephrology.

  13. Outcomes of patients with end-stage renal disease (ESRD) under chronic hemodialysis requiring continuous renal replacement therapy (CRRT) and patients without ESRD in acute kidney injury requiring CRRT: a single-center study.

    Science.gov (United States)

    Jung, Yeon Soon; Lee, Junseop; Shin, Ho Sik; Rim, Hark

    2012-10-01

    In most continuous renal replacement therapy (CRRT) studies, end-stage renal disease (ESRD) patients were excluded and the outcomes of patients with ESRD treated with chronic hemodialysis (HD) were unknown. The purposes of this study were to (1) evaluate short-term patient survival and (2) compare the survival of conventional HD patients needing CRRT with the survival of non-ESRD patients in acute kidney injury (AKI) requiring CRRT. We evaluated adults (>18 years) requiring CRRT who were treated in the intensive care unit (ICU) at Kosin University Gospel Hospital from January 1, 2009 to December 31, 2010. A total of 100 (24 ESRD, 76 non-ESRD) patients underwent CRRT during the study period. Patients were divided into two major groups: patients with ESRD requiring chronic dialysis and patients without ESRD (non-ESRD) with AKI. We compared the survival of conventional HD patients requiring CRRT with the survival of non-ESRD patients in AKI requiring CRRT. For non-ESRD patients, the 90-day survival rate was 41.6%. For ESRD patients, the 90-day survival rate was 55.3%. Multivariate Cox proportional hazards analyses demonstrated that conventional HD was not a significant predictor of mortality (hazard ratio [HR]: 0.334, 95% confidence interval [CI]: 0.063-1.763, P = 0.196), after adjustment for age, gender, presence of sepsis, APACHE score, use of vasoactive drugs, number of organ failures, ultrafiltration rate, and arterial pH. The survival rates of non-ESRD and ESRD patients requiring CRRT did not differ; ESRD with conventional HD patients may be not a significant predictor of mortality. © 2012 The Authors. Hemodialysis International © 2012 International Society for Hemodialysis.

  14. Heritability of Risk for Sudden Cardiac Arrest in ESRD.

    Science.gov (United States)

    Chan, Kevin E; Newton-Cheh, Christopher; Gusella, James F; Maddux, Franklin W

    2015-11-01

    Patients on dialysis are 20 times more likely to have a cardiac arrest compared with the general population. We considered whether inherited factors associate with cardiac arrest among patients on dialysis. From a sample of 647,457 patients on chronic dialysis, we identified 5117 pairs of patients who came from the same family. These patients were each matched to a control subject from the same population. McNemar's tests were used to compare the risk of cardiac arrest between the familial related and unrelated pairs. Genetically related family members who did not cohabitate had an odds ratio of 1.88 (95% confidence interval [95% CI], 1.25 to 2.84) for cardiac arrest compared with their phenotypically matched unrelated controls. Genetically related family members who lived together in the same environment had an odds ratio of 1.66 (95% CI, 1.20 to 2.28). Spouses, who are genetically unrelated but live together in the same environment, had an odds ratio of 0.95 (95% CI, 0.60 to 1.59) for cardiac arrest. The risk of cardiac arrest in patients on dialysis may be attributable to inherited factors. Additional studies are needed to identify such candidate genes that modify cardiovascular risk in ESRD. Copyright © 2015 by the American Society of Nephrology.

  15. Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children

    NARCIS (Netherlands)

    Visscher, H.; Ross, C. J. D.; Rassekh, S. R.; Sandor, G. S. S.; Caron, H. N.; van Dalen, E. C.; Kremer, L. C.; van der Pal, H. J.; Rogers, P. C.; Rieder, M. J.; Carleton, B. C.; Hayden, M. R.; Hayden, Michael; Carleton, Bruce; Ross, Colin; MacLeod, Stuart; Wasserman, Wyeth; Mitton, Craig; Smith, Anne; Hildebrand, Claudette; Pastrana, Lucila Castro; Ghannadan, Reza; Rassekh, Rod; Lim, Jonathan; Carter, Catherine; Miao, Fudan; Visscher, Henk; Pussegoda, Kusala; Higginson, Michelle; Butland, Stefanie; Yazdanpanah, Mojgan; Nijssen-Jordan, Cheri; Johnson, David; Verbeek, Linda; Kaczowka, Rick; Stevenson, Patti; Grundy, Paul; Stobart, Kent; Wilson, Bev; Desai, Sunil; Spavor, Maria; Churcher, Linda; Chow, Terence; Hall, Kevin; Honcharik, Nick; Israels, Sara; Chan, Shanna; Garnham, Byron; Staub, Michelle; Rieder, Michael; Malkin, Becky; Portwine, Carol; Cranston, Amy; Koren, Gideon; Ito, Shinya; Nathan, Paul; Greenberg, Mark; Bournissen, Facundo Garcia; Inoue, Miho; Sakaguchi, Sachi; Tanaka, Toshihiro; Fujii, Hisaki; Ogawa, Mina; Ingram, Ryoko; Kamiya, Taro; Karande, Smita; Silva, Mariana; Willing, Stephanie; Vaillancourt, Régis; Elliott-Miller, Pat; Johnston, Donna; Mankoo, Herpreet; Wong, Elaine; Wilson, Brenda; O'Connor, Lauren; Maher, Maurica; Bussières, Jean-Francois; Lebel, Denis; Barret, Pierre; Closon, Aurélie; Dubé, Marie-Pierre; Phillips, Michael; Jabado, Nada; Santo, Anelise Espirito; Nagy, Martine; Avard, Denise; Murray, Margaret; Boliver, Darlene; Tiller, Marilyn

    2013-01-01

    The use of anthracyclines as effective antineoplastic drugs is limited by the occurrence of cardiotoxicity. Multiple genetic variants predictive of anthracycline-induced cardiotoxicity (ACT) in children were recently identified. The current study was aimed to assess replication of these findings in

  16. The contribution of a 9p21.3 variant, a KIF6 variant, and C-reactive protein to predicting risk of myocardial infarction in a prospective study

    Directory of Open Access Journals (Sweden)

    Tracy Russell P

    2011-03-01

    Full Text Available Abstract Background Genetic risk factors might improve prediction of coronary events. Several variants at chromosome 9p21.3 have been widely reported to be associated with coronary heart disease (CHD in prospective and case-control studies. A variant of KIF6 (719Arg has also been reported to be associated with increased risk of CHD in large prospective studies, but not in case-control studies. We asked whether the addition of genetic information (the 9p21.3 or KIF6 variants or a well-established non-genetic risk factor (C-reactive protein [CRP] can improve risk prediction by the Framingham Risk Score (FRS in the Cardiovascular Health Study (CHS--a prospective observational study of risk factors for cardiovascular disease among > 5,000 participants aged 65 or older. Methods Improvement of risk prediction was assessed by change in the area under the receiver-operator characteristic curve (AUC and by net reclassification improvement (NRI. Results Among white participants the FRS was improved by addition of KIF6 719Arg carrier status among men as assessed by the AUC (from 0.581 to 0.596, P = 0.03 but not by NRI (NRI = 0.027, P = 0.32. Adding both CRP and 719Arg carrier status to the FRS improved risk prediction by the AUC (0.608, P = 0.02 and NRI (0.093, P = 0.008 in men, but not women (P ≥ 0.24. Conclusions While none of these risk markers individually or in combination improved risk prediction among women, a combination of KIF6 719Arg carrier status and CRP levels modestly improved risk prediction among white men; although this improvement is not significant after multiple-testing correction. These observations should be investigated in other prospective studies.

  17. Functional promoter variant in zinc finger protein 202 predicts severe atherosclerosis and ischemic heart disease

    DEFF Research Database (Denmark)

    Frikke-Schmidt, R.; Nordestgaard, Børge; Grande, Peer

    2008-01-01

    association with IHD in 10,431 individuals from the Danish general population, the CCHS ( Copenhagen City Heart Study), including 1,511 incident IHD events during 28 years of follow-up. Results were verified in 2 independent case-control studies including, respectively, 942 and 1,549 cases with IHD and 8......Objectives This study was designed to test the hypotheses that single nucleotide polymorphisms ( SNPs), in zinc finger protein 202 ( ZNF202), predict severe atherosclerosis and ischemic heart disease ( IHD). Background ZNF202 is a transcriptional repressor controlling promoter elements in genes...... involved in vascular maintenance and lipid metabolism. Methods We first determined genotype association for 9 ZNF202 SNPs with severe atherosclerosis ( ankle brachial index >0.7 vs.

  18. A Matter of Choice: Opportunities and Obstacles Facing People with ESRD.

    Science.gov (United States)

    Feder, Judith; Nadel, Mark V; Krishnan, Mahesh

    2016-03-07

    Kidney failure is an overwhelming, life-shattering event, but patients with ESRD do not see themselves as being at the end stage of their lives. On the contrary, patients opting for kidney dialysis are choosing to live. Ideally, then, public policy would support patients' choices about how to live-specifically, the choice to continue working. Many patients with ESRD faced with the limitations of their health status and the demands of their treatment understandably choose to leave their jobs, a choice that is facilitated by the availability of public disability and health insurance. However, other patients who have the desire and opportunity to continue working may not get the guidance and support that can actually make their employment possible. Specifically, current disability and health insurance may fail to provide timely treatment and employment counseling to help patients with ESRD remain in their jobs. We, therefore, propose that the Center for Medicare and Medicaid Services support ESRD Networks to initiate more timely employment and treatment counseling in both the ESRD and the late-stage pre-ESRD setting. Although it is too late to require such counseling in the new network scope of work for 2016-2020, active experimentation in the next few years can lay the groundwork for a subsequent contract. Copyright © 2016 by the American Society of Nephrology.

  19. The relationship between epicardial adipose tissue and malnutrition, inflammation, atherosclerosis/calcification syndrome in ESRD patients.

    Science.gov (United States)

    Turkmen, Kultigin; Kayikcioglu, Hatice; Ozbek, Orhan; Solak, Yalcin; Kayrak, Mehmet; Samur, Cigdem; Anil, Melih; Zeki Tonbul, Halil

    2011-08-01

    Malnutrition, inflammation, atherosclerosis/calcification (MIAC) and endothelial dysfunction are the most commonly encountered risk factors in the pathogenesis of cardiovascular disease in ESRD patients. Epicardial adipose tissue (EAT) is the true visceral fat depot of the heart. The relationship between CAD and EAT was shown in patients with high risk of coronary artery disease. In this study, we aimed to investigate the relationship between EAT and MIAC syndrome in ESRD patients. Eighty ESRD patients and 27 healthy subjects enrolled in this cross-sectional study. EAT and coronary artery calcification score were measured by a multidetector computed tomography (MDCT) scanner. Patients with serum albumin 10 ng/dl (normal range, 0-5 ng/dl) had inflammation; and those with CACS >10 had atheroscleosis/calcification. Total CACS and EAT measurements were significantly higher in ESRD patients when compared with healthy subjects. There was a statistically significant relationship between EAT and CACS in ESRD patients (r = 0.48). EAT measurements were higher in PD patients than HD patients. Twenty-four of the patients had no component, 31 had one component, 17 had two components, and nine had all of the MIAC components. EAT was found to be significantly increased when the presence of MIAC components increased. EAT was positively correlated with age, body mass index, and presence of MIAC. These parameters were also found as independent predictors of increased EAT. We found a relationship between EAT and components of MIAC syndrome in ESRD patients.

  20. Added value of soluble tumor necrosis factor-α receptor 1 as a biomarker of ESRD risk in patients with type 1 diabetes.

    Science.gov (United States)

    Forsblom, Carol; Moran, John; Harjutsalo, Valma; Loughman, Tony; Wadén, Johan; Tolonen, Nina; Thorn, Lena; Saraheimo, Markku; Gordin, Daniel; Groop, Per-Henrik; Thomas, Merlin C

    2014-08-01

    Recent studies have suggested that circulating levels of the tumor necrosis factor-α receptor 1 (sTNFαR1) may be a useful predictor for the risk of end-stage renal disease (ESRD) in patients with diabetes. However, its potential utility as a biomarker has not been formally quantified. Circulating levels of sTNFαR1 were assessed in 429 patients with type 1 diabetes and overt nephropathy from the Finnish Diabetic Nephropathy (FinnDiane) cohort study. Predictors of incident ESRD over a median of 9.4 years of follow-up were determined by Cox regression and Fine-Gray competing risk analyses. The added value of sTNFαR1 was estimated via time-dependent receiver operating characteristic curves, net reclassification index (NRI), and integrated discrimination improvement (IDI) for survival data. A total of 130 individuals developed ESRD (28%; ESRD incidence rate of 3.4% per year). In cause-specific modeling, after adjusting for baseline renal status, predictors of increased incidence of ESRD in patients with overt nephropathy were an elevated HbA1c, shorter duration of diabetes, and circulating levels of sTNFαR1. Notably, sTNFαR1 outperformed estimated glomerular filtration rate in terms of R(2). Circulating levels of the sTNFαR1 also remained associated with ESRD after adjusting for the competing risk of death. A prediction model including sTNFαR1 (as a -0.5 fractional polynomial) was superior to a model without it, as demonstrated by better global fit, an increment of R(2), the C index, and area under the curve. Estimates of IDI and NRI(>0) were 0.22 (95% CI 0.16-0.28; P added value as a biomarker, based on the absolute values of NRI and IDI. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  1. Using multiple linear regression and physicochemical changes of amino acid mutations to predict antigenic variants of influenza A/H3N2 viruses.

    Science.gov (United States)

    Cui, Haibo; Wei, Xiaomei; Huang, Yu; Hu, Bin; Fang, Yaping; Wang, Jia

    2014-01-01

    Among human influenza viruses, strain A/H3N2 accounts for over a quarter of a million deaths annually. Antigenic variants of these viruses often render current vaccinations ineffective and lead to repeated infections. In this study, a computational model was developed to predict antigenic variants of the A/H3N2 strain. First, 18 critical antigenic amino acids in the hemagglutinin (HA) protein were recognized using a scoring method combining phi (ϕ) coefficient and information entropy. Next, a prediction model was developed by integrating multiple linear regression method with eight types of physicochemical changes in critical amino acid positions. When compared to other three known models, our prediction model achieved the best performance not only on the training dataset but also on the commonly-used testing dataset composed of 31878 antigenic relationships of the H3N2 influenza virus.

  2. A variant in the KCNQ1 gene predicts future type 2 diabetes and mediates impaired insulin secretion

    DEFF Research Database (Denmark)

    Jonsson, Anna Elisabet; Isomaa, Bo; Tuomi, Tiinamaija

    2009-01-01

    Two independent genome-wide association studies for type 2 diabetes in Japanese subjects have recently identified common variants in the KCNQ1 gene that are strongly associated with type 2 diabetes. Here we studied whether a common variant in KCNQ1 would influence BMI as well as insulin secretion...

  3. Family Aggregation and Heritability of ESRD in Taiwan: A Population-Based Study.

    Science.gov (United States)

    Wu, Hsin Hsu; Kuo, Chang Fu; Li, I Jung; Weng, Cheng Hao; Lee, Cheng Chia; Tu, Kun Hua; Liu, Shou Hsuan; Chen, Yung Chang; Yang, Chih Wei; Luo, Shue Fen; See, Lai Chu; Yu, Kuang Hui; Huang, Lu Hsiang; Zhang, Weiya; Doherty, Michael; Tian, Ya Chung

    2017-11-01

    Aggregation of end-stage renal disease (ESRD) has been observed in families of European origin, as well as those of African origin. However, it is not well documented if this disease aggregates in Asian families. Furthermore, the contribution of genetic factors and shared environmental factors to family aggregation remains unclear. Population-based cross-sectional cohort study. All 23,422,955 individuals registered in the Taiwan National Health Insurance Research Database in 2013. Among these, 47.45%, 57.45%, 47.29%, and 1.51% had a known parent, child, sibling, or twin, respectively. We identified 87,849 patients who had a diagnosis of ESRD. Family history of ESRD. ESRD and heritability defined as the proportion of phenotypic variance attributable to genetic factors. Having an affected first-degree relative with ESRD was associated with an adjusted relative risk of 2.46 (95% CI, 2.32-2.62). Relative risks were 96.38 (95% CI, 48.3-192.34) for twins of patients with ESRD, 2.15 (95% CI, 2.02-2.29) for parents, 2.78 (95% CI, 2.53-3.05) for offspring, 4.96 (95% CI, 4.19-5.88) for siblings, and 1.66 (95% CI, 1.54-1.78) for spouses without genetic similarities. Heritability in this study was 31.1% to 11.4% for shared environmental factors and 57.5% for nonshared environmental factors. This was a registry database study and we did not have detailed information about clinical findings or the definite causes of ESRD. This whole population-based family study in Asia confirmed, in a Taiwanese population, that a family history of ESRD is a strong risk factor for this disease. Moderate heritability was noted and environmental factors were related to disease. Family history of ESRD is an important piece of clinical information. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  4. How the ESRD quality incentive program could potentially improve quality of life for patients on dialysis.

    Science.gov (United States)

    Moss, Alvin H; Davison, Sara N

    2015-05-07

    For over 20 years, the quality of medical care of the Medicare ESRD Program has been a concern. The Centers for Medicare and Medicaid Services have implemented the ESRD Quality Incentive Program, which uses the principles of value-based purchasing; dialysis providers are paid for performance on predefined quality measures, with a goal of improving patient outcomes and the quality of patient care. The ESRD Quality Incentive Program measures have been criticized, because they are largely disease oriented and use easy-to-obtain laboratory-based indicators, such as Kt/V and hemoglobin, that do not reflect outcomes that are most important to patients and have had a minimal effect on survival or quality of life. A key goal of improving quality of care is to enhance quality of life, a patient-important quality measure that matters more to many patients than even survival. None of the ESRD Quality Incentive Program measures assess patient-reported quality of life. As outlined in the National Quality Strategy, the Centers for Medicare and Medicaid Services are holding providers accountable in six priority domains, in which quality measures have been and are being developed for value-based purchasing. Three measures-patient experience and engagement, clinical care, and care coordination-are particularly relevant to quality care in the ESRD Program; the 2014 ESRD Quality Incentive Program includes six measures, none of which provide data from a patient-centered perspective. Value-based purchasing is a well intentioned step to improve care of patients on dialysis. However, the Centers for Medicare and Medicaid Services need to implement significant change in what is measured for the ESRD Quality Incentive Program to be patient centered and aligned with patients' values, preferences, and needs. This paper provides examples of potential quality measures for patient experience and engagement, clinical care, and care coordination, which if implemented, would be much more likely to

  5. Genetic variants and their interactions in the prediction of increased pre-clinical carotid atherosclerosis: the cardiovascular risk in young Finns study.

    Directory of Open Access Journals (Sweden)

    Sebastian Okser

    2010-09-01

    Full Text Available The relative contribution of genetic risk factors to the progression of subclinical atherosclerosis is poorly understood. It is likely that multiple variants are implicated in the development of atherosclerosis, but the subtle genotypic and phenotypic differences are beyond the reach of the conventional case-control designs and the statistical significance testing procedures being used in most association studies. Our objective here was to investigate whether an alternative approach--in which common disorders are treated as quantitative phenotypes that are continuously distributed over a population--can reveal predictive insights into the early atherosclerosis, as assessed using ultrasound imaging-based quantitative measurement of carotid artery intima-media thickness (IMT. Using our population-based follow-up study of atherosclerosis precursors as a basis for sampling subjects with gradually increasing IMT levels, we searched for such subsets of genetic variants and their interactions that are the most predictive of the various risk classes, rather than using exclusively those variants meeting a stringent level of statistical significance. The area under the receiver operating characteristic curve (AUC was used to evaluate the predictive value of the variants, and cross-validation was used to assess how well the predictive models will generalize to other subsets of subjects. By means of our predictive modeling framework with machine learning-based SNP selection, we could improve the prediction of the extreme classes of atherosclerosis risk and progression over a 6-year period (average AUC 0.844 and 0.761, compared to that of using conventional cardiovascular risk factors alone (average AUC 0.741 and 0.629, or when combined with the statistically significant variants (average AUC 0.762 and 0.651. The predictive accuracy remained relatively high in an independent validation set of subjects (average decrease of 0.043. These results demonstrate

  6. Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD.

    Science.gov (United States)

    Böger, Carsten A; Gorski, Mathias; Li, Man; Hoffmann, Michael M; Huang, Chunmei; Yang, Qiong; Teumer, Alexander; Krane, Vera; O'Seaghdha, Conall M; Kutalik, Zoltán; Wichmann, H-Erich; Haak, Thomas; Boes, Eva; Coassin, Stefan; Coresh, Josef; Kollerits, Barbara; Haun, Margot; Paulweber, Bernhard; Köttgen, Anna; Li, Guo; Shlipak, Michael G; Powe, Neil; Hwang, Shih-Jen; Dehghan, Abbas; Rivadeneira, Fernando; Uitterlinden, André; Hofman, Albert; Beckmann, Jacques S; Krämer, Bernhard K; Witteman, Jacqueline; Bochud, Murielle; Siscovick, David; Rettig, Rainer; Kronenberg, Florian; Wanner, Christoph; Thadhani, Ravi I; Heid, Iris M; Fox, Caroline S; Kao, W H

    2011-09-01

    Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

  7. RPA/ASN position on the use of disease management in ESRD care.

    Science.gov (United States)

    2002-02-01

    The care of patients with chronic renal insufficiency and ESRD is at a major crossroad, and there is considerable uncertainty about the future. There are substantial risks for both the patients and the caregivers as well as opportunities to improve patient care and the milieu in which the care is provided. The treatment of ESRD and chronic renal insufficiency is moving into an era of collaborative care with RCMs, physician assistants, and advanced practice nurses predicated in large part on the anticipated shortage of nephrologists as the ESRD patient population continues to increase. The future of reimbursement is uncertain and payers may well have difficulty responding to new models of providing care. It is imperative that nephrologists accept the challenge and assume the leadership role as disease management and other collaborative methodologies of caring for our patients develop.

  8. Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD.

    Directory of Open Access Journals (Sweden)

    Carsten A Böger

    2011-09-01

    Full Text Available Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD and end stage renal disease (ESRD. Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m(2 at follow-up and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls. SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1. SNPs in UMOD (OR = 0.92, p = 0.04 and GCKR (OR = 0.93, p = 0.03 were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

  9. Use of Oral Anticoagulation in the Management of Atrial Fibrillation in Patients with ESRD: Pro

    Science.gov (United States)

    Ball, Timothy; Cox, Katy Mathews; Assar, Manish D.

    2016-01-01

    Warfarin has had a thin margin of benefit over risk for the prevention of stroke and systemic embolism in patients with ESRD because of higher bleeding risks and complications of therapy. The successful use of warfarin has been dependent on the selection of patients with nonvalvular atrial fibrillation at relatively high risk of stroke and systemic embolism and lower risks of bleeding over the course of therapy. Without such selection strategies, broad use of warfarin has not proven to be beneficial to the broad population of patients with ESRD and nonvalvular atrial fibrillation. In a recent meta-analysis of use of warfarin in patients with nonvalvular atrial fibrillation and ESRD, warfarin had no effect on the risks of stroke (hazard ratio, 1.12; 95% confidence interval, 0.69 to 1.82; P=0.65) or mortality (hazard ratio, 0.96; 95% confidence interval, 0.81 to 1.13; P=0.60) but was associated with increased risk of major bleeding (hazard ratio, 1.30; 95% confidence interval, 1.08 to 1.56; P<0.01). In pivotal trials, novel oral anticoagulants were generally at least equal to warfarin for efficacy and safety in nonvalvular atrial fibrillation and mild to moderate renal impairment. Clinical data for ESRD are limited, because pivotal trials excluded such patients. Given the very high risk of stroke and systemic embolism and the early evidence of acceptable safety profiles of novel oral anticoagulants, we think that patients with ESRD should be considered for treatment with chronic anticoagulation provided that there is an acceptable bleeding profile. Apixaban is currently indicated in ESRD for this application and may be preferable to warfarin given the body of evidence for warfarin and its difficulty of use and attendant adverse events. PMID:27797888

  10. Association of hepatitis C virus infection with risk of ESRD: a population-based study.

    Science.gov (United States)

    Su, Fu-Hsiung; Su, Chien-Tien; Chang, Shih-Ni; Chen, Pei-Chun; Sung, Fung-Chang; Lin, Cheng-Chieh; Yeh, Chih-Ching

    2012-10-01

    The association between chronic hepatitis C virus (HCV) infection and end-stage renal disease (ESRD) has been widely debated. National population-based cohort study. Insurance claims data from the Taiwan National Health Insurance Research Database in 2000-2005. Chronic HCV infection as defined by the International Classification of Diseases, Ninth Revision, Clinical Modification. ESRD as defined by the International Classification of Diseases, Ninth Revision, Clinical Modification. We identified 6,291 adults with chronic HCV infection. The control group included 31,455 sex- and age-matched individuals without evidence of chronic hepatitis. The incidence of ESRD was 2.14-fold higher in patients with chronic HCV infection (HR, 1.53; 95% CI, 1.17-2.01; P = 0.002) than in patients without HCV infection. Age stratification analysis showed that patients aged 50-59 years with chronic HCV infection (HR, 7.77; 95% CI, 4.23-14.3; P < 0.001) had the highest risk of developing ESRD relative to patients aged 20-49 years without chronic HCV infection (interaction P < 0.001). Lack of clinical data. Patients with chronic HCV infection are at greater risk of developing ESRD than individuals without chronic HCV infection. In addition, the risk of developing ESRD is highest in younger patients with HCV infection. Early renal screening programs should be initiated for this high-risk group of young individuals with chronic HCV infection. Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  11. 42 CFR 413.210 - Conditions for payment under the end-stage renal disease (ESRD) prospective payment system.

    Science.gov (United States)

    2010-10-01

    ... REIMBURSEMENT; PAYMENT FOR END-STAGE RENAL DISEASE SERVICES; OPTIONAL PROSPECTIVELY DETERMINED PAYMENT RATES FOR SKILLED NURSING FACILITIES Payment for End-Stage Renal Disease (ESRD) Services and Organ Procurement Costs § 413.210 Conditions for payment under the end-stage renal disease (ESRD) prospective payment system...

  12. A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

    NARCIS (Netherlands)

    Bergman, Jorieke E. H.; Janssen, Nicole; van der Sloot, Almer M.; de Walle, Hermien E. K.; Schoots, Jeroen; Rendtorff, Nanna D.; Tranebjaerg, Lisbeth; Hoefsloot, Lies H.; van Ravenswaaij-Arts, Conny M. A.; Hofstra, Robert M. W.

    CHARGE syndrome is characterized by the variable occurrence of multisensory impairment, congenital anomalies, and developmental delay, and is caused by heterozygous mutations in the CHD7 gene. Correct interpretation of CHD7 variants is essential for genetic counseling. This is particularly difficult

  13. ACE I/D sequence variants but not MTHFR C677T, is strongly linked to malignant glioma risk and its variant DD genotype may act as a promising predictive biomarker for overall survival of glioma patients.

    Science.gov (United States)

    Pandith, Arshad A; Qasim, Iqbal; Zahoor, Wani; Shah, Parveen; Bhat, Abdul R

    2018-01-10

    ACE I/D and MTHFR C677T gene polymorphisms can be seen as candidate genes for glioma on the basis of their biological functions and their involvement in different cancers. The aim of this study was to analyze potential association and overall survival between MTHFR C677T and ACE I/D polymorphism in glioma patients in our population. We tested genotype distribution of 112 glioma patients against 141 cancer-free controls from the same region. Kaplan-Meier survival analysis was performed to evaluate overall survival of patients for both genes. No significant differences were found among MTHFR C677T wild type C and variant genotypes CT/TT with glioma patients. In ACE, the distribution of variant ID and DD was found to be significantly higher in glioma cases as compared to controls (pDD genotypes were highly presented in glioma cases 26.8% versus 10.6% in controls (pDD genotypes had the least estimated overall survival of 13.4months in comparison to 21. 7 and 17.6months for ACE II and I/D genotypes respectively. We conclude ACE I/D polymorphism plays a vital role in predisposition of higher risk for glioma. We also suggest that ACE DD genotypes may act as an important predictive biomarker for overall survival of glioma patients. Copyright © 2017. Published by Elsevier B.V.

  14. 77 FR 34047 - Medicare Program; Proposal Evaluation Criteria and Standards for End Stage Renal Disease (ESRD...

    Science.gov (United States)

    2012-06-08

    ... reports to CMS and the Secretary. More detailed information for each Aim, Domain, and sub-domain can be... domains will achieve Aim 1. Network patient-centered domains are Patient and Family Engagement; Patient... access to ESRD care through a Population Health Innovation Pilot Project in one of the following areas...

  15. The pattern, clinical characteristics and outcome of ESRD in Ile-Ife ...

    African Journals Online (AJOL)

    Background: The prevalence of chronic renal failure and End Stage Renal Disease (ESRD) has remained high worldwide and the epidemiology has changed significantly in the last decade in industrialised countries. While there have been significant improvements in these patient's outcomes in developed countries, their ...

  16. Accumulation of Advanced Glycation End Products and Chronic Complications in ESRD Treated by Dialysis

    NARCIS (Netherlands)

    Meerwaldt, Robbert; Zeebregts, Clark J.; Navis, Gerjan; Hillebrands, Jan-Luuk; Lefrandt, Joop D.; Smit, Andries J.

    Cardiovascular and connective tissue disorders are very common in patients with end-stage renal disease (ESRD), and the accumulation of advanced glycation end products (AGEs) is significantly increased in these patients. Accumulation of AGEs is believed to have a role in tissue protein aging and the

  17. Urgent-Start Peritoneal Dialysis and Hemodialysis in ESRD Patients: Complications and Outcomes

    National Research Council Canada - National Science Library

    Jin, Haijiao; Fang, Wei; Zhu, Mingli; Yu, Zanzhe; Fang, Yan; Yan, Hao; Zhang, Minfang; Wang, Qin; Che, Xiajing; Xie, Yuanyuan; Huang, Jiaying; Hu, Chunhua; Zhang, Haifen; Mou, Shan; Ni, Zhaohui

    2016-01-01

    ...) is a feasible alternative to hemodialysis (HD) in patients with end-stage renal disease (ESRD), but the impact of the dialysis modality on outcome, especially on short-term complications, in urgent-start dialysis has not been directly evaluated...

  18. Illness and treatment perceptions of ESRD patients: different stages, different perceptions?

    NARCIS (Netherlands)

    Heijmans, M.; Jansen, D.; Rijken, M.; Grootendorst, D.; Dekker, F.; Boeschoten, E.; Kaptein, A.A.

    2009-01-01

    This study aims to assess illness and treatment perceptions of patients with ESRD in different stages of the treatment process and to examine changes in these perceptions over time. Pre-dialysis patients (n=109), patients up to three years on dialysis (n=69) and patients longer than three years on

  19. Clinical predictors of decline in nutritional parameters over time in ESRD

    NARCIS (Netherlands)

    C.H. den Hoedt (Claire); M.L. Bots (Michiel); M.P.C. Grooteman (Muriel); N.C. van der Weerd (Neelke); E.L. Penne (Lars); A.H.A. Mazairac (Albert); R. Lévesque (Renée); P.J. Blankestijn (Peter); M.J. Nubé (Menso); P.M. ter Wee (Piet); M.A. van den Dorpel (Marinus)

    2014-01-01

    textabstractBackground and objectives: Inflammation and malnutrition are important features in patients with ESRD; however, data on changes in these parameters over time are scarce. This study aimed to gain insight into changes over time in serum albumin, body mass index, high-sensitivity C-reactive

  20. Clinical predictors of decline in nutritional parameters over time in ESRD

    NARCIS (Netherlands)

    Hoedt, C.H. den; Bots, M.L.; Grooteman, M.P.C.; Weerd, N.C. van der; Penne, E.L.; Mazairac, A.H.; Levesque, R.; Blankestijn, P.J.; Nube, M.J.; Wee, P.M. ter; Dorpel, M.A. van den; Dorval, M.; Lévesque, R.; Koopman, M.G.; Konings, C.J.; Haanstra, W.P.; Kooistra, M.; Jaarsveld, B. van; Noordzij, T.; Peltenburg, H.G.; Buren, M. van; Offerman, J.J.; Hoogeveen, E.K.; Heer, F. de; Ven, P.J. van der; Hovinga, T.K.; Bax, W.A.; Groeneveld, J.O.; Lavrijssen, A.T.; Schrander-van der Meer, A.M.; Reichert, L.J.; Huussen, J.; Rensma, P.L.; Schrama, Y.; Hamersvelt, H.W. van; Boer, W.H.; Kuijk, W.H.; Vervloet, M.; Wauters, I.M.; Sekse, I.

    2014-01-01

    BACKGROUND AND OBJECTIVES: Inflammation and malnutrition are important features in patients with ESRD; however, data on changes in these parameters over time are scarce. This study aimed to gain insight into changes over time in serum albumin, body mass index, high-sensitivity C-reactive protein,

  1. Association of eGFR-related loci identified by GWAS with incident CKD and ESRD

    NARCIS (Netherlands)

    C.A. Böger (Carsten); M. Gorski (Mathias); M. Li (Man); M.M. Hoffmann (Michael); C. Huang (Chunmei); Q. Yang (Qiong Fang); A. Teumer (Alexander); V. Krane (Vera); C.M. O'Seaghdha (Conall); Z. Kutalik (Zoltán); H.E. Wichmann (Heinz Erich); T. Haak (Thomas); E. Boes (Eva); S. Coassin (Stefan); J. Coresh (Josef); B. Kollerits (Barbara); M. Haun (Margot); B. Paulweber (Bernhard); A. Köttgen (Anna); M.G. Shlipak (Michael); N. Powe (Neil); S.J. Hwang; A. Dehghan (Abbas); F. Rivadeneira Ramirez (Fernando); A.G. Uitterlinden (André); A. Hofman (Albert); J.S. Beckmann (Jacques); B.K. Krämer (Bernhard); J.C.M. Witteman (Jacqueline); M. Bochud (Murielle); D.S. Siscovick (David); R. Rettig (Rainer); F. Kronenberg (Florian); C. Wanner (Christoph); R.I. Thadhani (Ravi); I.M. Heid (Iris); C.S. Fox (Caroline); W.H.L. Kao (Wen)

    2011-01-01

    textabstractFamily studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident

  2. Burden of end-stage renal disease (ESRD) in Latin America.

    Science.gov (United States)

    Rosa-Diez, Guillermo; Gonzalez-Bedat, María; Ferreiro, Alejandro; García-García, Guillermo; Fernandez-Cean, Juan; Douthat, Walter

    End-stage renal disease (ESRD) represents a major challenge for Latin America (LA). Epidemiological information needed to assist in the development of ESRD care in the region. The Latin American Dialysis and Renal Transplant Registry (RLADTR), has published several reports and its continuity has implied a sustained effort of the entire LA Nephrology community. This paper summarizes the results corresponding to year 2012. Our methods have been reported previously. Participant countries complete an annual survey collecting data on incident and prevalent patients undergoing renal replacement treatment (RRT) in all modalities. 20 countries participated in the surveys, more than 90% of the Latin America. The prevalence of ESRD under RRT in LA increased from 119 patients Per million population (pmp) in 1991 to 661 pmp in 2012. HD continues to be the treatment of choice in the region (82%). A wide rate variation in incidence is observed: from 472.7 in Jalisco (Mexico) to 14 pmp in Guatemala. Diabetes remained the leading cause of ESRD. The most frequent cause of death was cardiovascular. There is a wide rate variation of nephrologist by country, from 1.8 pmp in Honduras to 45.2 pmp in Cuba. The heterogeneity or even absence of registries in some LA countries is congruent with the inequities in access to RRT in such countries, as well as the availability of qualified personnel. The SLANH is currently running training programs as well as cooperation programs between LA countries to help the least developed start ESRD programs. In this spirit, RLADTR is training personnel to carry out dialysis and transplant registries in LA.

  3. Recovery of renal function among ESRD patients in the US medicare program.

    Directory of Open Access Journals (Sweden)

    Sumit Mohan

    Full Text Available BACKGROUND: Patients started on long term hemodialysis have typically had low rates of reported renal recovery with recent estimates ranging from 0.9-2.4% while higher rates of recovery have been reported in cohorts with higher percentages of patients with acute renal failure requiring dialysis. STUDY DESIGN: Our analysis followed approximately 194,000 patients who were initiated on hemodialysis during a 2-year period (2008 & 2009 with CMS-2728 forms submitted to CMS by dialysis facilities, cross-referenced with patient record updates through the end of 2010, and tracked through December 2010 in the CMS SIMS registry. RESULTS: We report a sustained renal recovery (i.e no return to ESRD during the available follow up period rate among Medicare ESRD patients of > 5% - much higher than previously reported. Recovery occurred primarily in the first 2 months post incident dialysis, and was more likely in cases with renal failure secondary to etiologies associated with acute kidney injury. Patients experiencing sustained recovery were markedly less likely than true long-term ESRD patients to have permanent vascular accesses in place at incident hemodialysis, while non-White patients, and patients with any prior nephrology care appeared to have significantly lower rates of renal recovery. We also found widespread geographic variation in the rates of renal recovery across the United States. CONCLUSIONS: Renal recovery rates in the US Medicare ESRD program are higher than previously reported and appear to have significant geographic variation. Patients with diagnoses associated with acute kidney injury who are initiated on long-term hemodialysis have significantly higher rates of renal recovery than the general ESRD population and lower rates of permanent access placement.

  4. TLR4/CD14 Variants-Related Serologic and Immunologic Dys-Regulations Predict Severe Sepsis in Febrile De-Compensated Cirrhotic Patients.

    Directory of Open Access Journals (Sweden)

    Wen-Chien Fan

    Full Text Available Genetic variants and dysfunctional monocyte had been reported to be associated with infection susceptibility in advanced cirrhotic patients. This study aims to explore genetic predictive markers and relevant immune dysfunction that contributed to severe sepsis in febrile acute de-compensated cirrhotic patents. Polymorphism analysis of candidate genes was undergone in 108 febrile acute de-compensated cirrhotic patients and 121 healthy volunteers. Various plasma inflammatory/regulatory cytokines, proportion of classical (CD 16-, phagocytic and non-classical (CD16+, inflammatory monocytes, lipopolysaccharide (LPS-stimulated toll-like receptor 4 (TLR4 and intracellular/extracellular cytokines on cultured non-classical monocytes, mCD14/HLA-DR expression and phagocytosis of classical monocytes were measured. For TLR4+896A/G variant allele carriers with severe sepsis, high plasma endotoxin/IL-10 inhibits HLA-DR expression and impaired phagocytosis were noted in their classical monocyte. In the same group, increased non-classical monocyte subset, enhanced LPS-stimulated TLR4 expression and TNFα/nitrite production, and systemic inflammation [high plasma soluble CD14 (sCD14 and total nitric oxide (NOx levels] were noted. For CD14-159C/T variant allele carriers with severe sepsis, persist endotoxemia inhibited mCD14/HLA-DR expression and impaired phagocytosis of their classical monocyte. In the same group, increased non-classical monocyte subset up-regulated TLR4-NFκB-iNOS and p38MAPK pathway, stimulated TNFα/nitrite production and elicited systemic inflammation. In febrile acute de-compensated cirrhotic patients, TLR4+896A/G and CD14-159C/T polymorphisms-related non-classical and classical monocytes dysfunction resulted in increased severe sepsis risk. Malnutrition, high plasma endotoxin and sCD14 levels, single TLR4+896A/G or CD14-159C/T variant allele carriers and double variant allele carriers are significant predictive factors for the development

  5. A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes.

    Science.gov (United States)

    Belalcazar, L Maria; Papandonatos, George D; McCaffery, Jeanne M; Peter, Inga; Pajewski, Nicholas M; Erar, Bahar; Allred, Nicholette D; Balasubramanyam, Ashok; Bowden, Donald W; Brautbar, Ariel; Pi-Sunyer, F Xavier; Ballantyne, Christie M; Huggins, Gordon S

    2015-06-01

    Overweight/obese individuals with Type 2 diabetes have low adiponectin levels, which may improve with lifestyle changes. We investigated whether genetic variants associated with adiponectin levels in genome-wide association studies (GWAS) would also be related with adiponectin changes in response to an intensive lifestyle intervention (ILI), potentially through mechanisms altering the adipose microenvironment via weight loss and/or improved cardiorespiratory fitness. Look AHEAD was a randomized trial comparing the cardiovascular benefits of ILI-induced weight loss and physical activity compared with diabetes support and education among overweight/obese individuals with Type 2 diabetes. In a subsample of Look AHEAD with adiponectin data and genetic consent (n=1,351), we evaluated the effects of 24 genetic variants, demonstrated by GWAS to be cross-sectionally associated with adiponectin, on adiponectin change 1-yr postintervention. We explored via mediational analyses whether any differential effects by treatment arm were occurring through weight loss and/or improved fitness. A variant, rs222857, in the CLDN7 locus, potentially associated with epithelial barrier integrity and tight junction physiology, and a putative cis expression quantitative trail locus for elongator acetyltransferase complex subunit 5 (ELP5), predicted adiponectin increases within ILI (log-adiponectin in overall sample per copy: β±SE=0.05±0.02, P=0.008; in non-Hispanic whites: 0.06±0.02, P=0.009). The favorable effects of rs222857 (minor allele frequency 45.5%) appeared to be mediated by mechanisms associated with improved fitness, and not weight loss. This is the first study to identify a genetic variant that modifies adiponectin response to lifestyle intervention in overweight/obese diabetic individuals. Copyright © 2015 the American Physiological Society.

  6. Combination Testing Using a Single MSH5 Variant alongside HLA Haplotypes Improves the Sensitivity of Predicting Coeliac Disease Risk in the Polish Population.

    Directory of Open Access Journals (Sweden)

    Agnieszka Paziewska

    Full Text Available Assessment of non-HLA variants alongside standard HLA testing was previously shown to improve the identification of potential coeliac disease (CD patients. We intended to identify new genetic variants associated with CD in the Polish population that would improve CD risk prediction when used alongside HLA haplotype analysis. DNA samples of 336 CD and 264 unrelated healthy controls were used to create DNA pools for a genome wide association study (GWAS. GWAS findings were validated with individual HLA tag single nucleotide polymorphism (SNP typing of 473 patients and 714 healthy controls. Association analysis using four HLA-tagging SNPs showed that, as was found in other populations, positive predicting genotypes (HLA-DQ2.5/DQ2.5, HLA-DQ2.5/DQ2.2, and HLA-DQ2.5/DQ8 were found at higher frequencies in CD patients than in healthy control individuals in the Polish population. Both CD-associated SNPs discovered by GWAS were found in the CD susceptibility region, confirming the previously-determined association of the major histocompatibility (MHC region with CD pathogenesis. The two most significant SNPs from the GWAS were rs9272346 (HLA-dependent; localized within 1 Kb of DQA1 and rs3130484 (HLA-independent; mapped to MSH5. Specificity of CD prediction using the four HLA-tagging SNPs achieved 92.9%, but sensitivity was only 45.5%. However, when a testing combination of the HLA-tagging SNPs and the MSH5 SNP was used, specificity decreased to 80%, and sensitivity increased to 74%. This study confirmed that improvement of CD risk prediction sensitivity could be achieved by including non-HLA SNPs alongside HLA SNPs in genetic testing.

  7. Verification of predicted alternatively spliced Wnt genes reveals two new splice variants (CTNNB1 and LRP5 and altered Axin-1 expression during tumour progression

    Directory of Open Access Journals (Sweden)

    Reich Jens G

    2006-06-01

    Full Text Available Abstract Background Splicing processes might play a major role in carcinogenesis and tumour progression. The Wnt pathway is of crucial relevance for cancer progression. Therefore we focussed on the Wnt/β-catenin signalling pathway in order to validate the expression of sequences predicted as alternatively spliced by bioinformatic methods. Splice variants of its key molecules were selected, which may be critical components for the understanding of colorectal tumour progression and may have the potential to act as biological markers. For some of the Wnt pathway genes the existence of splice variants was either proposed (e.g. β-Catenin and CTNNB1 or described only in non-colon tissues (e.g. GSK3β or hitherto not published (e.g. LRP5. Results Both splice variants – normal and alternative form – of all selected Wnt pathway components were found to be expressed in cell lines as well as in samples derived from tumour, normal and healthy tissues. All splice positions corresponded totally with the bioinformatical prediction as shown by sequencing. Two hitherto not described alternative splice forms (CTNNB1 and LRP5 were detected. Although the underlying EST data used for the bioinformatic analysis suggested a tumour-specific expression neither a qualitative nor a significant quantitative difference between the expression in tumour and healthy tissues was detected. Axin-1 expression was reduced in later stages and in samples from carcinomas forming distant metastases. Conclusion We were first to describe that splice forms of crucial genes of the Wnt-pathway are expressed in human colorectal tissue. Newly described splicefoms were found for β-Catenin, LRP5, GSK3β, Axin-1 and CtBP1. However, the predicted cancer specificity suggested by the origin of the underlying ESTs was neither qualitatively nor significant quantitatively confirmed. That let us to conclude that EST sequence data can give adequate hints for the existence of alternative splicing

  8. American Society of Nephrology Quiz and Questionnaire 2015: ESRD/RRT

    OpenAIRE

    Lok, Charmaine E.; Perazella, Mark A.; Choi, Michael J.

    2016-01-01

    The Nephrology Quiz and Questionnaire remains an extremely popular session for attendees of the Annual Kidney Week Meeting of the American Society of Nephrology. During the 2015 meeting, the conference hall was once again overflowing with eager quiz participants. Topics covered by the experts included electrolyte and acid-base disorders, glomerular disease, ESRD and dialysis, and kidney transplantation. Complex cases representing each of these categories together with single best answer quest...

  9. Long-Term Risk of Cancer in Survivors of Pediatric ESRD.

    Science.gov (United States)

    Ploos van Amstel, Sophie; Vogelzang, Judith L; Starink, Marcus V; Jager, Kitty J; Groothoff, Jaap W

    2015-12-07

    ESRD is associated with an increased risk of malignancies. We analyzed the incidence of cancer in patients with pediatric ESRD after long-term follow-up. All Dutch patients born before 1979 who were transplanted at age Cancer Registry. After a median of 25.3 years (1.3-37.8) of transplantation and at a median age of 33.5 years old (11.0-49.0), 105 primary malignancies had occurred in 54 of 249 patients. Among them, cutaneous squamous cell carcinoma was most frequent. Patients ages 25-30 years old had developed 16.5 times (95% confidence interval, 7.9 to 34.6) as many de novo tumors and 991 times (95% confidence interval, 313 to 3137) as many de novo cutaneous squamous cell carcinomas as their general population counterparts; in survivors ages 45-50 years old, these numbers were 81.5 (95% confidence interval, 50.7 to 131.1) and 2610 (95% confidence interval, 1596 to 4267), respectively. Cumulative incidence competing risk analysis showed that, after 30 years of transplantation, 41% of the survivors had developed cancer; 31% had developed a second de novo cancer cancer diagnosis. Cancer is highly prevalent among patients with pediatric ESRD after 25.3 years of transplantation, with a high rate of recurrence. Copyright © 2015 by the American Society of Nephrology.

  10. The association between dietary sodium intake, ESRD, and all-cause mortality in patients with type 1 diabetes

    National Research Council Canada - National Science Library

    Thomas, Merlin C; Moran, John; Forsblom, Carol; Harjutsalo, Valma; Thorn, Lena; Ahola, Aila; Wadén, Johan; Tolonen, Nina; Saraheimo, Markku; Gordin, Daniel; Groop, Per-Henrik

    2011-01-01

    Many guidelines recommend reduced consumption of salt in patients with type 1 diabetes, but it is unclear whether dietary sodium intake is associated with mortality and end-stage renal disease (ESRD...

  11. The predicted truncation from a cancer-associated variant of the MSH2 initiation codon alters activity of the MSH2-MSH6 mismatch repair complex.

    Science.gov (United States)

    Cyr, Jennifer L; Brown, Graham D; Stroop, Jennifer; Heinen, Christopher D

    2012-08-01

    Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes. MMR recognizes and repairs DNA mismatches and small insertion/deletion loops. Carriers of MMR gene variants have a high risk of developing colorectal, endometrial, ovarian, and other extracolonic carcinomas. We report on an ovarian cancer patient who carries a germline MSH2 c.1A>C variant which alters the translation initiation codon. Mutations affecting the MSH2 start codon have been described previously for LS-related malignancies. However, the patients often lack a clear family history indicative of LS and their tumors often fail to display microsatellite instability, a hallmark feature of LS. Therefore, the pathogenicity of start codon variants remains undefined. Loss of the MSH2 start codon has been predicted to result in a truncated protein translated from a downstream in-frame AUG that would lack the first 25 amino acids. We therefore purified recombinant MSH2(NΔ25)-MSH6 and MSH2(NΔ25)-MSH3 to examine their DNA lesion recognition and adenosine nucleotide processing functions in vitro. We found that the MSH2(NΔ25) mutant confers distinct biochemical defects on MSH2-MSH6, but does not have a significant effect on MSH2-MSH3. We confirmed that expression of the MSH2 c.1A>C cDNA results in the production of multiple protein products in human cells that may include the truncated and full-length forms of MSH2. An in vivo MMR assay revealed a slight reduction in MMR efficiency in these cells. These data suggest that mutation of the MSH2 initiation codon, while not a strong, high-risk disease allele, may have a moderate impact on disease phenotype. Copyright © 2011 Wiley Periodicals, Inc.

  12. In critically ill patients requiring CRRT, AKI is associated with increased respiratory failure and death versus ESRD.

    Science.gov (United States)

    Walcher, Angela; Faubel, Sarah; Keniston, Angela; Dennen, Paula

    2011-01-01

    To compare outcomes of critically ill patients with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) versus those with pre-existing end-stage renal disease (ESRD) requiring CRRT to identify factors that contribute to the increased mortality seen in AKI patients. Retrospective cohort of 257 intensive care unit (ICU) patients who received CRRT. AKI is defined as requiring CRRT with an admission serum creatinine ≤1 mg/dL; ESRD is defined as chronic dialysis dependence. Primary outcome was hospital mortality. Multivariate logistic regression was performed to determine the impact of APACHE II score, intubation, vasopressors, infection, diabetes, hypertension, gender, and race on mortality. Of 257 patients requiring CRRT, 28 had ESRD and 108 had AKI. Hospital mortality was higher in patients with AKI versus ESRD (69% vs. 39%, p = 0.0032). Severity of illness using APACHE II was similar in AKI and ESRD. Patients with AKI were more likely to require mechanical ventilation (89% vs. 57%, p = 0.0003). After multivariate analysis, the requirement for mechanical ventilation was the single factor associated with increased hospital mortality [odds ratio (OR): 3.1]. In ICU patients requiring CRRT, patients with AKI have a higher mortality than patients with ESRD due to an increased need for mechanical ventilation.

  13. Analgesics use and ESRD in younger age: a case-control study

    Directory of Open Access Journals (Sweden)

    Moehner Sabine

    2007-12-01

    Full Text Available Abstract Background An ad hoc peer-review committee was jointly appointed by Drug Authorities and Industry in Germany, Austria and Switzerland in 1999/2000 to review the evidence for a causal relation between phenacetin-free analgesics and nephropathy. The committee found the evidence as inconclusive and requested a new case-control study of adequate design. Methods We performed a population-based case-control study with incident cases of end-stage renal disease (ESRD under the age of 50 years and four age and sex-matched neighborhood controls in 170 dialysis centers (153 in Germany, and 17 in Austria from January 1, 2001 to December 31, 2004. Data on lifetime medical history, risk factors, treatment, job exposure and intake of analgesics were obtained in a standardized face-to-face interview using memory aids to enhance accuracy. Study design, study performance, analysis plan, and study report were approved by an independent international advisory committee and by the Drug Authorities involved. Unconditional logistic regression analyses were performed. Results The analysis included 907 cases and 3,622 controls who had never used phenacetin-containing analgesics in their lifetime. The use of high cumulative lifetime dose (3rd tertile of analgesics in the period up to five years before dialysis was not associated with later ESRD. Adjusted odds ratios with 95% confidence intervals were 0.8 (0.7 – 1.0 and 1.0 (0.8 – 1.3 for ever- compared with no or low use and high use compared with low use, respectively. The same results were found for all analgesics and for mono-, and combination preparations with and without caffeine. No increased risk was shown in analyses stratifying for dose and duration. Dose-response analyses showed that analgesic use was not associated with an increased risk for ESRD up to 3.5 kg cumulative lifetime dose (98 % of the cases with ESRD. While the large subgroup of users with a lifetime dose up to 0.5 kg (278 cases and

  14. Ethnicity and OPRM variant independently predict pain perception and patient-controlled analgesia usage for post-operative pain

    Directory of Open Access Journals (Sweden)

    Tan Ene-choo

    2009-06-01

    Full Text Available Abstract Background Morphine consumption can vary widely between individuals even for identical surgical procedures. As mu-opioid receptor (OPRM1 is known to modulate pain perception and mediate the analgesic effects of opioid compounds in the central nervous system, we examined the influence of two OPRM polymorphisms on acute post-operative pain and morphine usage in women undergoing elective caesarean delivery. Results Data on self-reported pain scores and amount of total morphine use according to patient-controlled analgesia were collected from 994 women from the three main ethnic groups in Singapore. We found statistically significant association of the OPRM 118A>G with self-administered morphine during the first 24-hour postoperative period both in terms of total morphine (p = 1.7 × 10-5 and weight-adjusted morphine (p = 6.6 × 10-5. There was also significant association of this OPRM variant and time-averaged self-rated pain scores (p = 0.024. OPRM 118G homozygotes used more morphine and reported higher pain scores than 118A carriers. Other factors which influenced pain score and morphine usage include ethnicity, age and paying class. Conclusion Our results suggest that ethnicity and OPRM 118A>G genotype are independent and significant contributors to variation in pain perception and postoperative morphine use in patients undergoing cesarean delivery.

  15. Genetic variants in 3′-UTRs of methylenetetrahydrofolate reductase (MTHFR) predict colorectal cancer susceptibility in Koreans

    Science.gov (United States)

    Joo Jeon, Young; Woo Kim, Jong; Mi Park, Hye; Kim, Jung O; Geun Jang, Hyo; Oh, Jisu; Gyu Hwang, Seong; Won Kwon, Sung; Oh, Doyeun; Keun Kim, Nam

    2015-01-01

    Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) play important roles in tumor development, progression, and metastasis. Moreover, recent studies have reported that a number of 3′-UTR polymorphisms potentially bind to specific microRNAs in a variety of cancers. The aim of this study was to investigate the association of four MTHFR polymorphisms, 2572C>A [rs4846049], 4869C>G [rs1537514], 5488C>T [rs3737967], and 6685T>C [rs4846048] with colorectal cancer (CRC) in Koreans. A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of MTHFR 3′-UTR polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis or TaqMan allelic discrimination assay. We found that MTHFR 2572C>A, 4869C>G, and 5488C>T genotypes were substantially associated with CRC susceptibility. Of the potentially susceptible polymorphisms, MTHFR 2572C>A was associated with increased homocysteine and decreased folate levels in the plasma based on MTHFR 677CC. Our study provides the evidences for 3′-UTR variants in MTHFR gene as potential biomarkers for use in CRC prevention. PMID:26046315

  16. Variation in predictive ability of common genetic variants by established strata: the example of breast cancer and age.

    Science.gov (United States)

    Aschard, Hugues; Zaitlen, Noah; Lindström, Sara; Kraft, Peter

    2015-01-01

    Recent studies of breast cancer and common genetic markers have failed to identify pervasive gene-gene and gene-environment interactions. Theoretical considerations also suggest that the contribution of modest interactions to risk discrimination in the general population is likely small. However, the clinical utility of common breast cancer risk markers may nonetheless differ across strata defined by known risk factors, such as age. We examined the age-specific per-allele odds ratios of 15 common single nucleotide polymorphisms (SNPs) found to be associated with breast cancer in 1142 breast cancer cases and 1145 controls from the Nurses' Health Study. We calculated the age-specific discriminatory ability of risk models incorporating these SNPs. We then conducted simulation studies to explore how hypothetical underlying genetic models may fit the observed results. Although all individual SNP-by-age interactions were modest, we found a negative interaction effect between age and a genetic risk score defined by the sum of risk alleles (P = 0.04). We also observed a decrease in discriminatory ability, as measured by the area under the curve (AUC), of the SNPs with age (P = 0.04). Simulation studies revealed models where the AUC can differ by strata defined by a risk factor without the presence of interactions; however, our study suggests that the observed differences in AUC are explained by the age-specific effect of the SNPs. The identification of risk factors that alter the effect of multiple genetic variants can help to explain the genetic architecture of multifactorial diseases and identify subgroups of persons who may benefit from genetic screening.

  17. Genomic prediction using preselected DNA variants from a GWAS with whole-genome sequence data in Holstein-Friesian cattle

    NARCIS (Netherlands)

    Veerkamp, Roel F.; Bouwman, Aniek C.; Schrooten, Chris; Calus, Mario P.L.

    2016-01-01

    Background: Whole-genome sequence data is expected to capture genetic variation more completely than common genotyping panels. Our objective was to compare the proportion of variance explained and the accuracy of genomic prediction by using imputed sequence data or preselected SNPs from a

  18. Interaction of CD38 Variant and Chronic Interpersonal Stress Prospectively Predicts Social Anxiety and Depression Symptoms Over Six Years.

    Science.gov (United States)

    Tabak, Benjamin A; Vrshek-Schallhorn, Suzanne; Zinbarg, Richard E; Prenoveau, Jason M; Mineka, Susan; Redei, Eva E; Adam, Emma K; Craske, Michelle G

    2016-01-01

    Variation in the CD38 gene, which regulates secretion of the neuropeptide oxytocin, has been associated with several social phenotypes. Specifically, rs3796863 A allele carriers have demonstrated increased social sensitivity. In 400 older adolescents, we used trait-state-occasion modeling to investigate how rs3796863 genotype, baseline ratings of chronic interpersonal stress, and their gene-environment (GxE) interaction predicted trait social anxiety and depression symptoms over six years. We found significant GxE effects for CD38 A-carrier genotypes and chronic interpersonal stress at baseline predicting greater social anxiety and depression symptoms. A significant GxE effect of smaller magnitude was also found for C/C genotype and chronic interpersonal stress predicting greater depression; however, this effect was small compared to the main effect of chronic interpersonal stress. Thus, in the context of chronic interpersonal stress, heightened social sensitivity associated with the rs3796863 A allele may prospectively predict risk for social anxiety and (to a lesser extent) depression.

  19. Interaction of CD38 Variant and Chronic Interpersonal Stress Prospectively Predicts Social Anxiety and Depression Symptoms Over Six Years

    Science.gov (United States)

    Tabak, Benjamin A.; Vrshek-Schallhorn, Suzanne; Zinbarg, Richard E.; Prenoveau, Jason M.; Mineka, Susan; Redei, Eva E.; Adam, Emma K.; Craske, Michelle G.

    2015-01-01

    Variation in the CD38 gene, which regulates secretion of the neuropeptide oxytocin, has been associated with several social phenotypes. Specifically, rs3796863 A allele carriers have demonstrated increased social sensitivity. In 400 older adolescents, we used trait-state-occasion modeling to investigate how rs3796863 genotype, baseline ratings of chronic interpersonal stress, and their gene-environment (GxE) interaction predicted trait social anxiety and depression symptoms over six years. We found significant GxE effects for CD38 A-carrier genotypes and chronic interpersonal stress at baseline predicting greater social anxiety and depression symptoms. A significant GxE effect of smaller magnitude was also found for C/C genotype and chronic interpersonal stress predicting greater depression; however, this effect was small compared to the main effect of chronic interpersonal stress. Thus, in the context of chronic interpersonal stress, heightened social sensitivity associated with the rs3796863 A allele may prospectively predict risk for social anxiety and (to a lesser extent) depression. PMID:26958455

  20. An Interview Study of Patient and Caregiver Perspectives on Advance Care Planning in ESRD.

    Science.gov (United States)

    Sellars, Marcus; Clayton, Josephine M; Morton, Rachael L; Luckett, Tim; Silvester, William; Spencer, Lucy; Pollock, Carol A; Walker, Rowan G; Kerr, Peter G; Tong, Allison

    2017-11-10

    Advance care planning (ACP) empowers patients to consider and communicate their current and future treatment goals. However, it can be an emotionally charged process for patients with kidney disease and their caregivers. This study aimed to describe the perspectives and attitudes of patients with end-stage renal disease (ESRD) and their caregivers toward ACP. Qualitative study. Patients with ESRD (n=24) and their caregivers (n=15) aged 36 to 91 years at various stages of ACP ("not commenced," "in progress," or "completed") from 3 renal services. Semistructured interviews. Transcripts were analyzed using thematic analysis. 5 major themes were identified: articulating core values (avoiding futile and undignified treatment, reevaluating terms of dialysis, framing a life worth living, and refusing to be a burden), confronting conversations (signifying death and defeat, accepting inevitable death, and alleviating existential tension), negotiating mutual understanding (broaching taboos and assisting conflicted caregivers), challenging patient autonomy (family pressures to continue dialysis, grief diminishing caregivers' capacity, and leveraging support), and decisional disempowerment (lacking medical transparency and disappointment with clinical disinterest). Only English-speaking patients/caregivers participated in the interview. ACP provides patients with ESRD and their caregivers a conduit for accepting and planning for impending death and to express treatment preferences based on self-dignity and value of living. However, ACP can be considered taboo, may require caregivers to overcome personal and decisional conflict, and may be complex if patients and caregivers are unable to accept the reality of the patient's illness. We suggest that ACP facilitators and clinicians make ACP more acceptable and less confrontational to patients and caregivers and that strategies be put in place to support caregivers who may be experiencing overwhelming grief or who have conflicting

  1. Variation in Cancer Incidence among Patients with ESRD during Kidney Function and Nonfunction Intervals.

    Science.gov (United States)

    Yanik, Elizabeth L; Clarke, Christina A; Snyder, Jon J; Pfeiffer, Ruth M; Engels, Eric A

    2016-05-01

    Among patients with ESRD, cancer risk is affected by kidney dysfunction and by immunosuppression after transplant. Assessing patterns across periods of dialysis and kidney transplantation may inform cancer etiology. We evaluated 202,195 kidney transplant candidates and recipients from a linkage between the Scientific Registry of Transplant Recipients and cancer registries, and compared incidence in kidney function intervals (time with a transplant) with incidence in nonfunction intervals (waitlist or time after transplant failure), adjusting for demographic factors. Incidence of infection-related and immune-related cancer was higher during kidney function intervals than during nonfunction intervals. Incidence was most elevated for Kaposi sarcoma (hazard ratio [HR], 9.1; 95% confidence interval (95% CI), 4.7 to 18), non-Hodgkin's lymphoma (HR, 3.2; 95% CI, 2.8 to 3.7), Hodgkin's lymphoma (HR, 3.0; 95% CI, 1.7 to 5.3), lip cancer (HR, 3.4; 95% CI, 2.0 to 6.0), and nonepithelial skin cancers (HR, 3.8; 95% CI, 2.5 to 5.8). Conversely, ESRD-related cancer incidence was lower during kidney function intervals (kidney cancer: HR, 0.8; 95% CI, 0.7 to 0.8 and thyroid cancer: HR, 0.7; 95% CI, 0.6 to 0.8). With each successive interval, incidence changed in alternating directions for non-Hodgkin's lymphoma, melanoma, and lung, pancreatic, and nonepithelial skin cancers (higher during function intervals), and kidney and thyroid cancers (higher during nonfunction intervals). For many cancers, incidence remained higher than in the general population across all intervals. These data indicate strong short-term effects of kidney dysfunction and immunosuppression on cancer incidence in patients with ESRD, suggesting a need for persistent cancer screening and prevention. Copyright © 2016 by the American Society of Nephrology.

  2. ESRD Databases, Public Policy, and Quality of Care: Translational Medicine and Nephrology.

    Science.gov (United States)

    McClellan, William M; Plantinga, Laura C; Wilk, Adam S; Patzer, Rachel E

    2017-01-06

    Efforts to improve care of patients with ESRD and the policies that guide those activities depend on evidence-based best practices derived from clinical trials and carefully conducted observational studies. Our review describes this process in the context of the translational research model (bench to bedside to populations), with a particular emphasis on bedside care. We illustrate some of its accomplishments and describe the limitations of the data and evidence supporting policy and practice. Copyright © 2016 by the American Society of Nephrology.

  3. Cancer Incidence Among US Medicare ESRD Patients Receiving Hemodialysis, 1996-2009

    Science.gov (United States)

    Butler, Anne M.; Olshan, Andrew F.; Kshirsagar, Abhijit V.; Edwards, Jessie K.; Nielsen, Matthew E.; Wheeler, Stephanie B.; Brookhart, M. Alan

    2016-01-01

    Background Patients with end-stage renal disease (ESRD) receiving dialysis have been reported to have increased risk of cancer. However, contemporary cancer burden estimates in this population are sparse and do not account for the high competing risk of death characteristic of dialysis patients. Study Design Retrospective cohort study. Setting & Participants US adult patients enrolled in Medicare's ESRD program who received in-center hemodialysis. Factors Demographic/clinical characteristics. Outcomes For overall and site-specific cancers identified using claims-based definitions, we calculated annual incidence rates (1996-2009). We estimated 5-year cumulative incidence since dialysis therapy initiation using competing-risk methods. Results We observed a constant rate of incident cancers for all sites combined, from 3,923 to 3,860 cases per 100,000 person-years (annual percentage change, 0.1; 95% CI, −0.4 to 0.6). Rates for some common site-specific cancers increased (ie, kidney/renal pelvis) and decreased (ie, colon/rectum, lung/bronchus, pancreas, and other sites). Of 482,510 incident hemodialysis patients, cancer was diagnosed in 37,128 within 5 years after dialysis therapy initiation. The 5-year cumulative incidence of any cancer was 9.48% (95% CI, 9.39%-9.57%) and was higher for certain subgroups: older age, males, nonwhites, non-Hispanics, nondiabetes primary ESRD cause, recent dialysis therapy initiation, and history of transplantation evaluation. Among blacks and whites, we observed 35,767 cases compared with 25,194 expected cases if the study population had experienced rates observed in the US general population (standardized incidence ratio [SIR], 1.42; 95% CI, 1.41-1.43). Risk was most elevated for cancers of the kidney/renal pelvis (SIR, 4.03; 95% CI, 3.88-4.19) and bladder (SIR, 1.57; 95% CI, 1.51-1.64). Limitations Claims-based cancer definitions have not been validated in the ESRD population. Information for cancer risk factors was not available in

  4. Cancer incidence among US Medicare ESRD patients receiving hemodialysis, 1996-2009.

    Science.gov (United States)

    Butler, Anne M; Olshan, Andrew F; Kshirsagar, Abhijit V; Edwards, Jessie K; Nielsen, Matthew E; Wheeler, Stephanie B; Brookhart, M Alan

    2015-05-01

    Patients with end-stage renal disease (ESRD) receiving dialysis have been reported to have increased risk of cancer. However, contemporary cancer burden estimates in this population are sparse and do not account for the high competing risk of death characteristic of dialysis patients. Retrospective cohort study. US adult patients enrolled in Medicare's ESRD program who received in-center hemodialysis. Demographic/clinical characteristics. For overall and site-specific cancers identified using claims-based definitions, we calculated annual incidence rates (1996-2009). We estimated 5-year cumulative incidence since dialysis therapy initiation using competing-risk methods. We observed a constant rate of incident cancers for all sites combined, from 3,923 to 3,860 cases per 100,000 person-years (annual percentage change, 0.1; 95% CI, -0.4 to 0.6). Rates for some common site-specific cancers increased (ie, kidney/renal pelvis) and decreased (ie, colon/rectum, lung/bronchus, pancreas, and other sites). Of 482,510 incident hemodialysis patients, cancer was diagnosed in 37,128 within 5 years after dialysis therapy initiation. The 5-year cumulative incidence of any cancer was 9.48% (95% CI, 9.39%-9.57%) and was higher for certain subgroups: older age, males, nonwhites, non-Hispanics, nondiabetes primary ESRD cause, recent dialysis therapy initiation, and history of transplantation evaluation. Among blacks and whites, we observed 35,767 cases compared with 25,194 expected cases if the study population had experienced rates observed in the US general population (standardized incidence ratio [SIR], 1.42; 95% CI, 1.41-1.43). Risk was most elevated for cancers of the kidney/renal pelvis (SIR, 4.03; 95% CI, 3.88-4.19) and bladder (SIR, 1.57; 95% CI, 1.51-1.64). Claims-based cancer definitions have not been validated in the ESRD population. Information for cancer risk factors was not available in our data source. These results suggest a high burden of cancer in the dialysis

  5. WS-SNPs&GO: a web server for predicting the deleterious effect of human protein variants using functional annotation.

    Science.gov (United States)

    Capriotti, Emidio; Calabrese, Remo; Fariselli, Piero; Martelli, Pier Luigi; Altman, Russ B; Casadio, Rita

    2013-01-01

    SNPs&GO is a method for the prediction of deleterious Single Amino acid Polymorphisms (SAPs) using protein functional annotation. In this work, we present the web server implementation of SNPs&GO (WS-SNPs&GO). The server is based on Support Vector Machines (SVM) and for a given protein, its input comprises: the sequence and/or its three-dimensional structure (when available), a set of target variations and its functional Gene Ontology (GO) terms. The output of the server provides, for each protein variation, the probabilities to be associated to human diseases. The server consists of two main components, including updated versions of the sequence-based SNPs&GO (recently scored as one of the best algorithms for predicting deleterious SAPs) and of the structure-based SNPs&GO(3d) programs. Sequence and structure based algorithms are extensively tested on a large set of annotated variations extracted from the SwissVar database. Selecting a balanced dataset with more than 38,000 SAPs, the sequence-based approach achieves 81% overall accuracy, 0.61 correlation coefficient and an Area Under the Curve (AUC) of the Receiver Operating Characteristic (ROC) curve of 0.88. For the subset of ~6,600 variations mapped on protein structures available at the Protein Data Bank (PDB), the structure-based method scores with 84% overall accuracy, 0.68 correlation coefficient, and 0.91 AUC. When tested on a new blind set of variations, the results of the server are 79% and 83% overall accuracy for the sequence-based and structure-based inputs, respectively. WS-SNPs&GO is a valuable tool that includes in a unique framework information derived from protein sequence, structure, evolutionary profile, and protein function. WS-SNPs&GO is freely available at http://snps.biofold.org/snps-and-go.

  6. KIR, HLA, and IL28B variant predict response to antiviral therapy in genotype 1 chronic hepatitis C patients in Japan.

    Directory of Open Access Journals (Sweden)

    Yuichi Nozawa

    Full Text Available Natural killer cell responses play a crucial role in virus clearance by the innate immune system. Although the killer immunoglobulin-like receptor (KIR in combination with its cognate human leukocyte antigen (HLA ligand, especially KIR2DL3-HLA-C1, is associated with both treatment-induced and spontaneous clearance of hepatitis C virus (HCV infection in Caucasians, these innate immunity genes have not been fully clarified in Japanese patients. We therefore investigated 16 KIR genotypes along with HLA-B and -C ligands and a genetic variant of interleukin (IL 28B (rs8099917 in 115 chronic hepatitis C genotype 1 patients who underwent pegylated-interferon-α2b (PEG-IFN and ribavirin therapy. HLA-Bw4 was significantly associated with a sustained virological response (SVR to treatment (P = 0.017; odds ratio [OR] = 2.50, , as was the centromeric A/A haplotype of KIR (P = 0.015; OR 3.37. In contrast, SVR rates were significantly decreased in patients with KIR2DL2 or KIR2DS2 (P = 0.015; OR = 0.30, and P = 0.025; OR = 0.32, respectively. Multivariate logistic regression analysis subsequently identified the IL28B TT genotype (P = 0.00009; OR = 6.87, 95% confidence interval [CI] = 2.62 - 18.01, KIR2DL2/HLA-C1 (P = 0.014; OR = 0.24, 95% CI = 0.08 - 0.75, KIR3DL1/HLA-Bw4 (P = 0.008, OR = 3.32, 95% CI = 1.37 - 8.05, and white blood cell count at baseline (P = 0.009; OR = 3.32, 95% CI = 1.35 - 8.16 as independent predictive factors of an SVR. We observed a significant association between the combination of IL28B TT genotype and KIR3DL1-HLA-Bw4 in responders (P = 0.0019, whereas IL28B TT along with KIR2DL2-HLA-C1 was related to a non-response (P = 0.0067. In conclusion, combinations of KIR3DL1/HLA-Bw4, KIR2DL2/HLA-C1, and a genetic variant of the IL28B gene are predictive of the response to PEG-IFN and ribavirin therapy in Japanese patients infected with genotype 1b HCV.

  7. Diagnosing FSGS without kidney biopsy - a novel INF2-mutation in a family with ESRD of unknown origin.

    Science.gov (United States)

    Münch, Johannes; Grohmann, Maik; Lindner, Tom H; Bergmann, Carsten; Halbritter, Jan

    2016-10-12

    Patients on renal replacement therapy are often unaware of their underlying condition and hence suffer from so-called end-stage renal disease (ESRD) of unknown origin. However, an exact diagnosis is not only important for better estimating the prognosis, but also when preparing for kidney transplantation. Whilst patients with FSGS without a confirmed genetic cause have a high recurrence rate in the transplanted organ, patients with a mutation generally exhibit no recurrence and have a good prognosis. Furthermore, renal biopsy, which may be helpful for differential diagnosis, is usually contraindicated in end-stage kidneys. We here present the case of familial ESRD of unknown origin, which could be resolved by targeted genetic testing prior to planning of kidney transplantation. A 32-year-old female with ESRD and nephrotic range proteinuria was admitted to our clinic. Family-history revealed that both mother and maternal grandmother had ESRD of unknown origin. As renal biopsy was impossible due to atrophic kidneys, we performed mutation analysis of genes known for dominant forms of FSGS and found a novel heterozygous mutation of INF2 (c.485 T > C, p.Leu162Pro). The same mutation could be detected in the index patient's mother (ESRD at age 50) and three brothers with normal serum-creatinine but mid or low range proteinuria. Genetic testing is warranted in families with ESRD of unknown origin and may provide a robust diagnosis even without kidney biopsy. It will help detecting relatives at risk who have to be excluded from potential kidney donation and who may benefit from timely initiation of protective measures in order to slow down disease progression.

  8. ESRD After Heart Failure, Myocardial Infarction, or Stroke in Type 2 Diabetic Patients With CKD

    DEFF Research Database (Denmark)

    Charytan, David M; Solomon, Scott D; Ivanovich, Peter

    2017-01-01

    BACKGROUND: How cardiovascular (CV) events affect progression to end-stage renal disease (ESRD), particularly in the setting of type 2 diabetes, remains uncertain. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 4,022 patients with type 2 diabetes, anemia, and chronic kidney disease from...... and during overall follow-up after an intercurrent CV event. LIMITATIONS: Population limited to clinical trial participants with diabetes and anemia. RESULTS: 155 of 652 (23.8%) ESRD cases occurred after an intercurrent CV event; 110 (16.9%) cases followed heart failure, 28 (4.3%) followed myocardial...

  9. Relative Incidence of ESRD Versus Cardiovascular Mortality in Proteinuric Type 2 Diabetes and Nephropathy : Results From the DIAMETRIC (Diabetes Mellitus Treatment for Renal Insufficiency Consortium) Database

    NARCIS (Netherlands)

    Packham, David K.; Alves, Tahira P.; Dwyer, Jamie P.; Atkins, Robert; de Zeeuw, Dick; Cooper, Mark; Shahinfar, Shahnaz; Lewis, Julia B.; Lambers Heerspink, Hiddo J.

    Background: Previous studies have shown that patients with chronic kidney disease, including those with diabetic nephropathy, are more likely to die of cardiovascular disease than reach end-stage renal disease (ESRD). This analysis was conducted to determine whether ESRD is a more common outcome

  10. Cumulative effect and predictive value of genetic variants associated with type 2 diabetes in Han Chinese: a case-control study.

    Directory of Open Access Journals (Sweden)

    Yun Qian

    Full Text Available Genome-wide association studies (GWAS have identified dozens of single nucleotide polymorphisms (SNPs associated with type 2 diabetes risk. We have previously confirmed the associations of genetic variants in HHEX, CDKAL1, VEGFA and FTO with type 2 diabetes in Han Chinese. However, the cumulative effect and predictive value of these GWAS identified SNPs on the risk of type 2 diabetes in Han Chinese are largely unknown.We conducted a two-stage case-control study consisting of 2,925 cases and 3,281 controls to examine the association of 30 SNPs identified by GWAS with type 2 diabetes in Han Chinese. Significant associations were found for proxy SNPs at KCNQ1 [odds ratio (OR = 1.41, P = 9.91 × 10-16 for rs2237897], CDKN2A/CDKN2B (OR = 1.30, P = 1.34 × 10-10 for rs10811661, CENTD2 (OR = 1.28, P = 9.88 × 10-4 for rs1552224 and SLC30A8 (OR = 1.19, P = 1.43 × 10-5 for rs13266634. We further evaluated the cumulative effect on type 2 diabetes of these 4 SNPs, in combination with 5 SNPs at HHEX, CDKAL1, VEGFA and FTO reported previously. Individuals carrying 12 or more risk alleles had a nearly 4-fold increased risk for developing type 2 diabetes compared with those carrying less than 6 risk alleles [adjusted OR = 3.68, 95% confidence interval (CI: 2.76-4.91]. Adding the genetic factors to clinical factors slightly improved the prediction of type 2 diabetes, with the area under the receiver operating characteristic curve increasing from 0.76 to 0.78. However, the difference was statistically significant (P < 0.0001.We confirmed associations of SNPs in KCNQ1, CDKN2A/CDKN2B, CENTD2 and SLC30A8 with type 2 diabetes in Han Chinese. The utilization of genetic information may improve the accuracy of risk prediction in combination with clinical characteristics for type 2 diabetes.

  11. Associations of anemia persistency with medical expenditures in Medicare ESRD patients on dialysis

    Directory of Open Access Journals (Sweden)

    Jiannong Liu

    2009-04-01

    Full Text Available Jiannong Liu1, Haifeng Guo1, David Gilbertson1, Robert Foley1,2, Allan Collins1,21Chronic Disease Research Group, Minneapolis Medical Research Foundation, Minneapolis, MN, USA; 2Department of Medicine, University of Minnesota, Minneapolis, MN, USAAbstract: Most end-stage renal disease (ESRD patients begin renal replacement therapy with hemoglobin levels below the recommended US National Kidney Foundation Dialysis Outcomes Quality Initiative Guidelines lower level of 110 g/L. Although most patients eventually reach this target, the time required varies substantially. This study aimed to determine whether length of time with below-target hemoglobin levels after dialysis initiation is associated with medical costs, and if so, whether intermediate factors underlie the associations. US patients initiating dialysis in 2002 were studied using the Centers for Medicare and Medicaid Services ESRD database. Anemia persistence (time in months with hemoglobin below 110 g/L was determined in a six-month entry period, and outcomes were assessed in the subsequent six-month follow-up period. The structural equation modeling technique was used to evaluate associations between persistent anemia and medical costs and to determine intermediate factors for these associations. The study included 28,985 patients. Mean per-patient-per-month medical cost was $6267 (standard deviation $5713 in the six-month follow-up period. Each additional month with hemoglobin below 110 g/L was associated with an 8.9% increment in medical cost. The increased cost was associated with increased erythropoietin use and blood transfusions, and increased rates of hospitalization and vascular access procedures in the follow-up period. Keywords: anemia persistency, end-stage renal disease, medical costs, structural equation modeling

  12. One- and 2-Year Mortality Prediction for Patients Starting Chronic Dialysis

    Directory of Open Access Journals (Sweden)

    Mikko Haapio

    2017-11-01

    Discussion: Mortality prediction algorithms could be more widely implemented into management of ESRD patients. The presented models are practical with only a limited number of variables and fairly good performance.

  13. CCR5 Delta 32 Genotype Leads to a Th2 Type Directed Immune Response in ESRD Patients

    NARCIS (Netherlands)

    Muntinghe, Friso L. H.; Abdulahad, Wayel H.; Huitema, Minke G.; Damman, Jeffrey; Seelen, Marc A.; Lems, Simon P. M.; Hepkema, Bouke G.; Navis, Gerjan; Westra, Johanna

    2012-01-01

    Background: In patients with end stage renal disease (ESRD) we observed protection from inflammation-associated mortality in CCR5 Delta 32 carriers, leading to CCR5 deficiency, suggesting impact of CCR5 Delta 32 on inflammatory processes. Animal studies have shown that CCR5 deficiency is associated

  14. Development of a behavioural self-regulation intervention to improve employment, autonomy and self-esteem in ESRD patients.

    NARCIS (Netherlands)

    Jansen, D.; Heijmans, M.; Rijken, M.

    2008-01-01

    Background: The aim was to develop a psychological intervention for ESRD patients and their partners aimed at maintaining/widening patients’ daily activities including work, and increasing patients’ autonomy and self-esteem. Methods: The intervention was based on self-regulation theory, social

  15. Genetic variants in microRNAs and microRNA target sites predict biochemical recurrence after radical prostatectomy in localized prostate cancer.

    Science.gov (United States)

    Huang, Shu-Pin; Lévesque, Eric; Guillemette, Chantal; Yu, Chia-Cheng; Huang, Chao-Yuan; Lin, Victor C; Chung, I-Che; Chen, Lih-Chyang; Laverdière, Isabelle; Lacombe, Louis; Fradet, Yves; Chang, Ta-Yuan; Lee, Hong-Zin; Juang, Shin-Hun; Bao, Bo-Ying

    2014-12-01

    Recent evidence indicates that microRNAs might participate in prostate cancer initiation, progression and treatment response. Germline variations in microRNAs might alter target gene expression and modify the efficacy of prostate cancer therapy. To determine whether genetic variants in microRNAs and microRNA target sites are associated with the risk of biochemical recurrence (BCR) after radical prostatectomy (RP). We retrospectively studied two independent cohorts composed of 320 Asian and 526 Caucasian men with pathologically organ-confined prostate cancer who had a median follow-up of 54.7 and 88.8 months after RP, respectively. Patients were systematically genotyped for 64 single-nucleotide polymorphisms (SNPs) in microRNAs and microRNA target sites, and their prognostic significance on BCR was assessed by Kaplan-Meier analysis and Cox regression model. After adjusting for known clinicopathologic risk factors, two SNPs (MIR605 rs2043556 and CDON rs3737336) remained associated with BCR. The numbers of risk alleles showed a cumulative effect on BCR [perallele hazard ratio (HR) 1.60, 95% confidence interval (CI) 1.16-2.21, p for trend = 0.005] in Asian cohort, and the risk was replicated in Caucasian cohort (HR 1.55, 95% CI 1.15-2.08, p for trend = 0.004) and in combined analysis (HR 1.57, 95% CI 1.26-1.96, p for trend <0.001). Results warrant replication in larger cohorts. This is the first study demonstrating that SNPs in microRNAs and microRNA target sites can be predictive biomarkers for BCR after RP. © 2014 UICC.

  16. The predicted truncation from a cancer-associated variant of the MSH2 initiation codon alters activity of the MSH2-MSH6 mismatch repair complex

    OpenAIRE

    Cyr, Jennifer L.; Brown, Graham D; Stroop, Jennifer; Heinen, Christopher D.

    2011-01-01

    Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes. M M R recognizes and repairs DNA mismatches and small insertion/deletion loops. Carriers of MMR gene variants have a high risk of developing colorectal, endometrial, ovarian, and other extracolonic carcinomas. We report on an ovarian cancer patient who carries a germline MSH2 c.1A>C variant which alters the translation initiation codon. Mutations affecting the MSH2 start codon have been described previousl...

  17. Mapping end-stage renal disease (ESRD): spatial variations on small area level in northern France, and association with deprivation.

    Science.gov (United States)

    Occelli, Florent; Deram, Annabelle; Génin, Michaël; Noël, Christian; Cuny, Damien; Glowacki, François

    2014-01-01

    Strong geographic variations in the incidence of end-stage renal disease (ESRD) are observed in developed countries. The reasons for these variations are unknown. They may reflect regional inequalities in the population's sociodemographic characteristics, related diseases, or medical practice patterns. In France, at the district level, the highest incidence rates have been found in the Nord-Pas-de-Calais region. This area, with a high population density and homogeneous healthcare provision, represents a geographic situation which is quite suitable for the study, over small areas, of spatial disparities in the incidence of ESRD, together with their correlation with a deprivation index and other risk factors. The Renal Epidemiology and Information Network is a national registry, which lists all ESRD patients in France. All cases included in the Nord-Pas-de-Calais registry between 2005 and 2011 were extracted. Adjusted and smoothed standardized incidence ratio (SIR) was calculated for each of the 170 cantons, thanks to a hierarchical Bayesian model. The correlation between ESRD incidence and deprivation was assessed using the quintiles of Townsend index. Relative risk (RR) and credible intervals (CI) were estimated for each quintile. Significant spatial disparities in ESRD incidence were found within the Nord-Pas-de-Calais region. The sex- and age-adjusted, smoothed SIRs varied from 0.66 to 1.64. Although no correlation is found with diabetic or vascular nephropathy, the smoothed SIRs are correlated with the Townsend index (RR: 1.18, 95% CI [1.00-1.34] for Q2; 1.28, 95% CI [1.11-1.47] for Q3; 1.30, 95% CI [1.14-1.51] for Q4; 1.44, 95% CI [1.32-1.74] for Q5). For the first time at this aggregation level in France, this study reveals significant geographic differences in ESRD incidence. Unlike the time of renal replacement care, deprivation is certainly a determinant in this phenomenon. This association is probably independent of the patients' financial ability to gain

  18. American Society of Nephrology Quiz and Questionnaire 2015: ESRD/RRT.

    Science.gov (United States)

    Lok, Charmaine E; Perazella, Mark A; Choi, Michael J

    2016-07-07

    The Nephrology Quiz and Questionnaire remains an extremely popular session for attendees of the Annual Kidney Week Meeting of the American Society of Nephrology. During the 2015 meeting, the conference hall was once again overflowing with eager quiz participants. Topics covered by the experts included electrolyte and acid-base disorders, glomerular disease, ESRD and dialysis, and kidney transplantation. Complex cases representing each of these categories together with single best answer questions were prepared and submitted by the panel of experts. Before the meeting, training program directors of nephrology fellowship programs and nephrology fellows in the United States answered the questions through an internet-based questionnaire. During the live session, members of the audience tested their knowledge and judgment on the same series of case-oriented questions in a quiz. The audience compared their answers in real time using a cellphone application containing the answers of the nephrology fellows and training program directors. The results of the online questionnaire were displayed, and then, the quiz answers were discussed. As always, the audience, lecturers, and moderators enjoyed this highly educational session. This article recapitulates the session and reproduces selected content of educational value for the readers of the Clinical Journal of the American Society of Nephrology Enjoy the clinical cases and expert discussions. Copyright © 2016 by the American Society of Nephrology.

  19. Single-center open-label randomized study of anemia management improvement in ESRD patients with secondary hyperparathyroidism

    Directory of Open Access Journals (Sweden)

    Bellasi Antonio

    2016-04-01

    Full Text Available Whether anemia and mineral bone abnormalities (chronic kidney disease–mineral bone disorder [CKD-MBD] are associated still remains to be elucidated. Both anemia and CKD-MBD have been associated with adverse cardiovascular outcome and poor quality of life. However, recent evidence suggests that use of large doses of erythropoietin-stimulating agents (ESAs to correct hemoglobin (Hb may be detrimental in CKD. The Optimal Anemia Treatment in End Stage Renal Disease (ESRD (Optimal ESRD Treatment study will assess whether lowering of parathyroid hormone (PTH is associated with a reduction in ESA consumption. The Optimal ESRD Treatment study is a pilot single-center open-label study with blinded end point (a prospective randomized open blinded end-point [PROBE] design enrolling 50 patients on maintenance dialysis. Eligible patients with intact PTH (iPTH 300-540 pg/mL and Hb 10-11.5 g/dL will be randomized 1:1 to strict PTH control (150-300 pg/mL versus standard care (PTH range 300-540 pg/mL. Available drugs for CKD-MBD and anemia treatment will be managed by the attending physician to maintain the desired levels of PTH (according to study arm allocation and Hb (10-11.5 g/dL. Echocardiographic data for cardiac structure and function as well as arterial stiffness will be assessed at study inception and completion. The Optimal ESRD Treatment study should shed light on the complicated interplay of anemia and CKD-MBD and on the feasibility of clinical trials in this domain. The study results are expected in the spring of 2017.

  20. Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk

    Science.gov (United States)

    Vachon, Celine M.; Scott, Christopher G.; Fasching, Peter A.; Hall, Per; Tamimi, Rulla M.; Li, Jingmei; Stone, Jennifer; Apicella, Carmel; Odefrey, Fabrice; Gierach, Gretchen L.; Jud, Sebastian M.; Heusinger, Katharina; Beckmann, Matthias W.; Pollan, Marina; Fernández-Navarro, Pablo; González-Neira, Anna; Benítez, Javier; van Gils, Carla H.; Lokate, Mariëtte; Onland-Moret, N. Charlotte; Peeters, Petra H.M.; Brown, Judith; Leyland, Jean; Varghese, Jajini S.; Easton, Douglas F.; Thompson, Deborah J.; Luben, Robert N.; Warren, Ruth ML; Wareham, Nicholas J.; Loos, Ruth JF; Khaw, Kay-Tee; Ursin, Giske; Lee, Eunjung; Gayther, Simon A.; Ramus, Susan J.; Eeles, Rosalind A.; Leach, Martin O.; Kwan-Lim, Gek; Couch, Fergus J.; Giles, Graham G.; Baglietto, Laura; Krishnan, Kavitha; Southey, Melissa C.; Le Marchand, Loic; Kolonel, Laurence N.; Woolcott, Christy; Maskarinec, Gertraud; Haiman, Christopher A; Walker, Kate; Johnson, Nichola; McCormack, Valerie A.; Biong, Margarethe; Alnæs, Grethe I.G.; Gram, Inger Torhild; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Lindström, Sara; Hankinson, Susan E.; Hunter, David J.; Andrulis, Irene L.; Knight, Julia A.; Boyd, Norman F.; Figueroa, Jonine D.; Lissowska, Jolanta; Wesolowska, Ewa; Peplonska, Beata; Bukowska, Agnieszka; Reszka, Edyta; Liu, JianJun; Eriksson, Louise; Czene, Kamila; Audley, Tina; Wu, Anna H.; Pankratz, V. Shane; Hopper, John L.; dos-Santos-Silva, Isabel

    2013-01-01

    Background Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biological mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to inter-individual differences in mammographic density measures. Methods We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and non-dense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, body mass index (BMI) and menopausal status. Results Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (p=0.00005) and adjusted percent density (p=0.001) whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (p=0.003), but not with adjusted dense area (p=0.07). Conclusion We identified two common breast cancer susceptibility variants associated with mammographic measures of radio-dense tissue in the breast gland. Impact We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association. PMID:22454379

  1. Variant Interpretation: Functional Assays to the Rescue.

    Science.gov (United States)

    Starita, Lea M; Ahituv, Nadav; Dunham, Maitreya J; Kitzman, Jacob O; Roth, Frederick P; Seelig, Georg; Shendure, Jay; Fowler, Douglas M

    2017-09-07

    Classical genetic approaches for interpreting variants, such as case-control or co-segregation studies, require finding many individuals with each variant. Because the overwhelming majority of variants are present in only a few living humans, this strategy has clear limits. Fully realizing the clinical potential of genetics requires that we accurately infer pathogenicity even for rare or private variation. Many computational approaches to predicting variant effects have been developed, but they can identify only a small fraction of pathogenic variants with the high confidence that is required in the clinic. Experimentally measuring a variant's functional consequences can provide clearer guidance, but individual assays performed only after the discovery of the variant are both time and resource intensive. Here, we discuss how multiplex assays of variant effect (MAVEs) can be used to measure the functional consequences of all possible variants in disease-relevant loci for a variety of molecular and cellular phenotypes. The resulting large-scale functional data can be combined with machine learning and clinical knowledge for the development of "lookup tables" of accurate pathogenicity predictions. A coordinated effort to produce, analyze, and disseminate large-scale functional data generated by multiplex assays could be essential to addressing the variant-interpretation crisis. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  2. Effectiveness of Topical Chia Seed Oil on Pruritus of End-stage Renal Disease (ESRD) Patients and Healthy Volunteers.

    Science.gov (United States)

    Jeong, Se Kyoo; Park, Hyun Jung; Park, Byeong Deog; Kim, Il-Hwan

    2010-05-01

    Several studies have been performed to evaluate the efficacy of dietary n-3 fatty acid for patients with renal dysfunction. While about 40% to 80% of patients with end-stage renal disease (ESRD) complain about pruritus and xerosis, there are few reports on the effects of topical n-3 fatty acid on these symptoms. In order to investigate the possible beneficial effects of topical n-3 fatty acid, oils extracted from chia (Salvia hispanica) seed were formulated into topical products, the effects of which were measured. Five healthy volunteers having xerotic pruritus symptoms and 5 patients with pruritus caused by either ESRD or diabetes were involved in this study. A topical formulation containing 4% chia seed oils were applied for an 8-week duration. Subjective itching symptoms were assessed on a 6-point scale, as were other skin functions, namely transepidermal water loss and skin capacitance. After the 8 weeks of application, significant improvements in skin hydration, lichen simplex chronicus, and prurigo nodularis were observed in all patients. A similar improvement was also observed among healthy volunteers with xerotic pruritus. Improvement of epidermal permeability barrier function and skin hydration, represented by trans-epidermal water loss and skin capacitance, respectively, were also observed. No adverse effects were observed in all the tested patients and volunteers. Chia seed oil can be used as an adjuvant moisturizing agent for pruritic skin, including that of ESRD patients.

  3. Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD.

    Science.gov (United States)

    Wong, Jakk; Piceno, Yvette M; DeSantis, Todd Z; Pahl, Madeleine; Andersen, Gary L; Vaziri, Nosratola D

    2014-01-01

    Intestinal microbiome constitutes a symbiotic ecosystem that is essential for health, and changes in its composition/function cause various illnesses. Biochemical milieu shapes the structure and function of the microbiome. Recently, we found marked differences in the abundance of numerous bacterial taxa between ESRD and healthy individuals. Influx of urea and uric acid and dietary restriction of fruits and vegetables to prevent hyperkalemia alter ESRD patients' intestinal milieu. We hypothesized that relative abundances of bacteria possessing urease, uricase, and p-cresol- and indole-producing enzymes is increased, while abundance of bacteria containing enzymes converting dietary fiber to short-chain fatty acids (SCFA) is reduced in ESRD. Reference sets of bacteria containing genes of interest were compiled to family, and sets of intestinal bacterial families showing differential abundances between 12 healthy and 24 ESRD individuals enrolled in our original study were compiled. Overlap between sets was assessed using hypergeometric distribution tests. Among 19 microbial families that were dominant in ESRD patients, 12 possessed urease, 5 possessed uricase, and 4 possessed indole and p-cresol-forming enzymes. Among 4 microbial families that were diminished in ESRD patients, 2 possessed butyrate-forming enzymes. Probabilities of these overlapping distributions were families possessing urease, uricase, and indole and p-cresol forming enzymes, and contraction of families possessing butyrate-forming enzymes. Given the deleterious effects of indoxyl sulfate, p-cresol sulfate, and urea-derived ammonia, and beneficial actions of SCFA, these changes in intestinal microbial metabolism contribute to uremic toxicity and inflammation.

  4. Pregnancy outcomes according to dialysis commencing before or after conception in women with ESRD.

    Science.gov (United States)

    Jesudason, Shilpanjali; Grace, Blair S; McDonald, Stephen P

    2014-01-01

    Pregnancy in ESRD is rare and poses substantial risk for mother and baby. This study describes a large series of pregnancies in women undergoing long-term dialysis treatment and reviews maternal and fetal outcomes. Specifically, women who had conceived before and after starting long-term dialysis are compared. All pregnancies reported to the Australian and New Zealand Dialysis and Transplantation Registry from 2001 to 2011 (n=77), following the introduction of specific parenthood data collection, were analyzed. Between 2001 and 2011, there were 77 pregnancies among 73 women. Of these, 53 pregnancies were in women who conceived after long-term dialysis was established and 24 pregnancies occurred before dialysis began. The overall live birth rate (after exclusion of elective terminations) was 73%. In pregnancies reaching 20 weeks gestation, the live birth rate was 82%. Women who conceived before dialysis commenced had significantly higher live birth rates (91% versus 63%; P=0.03), but infants had similar birthweight and gestational age. This difference in live birth rate was primarily due to higher rates of early pregnancy loss before 20 weeks in women who conceived after dialysis was established. In pregnancies that reached 20 weeks or more, the live birth rate was higher in women with conception before dialysis commenced (91% versus 76%; P=0.28). Overall, the median gestational age was 33.8 weeks (interquartile range, 30.6-37.6 weeks) and median birthweight was 1750 g (interquartile range, 1130-2417 g). More than 40% of pregnancies reached >34 weeks' gestation; prematurity at dialysis after conception have superior live birth rates compared with those already established on dialysis at the time of conception, although these pregnancies remain high risk.

  5. Pregnancy Outcomes According to Dialysis Commencing Before or After Conception in Women with ESRD

    Science.gov (United States)

    Grace, Blair S.; McDonald, Stephen P.

    2014-01-01

    Summary Background and objectives Pregnancy in ESRD is rare and poses substantial risk for mother and baby. This study describes a large series of pregnancies in women undergoing long-term dialysis treatment and reviews maternal and fetal outcomes. Specifically, women who had conceived before and after starting long-term dialysis are compared. Design, setting, participants, & measurement All pregnancies reported to the Australian and New Zealand Dialysis and Transplantation Registry from 2001 to 2011 (n=77), following the introduction of specific parenthood data collection, were analyzed. Results Between 2001 and 2011, there were 77 pregnancies among 73 women. Of these, 53 pregnancies were in women who conceived after long-term dialysis was established and 24 pregnancies occurred before dialysis began. The overall live birth rate (after exclusion of elective terminations) was 73%. In pregnancies reaching 20 weeks gestation, the live birth rate was 82%. Women who conceived before dialysis commenced had significantly higher live birth rates (91% versus 63%; P=0.03), but infants had similar birthweight and gestational age. This difference in live birth rate was primarily due to higher rates of early pregnancy loss before 20 weeks in women who conceived after dialysis was established. In pregnancies that reached 20 weeks or more, the live birth rate was higher in women with conception before dialysis commenced (91% versus 76%; P=0.28). Overall, the median gestational age was 33.8 weeks (interquartile range, 30.6–37.6 weeks) and median birthweight was 1750 g (interquartile range, 1130–2417 g). More than 40% of pregnancies reached >34 weeks’ gestation; prematurity at dialysis after conception have superior live birth rates compared with those already established on dialysis at the time of conception, although these pregnancies remain high risk. PMID:24235285

  6. Potentially Functional variants of ATG16L2 predict radiation pneumonitis and outcomes in patients with non-small cell lung cancer after definitive radiotherapy.

    Science.gov (United States)

    Wen, Juyi; Liu, Hongliang; Wang, Lili; Wang, Xiaomeng; Gu, Ning; Liu, Zhensheng; Xu, Ting; Gomez, Daniel R; Komaki, Ritsuko; Liao, Zhongxing; Wei, Qingyi

    2018-02-15

    Autophagy not only plays an important role in the progression of cancer but also is involved in tissue inflammatory response. However, few published studies have investigated associations between functional genetic variants of autophagy-related genes and radiation pneumonitis (RP) as well as clinical outcomes in patients with non-small cell lung cancer (NSCLC) after definitive radiotherapy. We genotyped nine potentially functional single nucleotide polymorphisms (SNPs) in four autophagy-related genes (ATG2B, ATG10, ATG12 and ATG16L2) in 393 North American NSCLC patients treated by definitive radiotherapy and assessed their associations with RP, local recurrence-free survival (LRFS), progression-free survival (PFS) and overall survival (OS) in multivariable Cox proportional hazards regression analyses. We found that the ATG16L2 rs10898880 CC variant genotype had a better LRFS, PFS and OS [adjusted hazards ratio (adjHR) = 0.59, 0.64 and 0.64; 95% confidence interval (95% CI = 0.45-0.79, 0.48-0.84 and 0.48-0.86); and P = 0.0004, 0.002 and 0.003, respectively], but a greater risk of developing severe RP (adjHR = 1.80, 96% CI = 1.04-3.12, P = 0.037), than patients with CC/CT genotypes. Further functional analyses suggested that the ATG16L2 rs10898880 C variant allele modulated the expression of the ATG16L2 gene. This is the first report that functional ATG16L2 C variant homozygous genotype may be a predictor of RP, LRFS, PFS, and OS in NSCLC patients after definitive radiotherapy. Additional larger, prospective studies are needed to confirm these findings. Copyright © 2018. Published by Elsevier Inc.

  7. Epidemiological Study of RRT-Treated ESRD in Nanjing - A Ten-Year Experience in Nearly Three Million Insurance Covered Population.

    Directory of Open Access Journals (Sweden)

    Yu-Chen Han

    Full Text Available The growing burden of end-stage renal disease (ESRD has been a great challenge to the health care system of China. However, the exact epidemiological data for ESRD in China remain unclear. We aimed to investigate the epidemiology of ESRD treated by renal replacement therapy (RRT in Nanjing based on analysing ten-year data of Nanjing three million insurance covered population.Using the electronic registry system of Urban Employee Basic Medical Insurance (UEBMI, we included all subjects insured by UEBMI in Nanjing from 2005 to 2014 and identified subjects who developed ESRD and started RRT in this cohort.The UEBMI population in Nanjing increased from 1,301,882 in 2005 to 2,921,065 in 2014, among which a total of 5,840 subjects developed ESRD and received RRT. Over the 10-year period, the adjusted incidence rates of RRT in the UEBMI cohort gradually decreased from 289.3pmp in 2005 to 218.8pmp in 2014. However, the adjusted prevalence rate increased steadily from 891.7pmp in 2005 to 1,228.6pmp in 2014. The adjusted annual mortality rate decreased from 138.4 per 1000 patient-years in 2005 to 97.8 per 1000 patient-years in 2014. The long-term survival rate fluctuated over the past decade, with the 1-year survival rate ranging from 85.1% to 91.7%, the 3-year survival rate from 69.9% to 78.3% and the 5-year survival rate from 58% to 65.4%.Nanjing is facing an increasing burden of ESRD with its improvement of medical reform. The ten-year complete registry data on RRT in urban employees in Nanjing provided a unique opportunity to understand the real threat of ESRD confronting China during its process of health care transition.

  8. Epidemiological Study of RRT-Treated ESRD in Nanjing - A Ten-Year Experience in Nearly Three Million Insurance Covered Population.

    Science.gov (United States)

    Han, Yu-Chen; Huang, Han-Ming; Sun, Ling; Tan, Chao-Ming; Gao, Min; Liu, Hong; Tang, Ri-Ning; Wang, Yan-Li; Wang, Bei; Ma, Kun-Ling; Liu, Bi-Cheng

    2016-01-01

    The growing burden of end-stage renal disease (ESRD) has been a great challenge to the health care system of China. However, the exact epidemiological data for ESRD in China remain unclear. We aimed to investigate the epidemiology of ESRD treated by renal replacement therapy (RRT) in Nanjing based on analysing ten-year data of Nanjing three million insurance covered population. Using the electronic registry system of Urban Employee Basic Medical Insurance (UEBMI), we included all subjects insured by UEBMI in Nanjing from 2005 to 2014 and identified subjects who developed ESRD and started RRT in this cohort. The UEBMI population in Nanjing increased from 1,301,882 in 2005 to 2,921,065 in 2014, among which a total of 5,840 subjects developed ESRD and received RRT. Over the 10-year period, the adjusted incidence rates of RRT in the UEBMI cohort gradually decreased from 289.3pmp in 2005 to 218.8pmp in 2014. However, the adjusted prevalence rate increased steadily from 891.7pmp in 2005 to 1,228.6pmp in 2014. The adjusted annual mortality rate decreased from 138.4 per 1000 patient-years in 2005 to 97.8 per 1000 patient-years in 2014. The long-term survival rate fluctuated over the past decade, with the 1-year survival rate ranging from 85.1% to 91.7%, the 3-year survival rate from 69.9% to 78.3% and the 5-year survival rate from 58% to 65.4%. Nanjing is facing an increasing burden of ESRD with its improvement of medical reform. The ten-year complete registry data on RRT in urban employees in Nanjing provided a unique opportunity to understand the real threat of ESRD confronting China during its process of health care transition.

  9. CD44 variant 9 is a potential biomarker of tumor initiating cells predicting survival outcome in hepatitis C virus-positive patients with resected hepatocellular carcinoma.

    Science.gov (United States)

    Kakehashi, Anna; Ishii, Naomi; Sugihara, Eiji; Gi, Min; Saya, Hideyuki; Wanibuchi, Hideki

    2016-05-01

    This study investigated whether the expression of CD44 variant 9 (CD44v9) might be a functional marker of tumor-initiating stem-like cells in primary hepatocellular carcinomas (HCCs) of hepatitis C virus (HCV)(+) patients and provide an indicator of patient survival, as well as associated mechanisms. A total of 90 HCV(+) HCC patients who underwent surgery from 2006 to 2011 were enrolled and monitored for 2-8 years. Expression of CD44v9 was validated immunohistochemically in all HCCs, followed by comparative proteome, survival, and clinicopathological analyses. CD44 variant 8--10 was further evaluated in diethylnitrosamine-induced HCCs of C57Bl/6J mice. Focally localized CD44v(+) cells with a membranous staining pattern were detected in human HCV(+) and mouse HCCs. CD44v9(+) cells of HCCs were predominantly negative for Ki67 and P-p38, indicating decrease of cell proliferation in the CD44v9(+) tumor cell population, likely to be related to suppression of intracellular oxidative stress due to activation of Nrf2-mediated signaling, DNA repair, and inhibition of xenobiotic metabolism. CD44v9 IHC evaluation in 90 HCV(+) HCC cases revealed that positive expression was significantly associated with poor overall and recurrence-free survival, a younger age, poor histological differentiation of HCCs, and high alkaline phosphatase levels compared with patients with negative expression. CD44v9 is concluded to be a potential biomarker of tumor-initiating stem-like cells and a prognostic marker in HCV(+) HCC patients associated with Nrf2-mediated resistance to oxidative stress. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  10. Genetic variants and non-genetic factors predict circulating vitamin D levels in Hispanic and non-Hispanic White women: the Breast Cancer Health Disparities Study

    Science.gov (United States)

    Wang, Wei; Ingles, Sue Ann; Torres-Mejía, Gabriela; Stern, Mariana C; Stanczyk, Frank Z; Schwartz, Gary G; Nelson, David O; Fejerman, Laura; Wolff, Roger K; Slattery, Martha L; John, Esther M

    2014-01-01

    Genome-wide association studies (GWAS) have identified common polymorphisms in or near GC, CYP2R1, CYP24A1, and NADSYN1/DHCR7 genes to be associated with circulating levels of 25-hydroxyvitamin D [25(OH)D] in European populations. To replicate these GWAS findings, we examined six selected polymorphisms from these regions and their relation with circulating 25(OH)D levels in 1,605 Hispanic women (629 U.S. Hispanics and 976 Mexicans) and 354 non-Hispanic White (NHW) women. We also assessed the potential interactions between these variants and known non-genetic predictors of 25(OH)D levels, including body mass index (BMI), sunlight exposure and vitamin D intake from diet and supplements. The minor alleles of the two GC polymorphisms (rs7041 and rs2282679) were significantly associated with lower 25(OH)D levels in both Hispanic and NHW women. The CYP2R1 polymorphism, rs2060793, also was significantly associated with 25(OH)D levels in both groups. We found no significant associations for the polymorphisms in the CYP24A1. In Hispanic controls, 25(OH)D levels were significantly associated with the rs12785878T and rs1790349G haplotype in the NADSYN1/DHCR7 region. Significant interactions between GC rs2282679 and BMI and between rs12785878 and time spent in outdoor activities were observed. These results provide further support for the contribution of common genetic variants to individual variability in circulating 25(OH)D levels. The observed interactions between SNPs and non-genetic factors warrant confirmation. PMID:24596595

  11. Predictive value of testing for multiple genetic variants in multifactorial diseases: implications for the discourse on ethical, legal and social issues

    Directory of Open Access Journals (Sweden)

    A. Cecile J.W. Janssens

    2006-12-01

    Full Text Available Multifactorial diseases such as type 2 diabetes, osteoporosis, and cardiovascular disease are caused by a complex interplay of many genetic and nongenetic factors, each of which conveys a minor increase in the risk of disease. Unraveling the genetic origins of these diseases is expected to lead to individualized medicine, in which the prevention and treatment strategies are personalized on the basis of the results of predictive genetic tests. This great optimism is counterbalanced by concerns about the ethical, legal, and social implications of genomic medicine, such as the protection of privacy and autonomy, stigmatization, discrimination, and the psychological burden of genetic testing. These concerns are translated from genetic testing in monogenic disorders, but this translation may not be appropriate. Multiple genetic testing (genomic profiling has essential differences from genetic testing in monogenic disorders. The differences lie in the lower predictive value of the test results, the pleiotropic effects of susceptibility genes, and the low inheritance of genomic profiles. For these reasons, genomic profiling may be more similar to nongenetic tests than to predictive tests for monogenic diseases. Therefore, ethical, legal, and social issues that apply to predictive genetic testing for monogenic diseases may not be relevant for the prediction of multifactorial disorders in genomic medicine.

  12. Do HDL and LDL subfractions play a role in atherosclerosis in end-stage renal disease (ESRD) patients?

    Science.gov (United States)

    Gluba-Brzózka, Anna; Franczyk, Beata; Banach, Maciej; Rysz-Górzyńska, Magdalena

    2017-01-01

    Significantly increased cardiovascular mortality in patients with chronic kidney (CKD) disease cannot be explained by traditional risk factors. Recent studies revealed that the quality of HDL and LDL cholesterol may be more important than their serum levels. The aim of this study was to assess which LDL and HDL subfractions were more abundant in end-stage renal disease (ESRD) patients and to analyse whether subfraction distribution could be associated with accelerated atherosclerotic processes. This study included 50 ESRD patients undergoing dialysis and 20 healthy volunteers. LDL and HDL subfractions were analysed in serum with the use of Lipoprint system. All patients had intima-media thickness (IMT) measured. Statistically significant differences in subfractions between control and study group were observed in case of: HDL1 (p < 0.0001), HDL2 (p = 0.009), HDL3 (p < 0.0001), HDL4 (p = 0.003), HDL5 (p = 0.01), HDL7 (p < 0.0001), HDL8 (p < 0.0001), HDL9 (p < 0.0001), HDL10 (p < 0.0001), large HDL (p < 0.0001), HDL Small (p < 0.0001) as well as IDL-B (p = 0.014), IDLA (p = 0.011), LDL2 (p = 0.007). Significant differences were also observed in HDL and LDL subfraction distribution between haemodialysis patients with normal and increased IMT: HDL6 (p = 0.020), HDL Large (HDL1-3) (p = 0.017), HDL Intermediate (HDL4-7) (p = 0.017). This study revealed that ESRD influenced HDL subfractions. In HD patients, large HDL subfractions are more abundant while small HDL fraction is more frequent in healthy persons. It failed to show the influence of end-stage disease on LDL subfraction levels. Shift in HDL subfractions might be responsible for the increased risk of atherosclerosis in CKD patients.

  13. Dietary Patterns and Risk of Death and Progression to ESRD in Individuals With CKD: A Cohort Study

    Science.gov (United States)

    Gutiérrez, Orlando M.; Muntner, Paul; Rizk, Dana V.; McClellan, William M.; Warnock, David G.; Newby, P.K.; Judd, Suzanne E.

    2014-01-01

    Background Nutrition is strongly linked with health outcomes in chronic kidney disease (CKD). However, few studies have examined relationships between dietary patterns and health outcomes in persons with CKD. Study Design Observational cohort study. Setting & Participants 3,972 participants with CKD (defined as an estimated glomerular filtration rate < 60 ml/min/1.73 m2 or an albumin-creatinine ratio ≥30 mg/g at baseline) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a prospective cohort study of 30,239 black and white adults at least 45 years of age. Predictors Five empirically derived dietary patterns identified via factor analysis: “Convenience” (Chinese and Mexican foods, pizza, other mixed dishes), “Plant-Based” (fruits, vegetables), “Sweets/Fats” (sugary foods), “Southern” (fried foods, organ meats, sweetened beverages), and “Alcohol/Salads” (alcohol, green-leafy vegetables, salad dressing). Outcomes All-cause mortality and end-stage renal disease (ESRD). Results A total of 816 deaths and 141 ESRD events were observed over approximately 6 years of follow-up. There were no statistically significant associations of Convenience, Sweets/Fats or Alcohol/Salads pattern scores with all-cause mortality after multivariable adjustment. In Cox regression models adjusted for sociodemographic factors, energy intake, co-morbidities, and baseline kidney function, higher Plant-Based pattern scores (indicating greater consistency with the pattern) were associated with lower risk of mortality (HR comparing fourth to first quartile, 0.77; 95%CI, 0.61–0.97) whereas higher Southern pattern scores were associated with greater risk of mortality (HR comparing fourth to first quartile, 1.51; 95%CI, 1.19–1.92). There were no associations of dietary patterns with incident ESRD in multivariable-adjusted models. Limitations Missing dietary pattern data, potential residual confounding from lifestyle factors. Conclusions A

  14. Health-related quality of life of Asian patients with end-stage renal disease (ESRD) in Singapore.

    Science.gov (United States)

    Yang, F; Griva, K; Lau, T; Vathsala, A; Lee, E; Ng, H J; Mooppil, N; Foo, M; Newman, S P; Chia, K S; Luo, N

    2015-09-01

    This study aimed to identify factors associated with the health-related quality of life (HRQOL) of multiethnic Asian end-stage renal disease (ESRD) patients treated with dialysis. The role of dialysis modality was also explored. Data used in this study were from two cross-sectional surveys of Singaporean ESRD patients on haemodialysis (HD) or peritoneal dialysis (PD). In both surveys, participants were assessed using the kidney disease quality of life (KDQOL) instrument and questions assessing socio-demographic characteristics. Clinical data including co-morbidity (measured by Charlson comorbidity index [CCI]), albumin level, haemoglobin level, and dialysis-related variables (e.g. dialysis vintage and dialysis adequacy) were retrieved from medical records. The 36-item KDQOL (KDQOL-36) was used to generate three summary scores (physical component summary [PCS], mental component summary [MCS] and kidney disease component summary [KDCS]) and two health utility scores (Short Form 6-dimension [SF-6D] and EuroQol 5-dimension [EQ-5D]). Linear regression analysis was performed to examine the association of factors with each of the HRQOL scale scores. Five hundred and two patients were included in the study (mean age 57.1 years; male 52.4 %; HD 236, PD 266). Mean [standard deviation (SD)] PCS, MCS and KDCS scores were 37.9 (9.7), 46.4 (10.8) and 57.6 (18.1), respectively. Mean (SD) health utility score was 0.66 (0.12) for SF-6D and 0.60 (0.21) for EQ-5D. In multivariate regression analysis, factors found to be significantly associated with better HRQOL included: young (60 years), low CCI (<5), high albumin (≥37 g/l) and high haemoglobin (≥11 g/dl) with PCS; long dialysis vintage (≥3.5 years) with MCS; old age, Malay ethnicity and PD modality with KDCS; low CCI, high albumin and high haemoglobin with EQ-5D and high albumin with SF-6D. Clinical characteristics are better predictors of HRQOL in ESRD patients than socio-demographics in Singapore. Dialysis modality has no

  15. Corticotrophin-Releasing Hormone Type 1 Receptor Gene (CRHR1 Variants Predict Posttraumatic Stress Disorder Onset and Course in Pediatric Injury Patients

    Directory of Open Access Journals (Sweden)

    Ananda B. Amstadter

    2011-01-01

    Full Text Available Posttraumatic stress disorder (PTSD is a common and disabling anxiety disorder that may occur in the aftermath of exposure to potentially traumatic life events. PTSD is moderately heritable, but few specific molecular variants accounting for this heritability have been identified. Genes regulating the hypothalamic-pituitary-adrenal (HPA axis, such as corticotrophin-releasing hormone type 1 receptor gene (CRHR1, have been implicated in traumatic-stress related phenotypes but have yet to be studied in relation to PTSD. The present study sought to examine the relation between 9 single nucleotide polymorphisms (SNPs in the CRHR1 gene and posttraumatic stress symptoms in a prospective study of pediatric injury patients (n = 103 who were first assessed in the acute aftermath of their injury at the hospital. Results indicated that multiple SNPs were associated with acute symptoms at a univariate level, and after correction for multiple testing, rs12944712 was significantly related to acute PTSD symptoms. Longitudinal latent growth curve analyses suggest that rs12944712 is also related to both acute symptom level and trajectory of symptoms over time. The present study adds support for the role of CRHR1 in the stress response following potentially traumatic event exposure in youth. It should be noted that the sample size in this study was small, and therefore statistical power was low; following, results from this study should be considered preliminary. Although results are not definitive, the findings from this study warrant future replication studies on how variation in this gene relates to response to traumatic event exposure in youth.

  16. Familial Risk and a Genome-Wide Supported DRD2 Variant for Schizophrenia Predict Lateral Prefrontal-Amygdala Effective Connectivity During Emotion Processing.

    Science.gov (United States)

    Quarto, Tiziana; Paparella, Isabella; De Tullio, Davide; Viscanti, Giovanna; Fazio, Leonardo; Taurisano, Paolo; Romano, Raffaella; Rampino, Antonio; Masellis, Rita; Popolizio, Teresa; Selvaggi, Pierluigi; Pergola, Giulio; Bertolino, Alessandro; Blasi, Giuseppe

    2017-09-16

    The brain functional mechanisms translating genetic risk into emotional symptoms in schizophrenia (SCZ) may include abnormal functional integration between areas key for emotion processing, such as the amygdala and the lateral prefrontal cortex (LPFC). Indeed, investigation of these mechanisms is also complicated by emotion processing comprising different subcomponents and by disease-associated state variables. Here, our aim was to investigate the relationship between risk for SCZ and effective connectivity between the amygdala and the LPFC during different subcomponents of emotion processing. Thus, we first characterized with dynamic causal modeling (DCM) physiological patterns of LPFC-amygdala effective connectivity in healthy controls (HC) during implicit and explicit emotion processing. Then, we compared DCM patterns in a subsample of HC, in patients with SCZ and in healthy siblings of patients (SIB), matched for demographics. Finally, we investigated in HC association of LPFC-amygdala effective connectivity with a genome-wide supported variant increasing genetic risk for SCZ and possibly relevant to emotion processing (DRD2 rs2514218). In HC, we found that a "bottom-up" amygdala-to-LPFC pattern during implicit processing and a "top-down" LPFC-to-amygdala pattern during explicit processing were the most likely directional models of effective connectivity. Differently, implicit emotion processing in SIB, SCZ, and HC homozygous for the SCZ risk rs2514218 C allele was associated with decreased probability for the "bottom-up" as well as with increased probability for the "top-down" model. These findings suggest that task-specific anomaly in the directional flow of information or disconnection between the amygdala and the LPFC is a good candidate endophenotype of SCZ. © The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  17. Diagnostic accuracy of fractional exhaled nitric oxide measurement in predicting cough-variant asthma and eosinophilic bronchitis in adults with chronic cough: A systematic review and meta-analysis.

    Science.gov (United States)

    Song, Woo-Jung; Kim, Hyun Jung; Shim, Ji-Su; Won, Ha-Kyeong; Kang, Sung-Yoon; Sohn, Kyoung-Hee; Kim, Byung-Keun; Jo, Eun-Jung; Kim, Min-Hye; Kim, Sang-Heon; Park, Heung-Woo; Kim, Sun-Sin; Chang, Yoon-Seok; Morice, Alyn H; Lee, Byung-Jae; Cho, Sang-Heon

    2017-09-01

    Individual studies have suggested the utility of fractional exhaled nitric oxide (Feno) measurement in detecting cough-variant asthma (CVA) and eosinophilic bronchitis (EB) in patients with chronic cough. We sought to obtain summary estimates of diagnostic test accuracy of Feno measurement in predicting CVA, EB, or both in adults with chronic cough. Electronic databases were searched for studies published until January 2016, without language restriction. Cross-sectional studies that reported the diagnostic accuracy of Feno measurement for detecting CVA or EB were included. Risk of bias was assessed with Quality Assessment of Diagnostic Accuracy Studies 2. Random effects meta-analyses were performed to obtain summary estimates of the diagnostic accuracy of Feno measurement. A total of 15 studies involving 2187 adults with chronic cough were identified. Feno measurement had a moderate diagnostic accuracy in predicting CVA in patients with chronic cough, showing the summary area under the curve to be 0.87 (95% CI, 0.83-0.89). Specificity was higher and more consistent than sensitivity (0.85 [95% CI, 0.81-0.88] and 0.72 [95% CI, 0.61-0.81], respectively). However, in the nonasthmatic population with chronic cough, the diagnostic accuracy to predict EB was found to be relatively lower (summary area under the curve, 0.81 [95% CI, 0.77-0.84]), and specificity was inconsistent. The present meta-analyses indicated the diagnostic potential of Feno measurement as a rule-in test for detecting CVA in adult patients with chronic cough. However, Feno measurement may not be useful to predict EB in nonasthmatic subjects with chronic cough. These findings warrant further studies to validate the roles of Feno measurement in clinical practice of patients with chronic cough. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  18. Geriatric nutritional risk index accurately predicts cardiovascular mortality in incident hemodialysis patients.

    Science.gov (United States)

    Takahashi, Hiroshi; Ito, Yasuhiko; Ishii, Hideki; Aoyama, Toru; Kamoi, Daisuke; Kasuga, Hirotake; Yasuda, Kaoru; Maruyama, Shoichi; Matsuo, Seiichi; Murohara, Toyoaki; Yuzawa, Yukio

    2014-07-01

    Cardiovascular disease (CVD) is a leading cause of death in end-stage renal disease (ESRD) patients. Protein-energy wasting (PEW) or malnutrition is common in this population, and is associated with increasing risk of mortality. The geriatric nutritional risk index (GNRI) has been developed as a tool to assess the nutritional risk, and is associated with mortality not only in elderly patients but also in ESRD patients. However, whether the GNRI could predict the mortality due to CVD remains unclear in this population. We investigated the prognostic value of GNRI at initiation of hemodialysis (HD) therapy for CVD mortality in a large cohort of ESRD patients. Serum albumin, body weight, and height for calculating GNRI were measured in 1568 ESRD patients. Thereafter, the patients were divided into quartiles according to GNRI levels [quartile 1 (Q1): 97.3], and were followed up for up to 10 years. GNRI levels independently correlated with serum C-reactive-protein levels (β = -0.126, p index was also greater in an established CVD risk model with GNRI (0.749) compared to that with albumin (0.730), body mass index (0.732), and alone (0.710). Similar results were observed for all-cause mortality. GNRI at initiation of HD therapy could predict CVD mortality with incremental value of the predictability compared to serum albumin and body mass index in ESRD patients. Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

  19. Extreme Levels of HbA1c Increase Incident ESRD Risk in Chinese Patients with Type 2 Diabetes: Competing Risk Analysis in National Cohort of Taiwan Diabetes Study.

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    Li-Na Liao

    Full Text Available Whether HbA1c is a predictor of end-stage renal disease (ESRD in type 2 diabetes patients remains unclear. This study evaluated relationship between HbA1c and ESRD in Chinese patients with type 2 diabetes.Patients aged ≥ 30 years who were free of ESRD (n = 51 681 were included from National Diabetes Care Management Program from 2002-2003. Extended Cox proportional hazard model with competing risk of death served to evaluate association between HbA1c level and ESRD.A total of 2613 (5.06% people developed ESRD during a follow-up period of 8.1 years. Overall incidence rate of ESRD was 6.26 per 1000 person-years. Patients with high levels of HbA1c had a high incidence rate of ESRD, from 4.29 for HbA1c of  6.0%-6.9% to 10.33 for HbA1c ≥ 10.0% per 1000 person-years. Patients with HbA1c < 6.0% particularly had a slightly higher ESRD incidence (4.34 per 1000 person-years than those with HbA1c  of 6.0%-6.9%. A J-shaped relationship between HbA1c level and ESRD risk was observed. After adjustment, patients with HbA1c < 6.0% and ≥ 10.0% exhibited an increased risk of ESRD (HR: 1.99, 95% CI: 1.62-2.44; HR: 4.42, 95% CI: 3.80-5.14, respectively compared with those with HbA1c of 6.0%-6.9%.Diabetes care has focused on preventing hyperglycemia, but not hypoglycemia. Our study revealed that HbA1c level ≥ 7.0% was linked with increased ESRD risk in type 2 diabetes patients, and that HbA1c < 6.0% also had the potential to increase ESRD risk. Our study provides epidemiological evidence that appropriate glycemic control is essential for diabetes care to meet HbA1c targets and improve outcomes without increasing the risk to this population. Clinicians need to pay attention to HbA1c results on diabetic nephropathy.

  20. Variant profiling of evolving prokaryotic populations

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    Markus Zojer

    2017-02-01

    Full Text Available Genomic heterogeneity of bacterial species is observed and studied in experimental evolution experiments and clinical diagnostics, and occurs as micro-diversity of natural habitats. The challenge for genome research is to accurately capture this heterogeneity with the currently used short sequencing reads. Recent advances in NGS technologies improved the speed and coverage and thus allowed for deep sequencing of bacterial populations. This facilitates the quantitative assessment of genomic heterogeneity, including low frequency alleles or haplotypes. However, false positive variant predictions due to sequencing errors and mapping artifacts of short reads need to be prevented. We therefore created VarCap, a workflow for the reliable prediction of different types of variants even at low frequencies. In order to predict SNPs, InDels and structural variations, we evaluated the sensitivity and accuracy of different software tools using synthetic read data. The results suggested that the best sensitivity could be reached by a union of different tools, however at the price of increased false positives. We identified possible reasons for false predictions and used this knowledge to improve the accuracy by post-filtering the predicted variants according to properties such as frequency, coverage, genomic environment/localization and co-localization with other variants. We observed that best precision was achieved by using an intersection of at least two tools per variant. This resulted in the reliable prediction of variants above a minimum relative abundance of 2%. VarCap is designed for being routinely used within experimental evolution experiments or for clinical diagnostics. The detected variants are reported as frequencies within a VCF file and as a graphical overview of the distribution of the different variant/allele/haplotype frequencies. The source code of VarCap is available at https://github.com/ma2o/VarCap. In order to provide this workflow to

  1. IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic hepatitis C virus infection in a European Cohort: a cross-sectional study.

    Directory of Open Access Journals (Sweden)

    Vijayaprakash Suppiah

    2011-09-01

    Full Text Available To date, drug response genes have not proved as useful in clinical practice as was anticipated at the start of the genomic era. An exception is in the treatment of chronic hepatitis C virus (HCV genotype 1 infection with pegylated interferon-alpha and ribavirin (PegIFN/R. Viral clearance is achieved in 40%-50% of patients. Interleukin 28B (IL28B genotype predicts treatment-induced and spontaneous clearance. To improve the predictive value of this genotype, we studied the combined effect of variants of IL28B with human leukocyte antigen C (HLA-C, and its ligands the killer immunoglobulin-like receptors (KIR, which have previously been implicated in HCV viral control.We genotyped chronic hepatitis C (CHC genotype 1 patients with PegIFN/R treatment-induced clearance (n = 417 and treatment failure (n = 493, and 234 individuals with spontaneous clearance, for HLA-C C1 versus C2, presence of inhibitory and activating KIR genes, and two IL28B SNPs, rs8099917 and rs12979860. All individuals were Europeans or of European descent. IL28B SNP rs8099917 "G" was associated with absence of treatment-induced clearance (odds ratio [OR] 2.19, p = 1.27×10(-8, 1.67-2.88 and absence of spontaneous clearance (OR 3.83, p = 1.71×10(-14, 2.67-5.48 of HCV, as was rs12979860, with slightly lower ORs. The HLA-C C2C2 genotype was also over-represented in patients who failed treatment (OR 1.52, p = 0.024, 1.05-2.20, but was not associated with spontaneous clearance. Prediction of treatment failure improved from 66% with IL28B to 80% using both genes in this cohort (OR 3.78, p = 8.83×10(-6, 2.03-7.04. There was evidence that KIR2DL3 and KIR2DS2 carriage also altered HCV treatment response in combination with HLA-C and IL28B.Genotyping for IL28B, HLA-C, and KIR genes improves prediction of HCV treatment response. These findings support a role for natural killer (NK cell activation in PegIFN/R treatment-induced clearance, partially mediated by IL28B.

  2. Desmoplastic variant of ameloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Sohn, Jeong Ick; Kim, Dong Youn; Choi, Karp Shik [Dept. of Dental Radiology, College of Dentistry, Kyungpook National University, Daegu (Korea, Republic of)

    1995-02-15

    Desmoplastic variant of ameloblastoma is new and unusual variant of ameloblastoma with extensive stromal desmoplastic proliferation. The authors experienced a case of desmoplastic variant of amleloblastoma with moderate-defined radiolucency on the right maxillary anterior area in 62-year-old female. As a result of careful analysis of clinical, radiological examinations, we diagnosed it as desmoplastic variant of ameloblastoma. The following results were obtained; 1. Main clinical symptoms were nontender bony swelling with normal intact overlying mucosa on the right maxillary anterior area. 2. Radiographically, moderate-defined, multilocular radioluceney on the right maxillary anterior area were shown, and severe cortical bony thinning and expansion to labial and palatal sides were also observed. And this lesion was shown to be extended to the right nasal cavity. 3. Histopathologically, follicle-like epithelial islands with densely abundant collagenous stroma were morphologically compressed.

  3. A patient-centered vision of care for ESRD: dialysis as a bridging treatment or as a final destination?

    Science.gov (United States)

    Vandecasteele, Stefaan J; Kurella Tamura, Manjula

    2014-08-01

    The ESRD population is heterogeneous, including patients without severe comorbidity for whom dialysis is a bridge to transplantation or a long-term maintenance treatment, as well as patients with a limited life expectancy as a result of advanced age or severe comorbidity for whom dialysis will be the final treatment destination. The complex medical and social context of this latter group fits poorly in the homogeneous, disease-centered, and process-driven approach of many clinical practice guidelines for dialysis. In this commentary, we argue that the standards of treatment allocated to each individual patient should be defined not merely by his or her disease state, but also by his or her preferences and prognosis. In this more patient-centered approach, three attainable treatment goals with a corresponding therapeutic approach could be defined: (1) dialysis as bridging or long-term maintenance treatment, (2) dialysis as final treatment destination, and (3) active medical management without dialysis. For patients with a better overall prognosis, this approach will emphasize complication prevention and long-term survival. For patients with a limited overall prognosis, strictly disease-centered interventions often impose a treatment burden that does not translate into a proportional improvement in quantity or quality of life. For these patients, a patient-centered approach will place more emphasis on palliative management strategies that are less disease specific. Copyright © 2014 by the American Society of Nephrology.

  4. Assessment of Functional Effects of Unclassified Genetic Variants

    NARCIS (Netherlands)

    Couch, Fergus J.; Rasmussen, Lene Juel; Hofstra, Robert; Monteiro, Alvaro N. A.; Greenblatt, Marc S.; de Wind, Niels

    2008-01-01

    Inherited predisposition to disease is often linked to reduced activity of a disease associated gene product. Thus, quantitation of the influence of inherited variants on gene function can potentially be used to predict the disease relevance of these variants. While many disease genes have been

  5. Progression of stages 3b–5 chronic kidney disease—Preliminary results of Taiwan National Pre-ESRD Disease Management Program in Southern Taiwan

    Directory of Open Access Journals (Sweden)

    Chun-Mei Lin

    2013-12-01

    Conclusion: Even though we cannot conclude with certainty that the Taiwan pre-ESRD disease management program is beneficial in slowing the progression of CKD stages 3b–5, our preliminary results seem to suggest this trend. Furthermore, the program may be improved by integrating it with other programs, such as those on diabetes and hypertension, thus making it a more patient-centered, multidisciplinary program.

  6. End Stage Renal Disease: Not a Contraindication for Minor Oral Surgery-Protocol for the Management of Oral Surgery patients with ESRD on Hemodialysis.

    Science.gov (United States)

    Pendem, Sneha; Lakshmi Narayana, G; Ravi, Poornima

    2017-06-01

    To describe a safe and effective protocol for the management of patients with end stage renal disease (ESRD) undergoing minor oral surgery. A prospective cohort study was conducted on all patients with ESRD who were referred for dental consultation. A definite protocol was designed in consultation with the nephrologist to minimize the risk of bleeding and wound healing complications during and after the minor surgical procedures. 36 patients consented for the protocol to be followed while 4 patients did not comply with the protocol and in 2 cases the protocol could be followed. The intra operative, post operative bleeding, and the wound healing were assessed in these patients. 36 patients had uneventful extractions as the blood pressure was brought down to pre hypertensive stage following the protocol. 4 patients who did not comply with the protocol had episodes of bleeding in the post operative period. There were two special scenarios where additional precautions had to be taken have been discussed. The wound healing was satisfactory in all these patients. The protocol discussed in this article helps us provide safe minor oral surgical treatment in patients with ESRD.

  7. P-Cresyl Sulfate Is a Valuable Predictor of Clinical Outcomes in Pre-ESRD Patients

    Directory of Open Access Journals (Sweden)

    Cheng-Jui Lin

    2014-01-01

    Full Text Available Background/Aims. Previous studies have reported p-cresyl sulfate (PCS was related to endothelial dysfunction and adverse clinical effect. We investigate the adverse effects of PCS on clinical outcomes in a chronic kidney disease (CKD cohort study. Methods. 72 predialysis patients were enrolled from a single medical center. Serum biochemistry data and PCS were measured. The clinical outcomes including cardiovascular event, all-cause mortality, and dialysis event were recorded during a 3-year follow-up. Results. After adjusting other independent variables, multivariate Cox regression analysis showed age (HR: 1.12, P=0.01, cardiovascular disease history (HR: 6.28, P=0.02, and PCS (HR: 1.12, P=0.02 were independently associated with cardiovascular event; age (HR: 0.91, P6 mg/L were significantly associated with cardiovascular and dialysis event (log rank P=0.03, log rank P<0.01, resp.. Conclusion. Our study shows serum PCS could be a valuable marker in predicting cardiovascular event and renal function progression in CKD patients without dialysis.

  8. Three-dimensional structure of β-cell-specific zinc transporter, ZnT-8, predicted from the type 2 diabetes-associated gene variant SLC30A8 R325W

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    Weijers Rob NM

    2010-06-01

    to the correct sites in the pancreatic islet cells and are consistent with the observation that the SLC30A8 gene variant R325W has a low predicted value for future type 2 diabetes at population-based level.

  9. Prediction

    CERN Document Server

    Sornette, Didier

    2010-01-01

    This chapter first presents a rather personal view of some different aspects of predictability, going in crescendo from simple linear systems to high-dimensional nonlinear systems with stochastic forcing, which exhibit emergent properties such as phase transitions and regime shifts. Then, a detailed correspondence between the phenomenology of earthquakes, financial crashes and epileptic seizures is offered. The presented statistical evidence provides the substance of a general phase diagram for understanding the many facets of the spatio-temporal organization of these systems. A key insight is to organize the evidence and mechanisms in terms of two summarizing measures: (i) amplitude of disorder or heterogeneity in the system and (ii) level of coupling or interaction strength among the system's components. On the basis of the recently identified remarkable correspondence between earthquakes and seizures, we present detailed information on a class of stochastic point processes that has been found to be particu...

  10. Genetic variants linked to education predict longevity

    NARCIS (Netherlands)

    R.E. Marioni (Riccardo); Ritchie, S.J. (Stuart J.); P.K. Joshi (Peter); S. Hagenaars (Saskia); A. Okbay (Aysu); K. Fischer (Krista); Adams, M.J. (Mark J.); W.D. Hill (W. David); G. Davies (Gail); Nagy, R. (Reka); Amador, C. (Carmen); K. Läll; A. Metspalu (Andres); D.C. Liewald (David C.); A. Campbell (Archie); J.F. Wilson (James F.); C. Hayward (Caroline); T. Esko (Tõnu); D.J. Porteous (David J.); Gale, C.R. (Catharine R.); I.J. Deary (Ian J.)

    2016-01-01

    textabstractEducational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian

  11. Genetic variants linked to education predict longevity

    NARCIS (Netherlands)

    Marioni, R.E.; Ritchie, S.J.; Joshi, P.K.; Hagenaars, S.P.; Okbay, A.; Fischer, K.; Adams, M.J.; Hill, W.D.; Davies, G.; Nagy, R.; Amador, C.; Lall, K.; Metspalu, A.; Liewald, D.C.; Campbell, A.; Wilson, J.F.; Hayward, C.; Esko, T.; Porteous, D.J.; Gale, C.R.; Deary, I.J.; Galesloot, T.E.; Franke, B.; Kiemeney, L.A.L.M.; et al.,

    2016-01-01

    Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = approximately 17,000; UK Biobank, n = approximately 115,000; and the

  12. Hemoglobin Variants in Mice

    Energy Technology Data Exchange (ETDEWEB)

    Popp, Raymond A.

    1965-04-22

    Variability among mammalian hemoglobins was observed many years ago (35). The chemical basis for differences among hemoglobins from different species of mammals has been studied by several investigators (5, 11, 18, 48). As well as interspecies differences, hemoglobin variants are frequently found within a species of mammals (2, 3, 7, 16) The inheritance of these intraspecies variants can be studied, and pedigrees indicate that the type of hemoglobin synthesized in an individual is genetically controlled (20). Several of the variant human hemoglobins are f'unctionally deficient (7, 16). Such hemoglobin anomalies are of basic interest to man because of the vital role of hemoglobin for transporting oxygen to all tissues of the body.

  13. A simple tool to predict end-stage renal disease within 1 year in elderly adults with advanced chronic kidney disease.

    Science.gov (United States)

    Drawz, Paul E; Goswami, Puja; Azem, Reem; Babineau, Denise C; Rahman, Mahboob

    2013-05-01

    To develop and validate a model to predict 1-year risk of end-stage renal disease (ESRD) in elderly subjects with advanced chronic kidney disease (CKD). Retrospective. Veterans Affairs Medical Center. Individuals aged 65 and older with CKD with an estimated glomerular filtration rate (eGFR) less than 30 mL/min per 1.73 m(2) . The outcome was ESRD within 1 year of the index eGFR. Cox regression was used to develop a predictive model (Veterans Affairs (VA) risk score) that was validated in a separate cohort. Of the 1,866 participants in the developmental cohort, 77 developed ESRD. Risk factors for ESRD in the final model were age, congestive heart failure, systolic blood pressure, eGFR, potassium, and albumin. In the validation cohort, the C index for the VA risk score was 0.823. The risk for developing ESRD at 1 year from lowest to highest tertile was 0.08%, 2.7%, and 11.3% (P elderly adults. The Tangri model also had good predictive ability. Individuals and physicians can use these risk models to inform decisions regarding preparation for renal replacement therapy in individuals with advanced CKD. © 2013, Copyright the Authors Journal compilation © 2013, The American Geriatrics Society.

  14. [Histone variants and histone exchange].

    Science.gov (United States)

    Wu, Nan; Gui, Jian-Fang

    2006-04-01

    Histones, as the basic components of nucleosome, are essential to chromatin structure and function. To adapt to various states of chromatin, corresponding histone variants are incorporated in nucleosome, and certain modifications also occur on the variants' tails. These variants change the conformation and stability of nucleosome to facilitate transcriptional activation or deactivation, DNA repairing, heterochromatin formation, and others. During histone exchange, chromatin remodeling complex facilitates histone variant deposition into nucleosome, and different variants have diverse deposition pathways. Recently, research on histone variants is not only a new hotspot in epigenetics, but also a new annotation of "histone code". In addition, histone exchange reveals new changing mechanism of DNA-histone interaction.

  15. ESRD - General Information Data

    Data.gov (United States)

    U.S. Department of Health & Human Services — This page presents Public Use Files and other publicly-available data on CMS End-Stage Renal Disease Program. The focus is on the congressionally mandated Program...

  16. Functional characterization of the plasmacytoma variant translocation 1 gene (PVT1 in diabetic nephropathy.

    Directory of Open Access Journals (Sweden)

    M Lucrecia Alvarez

    Full Text Available We previously observed association between variants in the plasmacytoma variant translocation 1 gene (PVT1 and end-stage renal disease (ESRD attributed to both type 1 and type 2 diabetes, and demonstrated PVT1 expression in a variety of renal cell types. While these findings suggest a role for PVT1 in the development of ESRD, potential mechanisms for involvement remain unknown. The goal of this study was to identify possible molecular mechanisms by which PVT1 may contribute to the development and progression of diabetic kidney disease. We knocked-down PVT1 expression in mesangial cells using RNA interference, and analyzed RNA and protein levels of fibronectin 1 (FN1, collagen, type IV, alpha 1 (COL4A1, transforming growth factor beta 1 (TGFB1 and plasminogen activator inhibitor-1 (SERPINE1 or PAI-1 by qPCR and ELISA, respectively. PVT1 expression was significantly upregulated by glucose treatment in human mesangial cells, as were levels of FN1, COL4A1, TGFB1, and PAI-1. Importantly, PVT1 knockdown significantly reduced mRNA and protein levels of the major ECM proteins, FN1 and COL4A1, and two key regulators of ECM proteins, TGFB1 and PAI-1. However, we observed a higher and more rapid reduction in levels of secreted FN1, COL4A1, and PAI-1 compared with TGFB1, suggesting that at least some of the PVT1 effects on ECM proteins may be independent of this cytokine. These results indicate that PVT1 may mediate the development and progression of diabetic nephropathy through mechanisms involving ECM accumulation.

  17. Histone variants and lipid metabolism

    NARCIS (Netherlands)

    Borghesan, Michela; Mazzoccoli, Gianluigi; Sheedfar, Fareeba; Oben, Jude; Pazienza, Valerio; Vinciguerra, Manlio

    2014-01-01

    Within nucleosomes, canonical histones package the genome, but they can be opportunely replaced with histone variants. The incorporation of histone variants into the nucleosome is a chief cellular strategy to regulate transcription and cellular metabolism. In pathological terms, cellular steatosis

  18. Comparison of mortality in ESRD patients on convective and diffusive extracorporeal treatments. The Registro Lombardo Dialisi E Trapianto.

    Science.gov (United States)

    Locatelli, F; Marcelli, D; Conte, F; Limido, A; Malberti, F; Spotti, D

    1999-01-01

    The aim of this study was to evaluate the effect of convective [hemodiafiltration (HDF) or hemofiltration (HF)] versus diffusive treatments [hemodialysis (HD)] on end-stage renal disease (ESRD) patient mortality and dialysis-related amyloidosis (DRA) using data from the Lombardy Registry. For this purpose, 6, 444 patients (aged 56.4 +/- 15.6 years, females 39.5%, diabetics 10. 6%) who started renal replacement therapy (RRT) on HD, HDF, or HF between 1983 and 1995 were considered. A total of 1,082 patients were treated with HDF or HF (first choice in the case of 188), with a median follow-up of 29.7 months. The median follow-up of the 6,298 patients on HD (first choice in the case of 6256) was 22.4 months. The time of survival on dialysis to carpal tunnel syndrome (CTS) surgery was evaluated as a hard marker of DRA morbidity. Survival was compared by means of the Cox proportional regression hazards model, using CTS surgery and all deaths as events for morbidity and mortality, respectively. Explanatory covariates were age, gender, and comorbidities; dialysis modality was tested as a time-dependent covariate. The relative risk (RR) for CTS surgery was significantly higher in older patients [RR = 1.04 per year of age on admission to RRT, 95% confidence interval (CI) 1.02 to 1.06; P = 0. 0001], in diabetics (RR = 2.63, 95% CI 1.30 to 5.31; P = 0.0007), and in patients with heart disease (RR = 5.36, 95% CI 2.27 to 12.68 P = 0.0001). Adjusting for age and diabetic status, the RR for CTS surgery was 42% lower in the patients treated with HDF or HF (RR = 0. 58, 95% CI 0.35 to 0.95, P = 0.03). The RR for mortality, adjusted for age, gender, and comorbidities, was 10% lower in patients treated with HDF or HF (RR = 0.90, 95% CI 0.76 to 1.06; P = NS). These results support the hypothesis that convective treatments are associated with a nonsignificant trend toward better survival and significantly delay the need for CTS surgery. An older age and the presence of diabetes and

  19. Empowering Esrd Patients For Assisted Self Nutritional Care: A Simple But Effective Intervention For Improving Nutritional Status Of Hemodialysis Patients

    Directory of Open Access Journals (Sweden)

    Pratim Sengupta

    2012-06-01

    Full Text Available Protein energy wasting (PEW is a prevalent problem among hemodialysis patients. Lack of adherence to dietary principle based conventional diet charts often fail to satisfy the nutritional requirements of the patients. We studied the effect of simple nutritional training and empowerment of the patients to formulate their own dietary menu in nutritional parameters of hemodialysis patients in 68 stable non diabetic End stage renal disease (ESRD patients who are on maintenance hemodialysis. The factors which otherwise can affect the nutritional status like sepsis, malignancy,tuberculosis were excluded. At the beginning patient's baseline nutritional status was assessed by anthropometric measurements, Subjective Global Assessment and serum albumin level. Body composition was assessed by linear regression equation (Durin-Womersley and Siri equation. The patients were divided in two comparable groups (Group-A&B. In group A patients were prescribed individualized dietary prescription; based on their nutritional allowance as per KDOQI guideline. In Group-B the patients were initially made familiar with the dietary principals of the commonly consumed food. Then they were trained by renal nutritionist by study material, visual aid, and proportional food models and one to one discussion to formulate a dietary menu, by these they were empowered to formulate their own dietary menu. They were constantly assisted when faced any problem. In both the group the nutritional parameters were reassessed after three months of intervention. The results were analyzed statistically. There was statistically significant mean increment in the fat free mass index in GroupB[0.8%(Gr.-AVs1.0%(Gr.-B,(p<0.05], the mean increment in the serum albumin in the GroupB was also significantly higher than GroupA[(0.6gm/dl(Gr.A Vs 0.9 gm/dl(Gr.B, p<0.0].Compared to Group-A there was statistically favorable anthropometric changes in Group-B. In conclusion patient empowerment and self

  20. Protocol of a mixed method, randomized controlled study to assess the efficacy of a psychosocial intervention to reduce fatigue in patients with End-Stage Renal Disease (ESRD).

    Science.gov (United States)

    van der Borg, Wieke E; Schipper, Karen; Abma, Tineke A

    2016-07-08

    Patients with end-stage renal disease (ESRD) commonly suffer from severe fatigue, which strongly impacts their quality of life (QoL). Although fatigue is often attributed to disease- and treatment characteristics, research also shows that behavioural, psychological and social factors affect perceived fatigue in dialysis patients. Whereas studies on fatigue in other chronic patient groups suggest that psychological or psychosocial interventions are effective in reducing fatigue, such interventions are not yet available for ESRD patients on dialysis treatment. The objective of this study is to examine the efficacy of a psychosocial intervention for dialysis patients aimed at reducing fatigue (primary outcome) and improving QoL (secondary outcome). The intervention consists of counselling sessions led by a social worker. The implementation process and patients' and social workers' expectations and experiences with the intervention will also be evaluated. This study follows a mixed-methods design in which both quantitative and qualitative data will be collected. A multi-centre, randomised controlled trial (RCT) with repeated measures will be conducted to quantitatively assess the efficacy of the psychosocial intervention in reducing fatigue and improving QoL in ESRD patients. Additional secondary outcomes and medical parameters will be assessed. Outcomes will be compared to patients receiving usual care. A sample of 74 severely fatigued dialysis patients will be recruited from 10 dialysis centres. Patients will be randomly assigned to the intervention or control group. Outcomes will be assessed at baseline, post intervention/16 weeks, and at three and six-month follow-ups. A qualitative process evaluation will be conducted parallel to/following the effectiveness RCT. Interviews and focus groups will be conducted to gain insight into patients' and social workers' perspectives on outcomes and implementation procedures. Implementation fidelity will be assessed by audio

  1. Three-dimensional spatial analysis of missense variants in RTEL1 identifies pathogenic variants in patients with Familial Interstitial Pneumonia.

    Science.gov (United States)

    Sivley, R Michael; Sheehan, Jonathan H; Kropski, Jonathan A; Cogan, Joy; Blackwell, Timothy S; Phillips, John A; Bush, William S; Meiler, Jens; Capra, John A

    2018-01-23

    Next-generation sequencing of individuals with genetic diseases often detects candidate rare variants in numerous genes, but determining which are causal remains challenging. We hypothesized that the spatial distribution of missense variants in protein structures contains information about function and pathogenicity that can help prioritize variants of unknown significance (VUS) and elucidate the structural mechanisms leading to disease. To illustrate this approach in a clinical application, we analyzed 13 candidate missense variants in regulator of telomere elongation helicase 1 (RTEL1) identified in patients with Familial Interstitial Pneumonia (FIP). We curated pathogenic and neutral RTEL1 variants from the literature and public databases. We then used homology modeling to construct a 3D structural model of RTEL1 and mapped known variants into this structure. We next developed a pathogenicity prediction algorithm based on proximity to known disease causing and neutral variants and evaluated its performance with leave-one-out cross-validation. We further validated our predictions with segregation analyses, telomere lengths, and mutagenesis data from the homologous XPD protein. Our algorithm for classifying RTEL1 VUS based on spatial proximity to pathogenic and neutral variation accurately distinguished 7 known pathogenic from 29 neutral variants (ROC AUC = 0.85) in the N-terminal domains of RTEL1. Pathogenic proximity scores were also significantly correlated with effects on ATPase activity (Pearson r = -0.65, p = 0.0004) in XPD, a related helicase. Applying the algorithm to 13 VUS identified from sequencing of RTEL1 from patients predicted five out of six disease-segregating VUS to be pathogenic. We provide structural hypotheses regarding how these mutations may disrupt RTEL1 ATPase and helicase function. Spatial analysis of missense variation accurately classified candidate VUS in RTEL1 and suggests how such variants cause disease. Incorporating

  2. VARIANT project - further progress

    Science.gov (United States)

    Korepanov, V.; Negoda, O.; Alleyne, H.; Balikhin, M.; Fedorov, A.; Juchniewicz, J.; Klimov, S.; Krasnoselskikh, V.; Lefeuvre, F.; Lizunov, G.

    VARIANT is a joint international space experiment which will be performed onboard the Ukrainian remote sensing satellite SICH-1M, that will be launched in 2003 at the polar circular orbit with the altitude 670s30 km. The scientific payload includes three instruments for registration of space current density: split Langmuir probe, Rogovski coil and Faraday cup. The equipment also includes sensors for measurements of electric and magnetic fields in the frequency range from DC to 40 kHz. Main objectives of the VARIANT mission are as follows: u direct comparison of the spectral characteristics of the electric and magnetic fields with the characteristics of the field aligned currents in the polar regions; mapping of the field aligned current distribution; u comparative study of the field aligned current structures with the characteristics of the ionospheric convection observed by the system of radars SuperDARN; u comparative study of technological problems associated with different techniques of current density measurements; and the secondary objectives are: u active experiments with the onboard radar; registration of the signatures of the seismo-active and volcanic phenomena; investigation of the man-made impact upon the ionosphere (anthropogenichazards, pollution, etc). Recent space experiments tendency U smaller and cheaper U stimulated the new approach to the functions division between scientific instruments and DPU. The peculiarities of such approach and the practical example of onboard DPU for VARIANT experiment to be launched next year are reported. Flight model of the VARIANT instrument is already installed onboard the satellite and successfully tested. The methodological questions of the spatial current density direct measurement in space plasma are constantly studied and recent advances in this branch, as well as the experimental tests results are discussed. This work was partially supported by NSAU contract 1221 and INTAS grant 2000-465.

  3. Serum Vascular Adhesion Protein-1 Predicts End-Stage Renal Disease in Patients with Type 2 Diabetes.

    Directory of Open Access Journals (Sweden)

    Hung-Yuan Li

    Full Text Available Diabetes is the leading cause of end-stage renal disease (ESRD worldwide. Vascular adhesion protein-1 (VAP-1 participates in inflammation and catalyzes the deamination of primary amines into aldehydes, hydrogen peroxide, and ammonia, both of which are involved in the pathogenesis of diabetic complications. We have shown that serum VAP-1 is higher in patients with diabetes and in patients with chronic kidney disease (CKD, and can predict cardiovascular mortality in subjects with diabetes. In this study, we investigated if serum VAP-1 can predict ESRD in diabetic subjects.In this prospective cohort study, a total of 604 type 2 diabetic subjects were enrolled between 1996 to 2003 at National Taiwan University Hospital, Taiwan, and were followed for a median of 12.36 years. The development of ESRD was ascertained by linking our database with the nationally comprehensive Taiwan Society Nephrology registry. Serum VAP-1 concentrations at enrollment were measured by time-resolved immunofluorometric assay.Subjects with serum VAP-1 in the highest tertile had the highest incidence of ESRD (p<0.001. Every 1-SD increase in serum VAP-1 was associated with a hazard ratio of 1.55 (95%CI 1.12-2.14, p<0.01 for the risk of ESRD, adjusted for smoking, history of cardiovascular disease, body mass index, hypertension, HbA1c, duration of diabetes, total cholesterol, use of statins, ankle-brachial index, estimated GFR, and proteinuria. We developed a risk score comprising serum VAP-1, HbA1c, estimated GFR, and proteinuria, which could predict ESRD with good performance (area under the ROC curve = 0.9406, 95%CI 0.8871-0.9941, sensitivity = 77.3%, and specificity = 92.8%. We also developed an algorithm based on the stage of CKD and a risk score including serum VAP-1, which can stratify these subjects into 3 categories with an ESRD risk of 0.101%/year, 0.131%/year, and 2.427%/year, respectively.In conclusion, serum VAP-1 can predict ESRD and is a useful biomarker to

  4. Polymorphism of the transcription factor 7-like 2 Gene (TCF7L2) interacts with obesity on type-2 diabetes in the PREDIMED Study emphasizing the heterogeneity of genetic variants in type-2 diabetes risk prediction: time for...

    Science.gov (United States)

    Nutrigenetic studies analyzing gene-diet interactions of the TCF7L2-rs7903146 C > T polymorphism on type-2 diabetes (T2D) have shown controversial results. A reason contributing to this may be the additional modulation by obesity. Moreover, TCF7L2-rs7903146 is one of the most influential variants in...

  5. Accuracy and equivalence testing of crown ratio models and assessment of their impact on diameter growth and basal area increment predictions of two variants of the Forest Vegetation Simulator

    Science.gov (United States)

    Laura P. Leites; Andrew P. Robinson; Nicholas L. Crookston

    2009-01-01

    Diameter growth (DG) equations in many existing forest growth and yield models use tree crown ratio (CR) as a predictor variable. Where CR is not measured, it is estimated from other measured variables. We evaluated CR estimation accuracy for the models in two Forest Vegetation Simulator variants: the exponential and the logistic CR models used in the North...

  6. A combined analysis of 48 type 2 diabetes genetic risk variants shows no discriminative value to predict time to first prescription of a glucose lowering drug in Danish patients with screen detected type 2 diabetes

    DEFF Research Database (Denmark)

    Hornbak, Malene; Allin, Kristine Højgaard; Jensen, Majken Linnemann

    2014-01-01

    OBJECTIVE: To investigate the genetic influence of 48 type 2 diabetes susceptibility variants on disease progression measured as risk of early prescription redemption of glucose lowering drugs in screen-detected patients with type 2 diabetes. METHODS: We studied type 2 diabetes progression in 1,4...

  7. Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group

    NARCIS (Netherlands)

    Tallman, Martin S.; Kim, Haesook T.; Montesinos, Pau; Appelbaum, Frederick R.; de la Serna, Javier; Bennett, John M.; Deben, Guillermo; Bloomfield, Clara D.; Gonzalez, Jose; Feusner, James H.; Gonzalez, Marcos; Gallagher, Robert; Gonzalez-San Miguel, Jose D.; Larson, Richard A.; Milone, Gustavo; Paietta, Elisabeth; Rayon, Chelo; Rowe, Jacob M.; Rivas, Concha; Schiffer, Charles A.; Vellenga, Edo; Shepherd, Lois; Slack, James L.; Wiernik, Peter H.; Willman, Cheryl L.; Sanz, Miguel A.

    2010-01-01

    Few studies have examined the outcome of large numbers of patients with the microgranular variant (M3V) of acute promyelocytic leukemia (APL) in the all-trans retinoic acid era. Here, the outcome of 155 patients treated with all-transretinoic acid-based therapy on 3 clinical trials, North American

  8. Variants of glycoside hydrolases

    Energy Technology Data Exchange (ETDEWEB)

    Teter, Sarah; Ward, Connie; Cherry, Joel; Jones, Aubrey; Harris, Paul; Yi, Jung

    2017-07-11

    The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  9. MBL2 gene variants coding for mannose-binding lectin deficiency are associated with increased risk of nephritis in Danish patients with systemic lupus erythematosus.

    Science.gov (United States)

    Tanha, N; Troelsen, L; From Hermansen, M-L; Kjær, L; Faurschou, M; Garred, P; Jacobsen, S

    2014-10-01

    Autoimmunity may in part result from deficiencies in the processing of apoptotic debris. As mannose-binding lectin (MBL) is involved in such processes, we hypothesized that the variants in the MBL2 gene resulting in MBL deficiency confer an increased risk of nephritis in systemic lupus erythematosus (SLE). A total of 171 SLE patients attending a Danish tertiary rheumatology referral center were included. Common variant alleles in exon 1 of the MBL2 gene (R52C, rs5030737; G54D, rs1800450; G57E, rs1800451) were genotyped. The normal allele and variant alleles are termed A and O, respectively. The follow-up period was defined as the time from fulfillment of the ACR 1987 classification criteria for SLE until the occurrence of an event (nephritis, end-stage renal disease (ESRD), or death) or end of follow-up. Cox regression analyses were controlled for gender, age and race. During a median follow-up of 5.7 years, nephritis developed in 94 patients, and ESRD developed in 16 of these patients. Twenty-seven patients died. The distribution of the MBL2 genotypes A/A, A/O and O/O was 58%, 35% and 7.0%, respectively. Compared to the rest, O/O patients had 2.6 times (95% CI: 1.2-5.5) higher risk of developing nephritis, and their risk of death after 10 years was 6.0 times increased (95% CI: 1.0-36). MBL serum levels below 100 ng/ml were associated with a 2.0 (95% CI: 1.2-3.4; p = 0.007) increased risk of developing nephritis. ESRD and histological class of nephritis were not associated with MBL deficiency. Genetically determined MBL deficiency was associated with development of nephritis in SLE patients, but not with histological class of nephritis or ESRD. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  10. NECTAR: a database of codon-centric missense variant annotations.

    Science.gov (United States)

    Gong, Sungsam; Ware, James S; Walsh, Roddy; Cook, Stuart A

    2014-01-01

    NECTAR (Non-synonymous Enriched Coding muTation ARchive; http://nectarmutation.org) is a database and web application to annotate disease-related and functionally important amino acids in human proteins. A number of tools are available to facilitate the interpretation of DNA variants identified in diagnostic or research sequencing. These typically identify previous reports of DNA variation at a given genomic location, predict its effects on transcript and protein sequence and may predict downstream functional consequences. Previous reports and functional annotations are typically linked by the genomic location of the variant observed. NECTAR collates disease-causing variants and functionally important amino acid residues from a number of sources. Importantly, rather than simply linking annotations by a shared genomic location, NECTAR annotates variants of interest with details of previously reported variation affecting the same codon. This provides a much richer data set for the interpretation of a novel DNA variant. NECTAR also identifies functionally equivalent amino acid residues in evolutionarily related proteins (paralogues) and, where appropriate, transfers annotations between them. As well as accessing these data through a web interface, users can upload batches of variants in variant call format (VCF) for annotation on-the-fly. The database is freely available to download from the ftp site: ftp://ftp.nectarmutation.org.

  11. Tubulointerstitial damage predicts end stage renal disease in lupus nephritis with preserved to moderately impaired renal function: A retrospective cohort study.

    Science.gov (United States)

    Broder, Anna; Mowrey, Wenzhu B; Khan, Hina N; Jovanovic, Bojana; Londono-Jimenez, Alejandra; Izmirly, Peter; Putterman, Chaim

    2018-02-01

    The presence of tubulointerstitial damage (TID) on renal biopsy is considered to be a late sequela of lupus nephritis (LN). The objective of this study was to determine if TID predicts progression to end stage renal disease (ESRD) in LN patients without advanced kidney disease. All SLE patients with an index biopsy consistent with LN between January 2005 and July 2015, and eGFR ≥ 30mL/min/1.73m2 were included. Moderate-to-severe TID was defined as the presence of moderate-to-severe tubular atrophy and/or interstitial fibrosis. Time to ESRD was defined as time from the index biopsy date to incident ESRD date; non-ESRD patients were censored at the time of death or the last visit before December 2015. Time-dependent analyses were conducted to evaluate whether moderate-to-severe TID was predictive of ESRD progression. Of the 131 LN patients with eGFR ≥ 30mL/min/1.73m2, 17 (13%) patients progressed to ESRD. Moderate-to-severe TID was present in 13% of biopsies with eGFR ≥ 60mL/min/1.73m2 and in 33% of biopsies with eGFR between 30 and 60mL/min/1.73m2. Moderate-to-severe TID was associated with a higher risk of ESRD progression: adjusted hazard ratio (HR) = 4.1, 95% CI: 1.4-12.1, p = 0.01 for eGFR ≥ 30mL/min/1.73m2; HR = 6.2, 95% CI: 1.7-23.2, p = 0.008 for eGFR ≥ 60mL/min/1.73m2. There was no association between tubulointerstitial inflammation (TII) and ESRD progression. Moderate-to-severe TID, but not TII, was a strong predictor of ESRD progression independent of eGFR or glomerular findings, therefore, providing an important window for potential early interventions. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic

    DEFF Research Database (Denmark)

    Ahlborn, Lise B; Dandanell, Mette; Steffensen, Ane Y

    2015-01-01

    needed to classify whether these uncertain variants are pathogenic or benign. In this study, we investigated 14 BRCA1 variants by in silico splicing analysis and mini-gene splicing assay. All 14 alterations were missense variants located within the BRCT domain of BRCA1 and had previously been examined...... by functional analysis at the protein level. Results from a validated mini-gene splicing assay indicated that nine BRCA1 variants resulted in splicing aberrations leading to truncated transcripts and thus can be considered pathogenic (c.4987A>T/p.Met1663Leu, c.4988T>A/p.Met1663Lys, c.5072C>T/p.Thr1691Ile, c...... to have no or an uncertain effect on the protein level, whereas one variant (c.5072C>T/p.Thr1691Ile) were shown to have a strong effect on the protein level as well. In conclusion, our study emphasizes that in silico splicing prediction and mini-gene splicing analysis are important for the classification...

  13. The pathogenicity of genetic variants previously associated with left ventricular non-compaction

    DEFF Research Database (Denmark)

    Abbasi, Yeganeh; Jabbari, Javad; Jabbari, Reza

    2016-01-01

    an updated list of previously reported LVNC-associated variants with biologic description and investigate the prevalence of LVNC variants in healthy general population to find false-positive LVNC-associated variants. METHODS AND RESULTS: The Human Gene Mutation Database and PubMed were systematically...... searched to identify all previously reported LVNC-associated variants. Thereafter, the Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC), that both represent the background population, was searched for all variants. Four in silico prediction tools were assessed to determine...

  14. Identification of HPV variants.

    Science.gov (United States)

    Cason, John; Bible, Jon; Mant, Christine

    2005-01-01

    The vast majority of anogenital carcinomas are caused by high-risk human papillomaviruses (HPVs), and among Western nations HPV-16 is usually the most predominant cancer-associated type. As a DNA virus, HPV type 16 has a relatively stable genome that is believed to have co-evolved with its host over the millennia. Nevertheless, among the "wild" populations of HPV-16 that are circulating, a large number of variants have been identified, and these may have considerably different pathogenic potentials. In this chapter, methods for screening and characterizing HPV-16 sequence variants are described. In particular, we describe methods for the identification of variation within the HPV-16 E5 open reading frame and for the detection of the nt 131 A-->G mutation of the E6 ORF, using restriction fragment length polymorphism assays. In addition, we describe approaches for DNA sequencing and analysis. Such methods are likely to be of particular interest to those involved in epidemiological investigations of virus transmission and pathogenicity studies.

  15. Is kidney function affecting the management of myocardial infarction? A retrospective cohort study in patients with normal kidney function, chronic kidney disease stage III-V, and ESRD.

    Science.gov (United States)

    Saad, Marc; Karam, Boutros; Faddoul, Geovani; Douaihy, Youssef El; Yacoub, Harout; Baydoun, Hassan; Boumitri, Christine; Barakat, Iskandar; Saifan, Chadi; El-Charabaty, Elie; Sayegh, Suzanne El

    2016-01-01

    Patients with chronic kidney disease (CKD) are three times more likely to have myocardial infarction (MI) and suffer from increased morbidity and higher mortality. Traditional and unique risk factors are prevalent and constitute challenges for the standard of care. However, CKD patients have been largely excluded from clinical trials and little evidence is available to guide evidence-based treatment of coronary artery disease in patients with CKD. Our objective was to assess whether a difference exists in the management of MI (ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction) among patients with normal kidney function, CKD stage III-V, and end-stage renal disease (ESRD) patients. We conducted a retrospective cohort study on patients admitted to Staten Island University Hospital for the diagnosis of MI between January 2005 and December 2012. Patients were assigned to one of three groups according to their kidney function: Data collected on the medical management and the use of statins, platelet inhibitors, beta-blockers, and angiotensin converting enzyme inhibitors/angiotensin receptor blockers were compared among the three cohorts, as well as medical interventions including: catheterization and coronary artery bypass graft (CABG) when indicated. Chi-square test was used to compare the proportions between nominal variables. Binary logistic analysis was used in order to determine associations between treatment modalities and comorbidities, and to account for possible confounding factors. Three hundred and thirty-four patients (mean age 67.2±13.9 years) were included. In terms of management, medical treatment was not different among the three groups. However, cardiac catheterization was performed less in ESRD when compared with no CKD and CKD stage III-V (45.6% vs 74% and 93.9%) (Pmanagement of their cardiac disease. In our study, medical therapy was achieved at high percentage and was comparable among groups of different

  16. Comparison of outcomes between emergent-start and planned-start peritoneal dialysis in incident ESRD patients: a prospective observational study.

    Science.gov (United States)

    Li, Wen-Yi; Wang, Yi-Cheng; Hwang, Shang-Jyh; Lin, Shih-Hua; Wu, Kwan-Dun; Chen, Yung-Ming

    2017-12-11

    The clinical consequences of starting chronic peritoneal dialysis (PD) after emergent dialysis via a temporary hemodialysis (HD) catheter has rarely been evaluated within a full spectrum of treated end-stage renal disease (ESRD). We investigated the longer-term outcomes of patients undergoing emergent-start PD in comparison with that of other practices of PD or HD in a prospective cohort of new-onset ESRD. This was a 2-year prospective observational study. We enrolled 507 incident ESRD patients, among them 111 chose PD (43 planned-start, 68 emergent-start) and 396 chose HD (116 planned-start, 280 emergent-start) as the long-term dialysis modality. The logistic regression model was used to identify variables associated with emergent-start dialysis. The Kaplan-Meier survival analysis was used to determine patient survival and technique failure. The propensity score-adjusted Cox regression model was used to identify factors associated with patient outcomes. During the 2-year follow-up, we observed 5 (4.5%) deaths, 15 (13.5%) death-censored technique failures (transfer to HD) and 3 (2.7%) renal transplantations occurring in the PD population. Lack of predialysis education, lower predialysis estimated glomerular filtration rate and serum albumin were predictors of being assigned to emergent dialysis initiation. The emergent starters of PD displayed similar risks of patient survival, technique failure and overall hospitalization, compared with the planned-start counterparts. By contrast, the concurrent planned-start and emergent-start HD patients with an arteriovenous fistula or graft were protected from early overall death and access infection-related mortality, compared with the emergent HD starters using a central venous catheter. In late-referred chronic kidney disease patients who have initiated emergent dialysis via a temporary HD catheter, post-initiation PD can be a safe and effective long-term treatment option. Nevertheless, due to the potential complications

  17. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy.

    Science.gov (United States)

    Holstege, Henne; van der Lee, Sven J; Hulsman, Marc; Wong, Tsz Hang; van Rooij, Jeroen Gj; Weiss, Marjan; Louwersheimer, Eva; Wolters, Frank J; Amin, Najaf; Uitterlinden, André G; Hofman, Albert; Ikram, M Arfan; van Swieten, John C; Meijers-Heijboer, Hanne; van der Flier, Wiesje M; Reinders, Marcel Jt; van Duijn, Cornelia M; Scheltens, Philip

    2017-08-01

    Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign. We tested this pathogenicity screen in SORL1 variants reported in two independent published studies. SORL1 variant pathogenicity is defined by the Combined Annotation Dependent Depletion (CADD) score and the minor allele frequency (MAF) reported by the Exome Aggregation Consortium (ExAC) database. Variants predicted strongly damaging (CADD score >30), which are extremely rare (ExAC-MAF <1 × 10-5) increased AD risk by 12-fold (95% CI 4.2-34.3; P=5 × 10-9). Protein-truncating SORL1 mutations were all unknown to ExAC and occurred exclusively in AD cases. More common SORL1 variants (ExAC-MAF≥1 × 10-5) were not associated with increased AD risk, even when predicted strongly damaging. Findings were independent of gender and the APOE-ɛ4 allele. High-risk SORL1 variants were observed in a substantial proportion of the AD cases analyzed (2%). Based on their effect size, we propose to consider high-risk SORL1 variants next to variants in APOE, PSEN1, PSEN2 and APP for personalized risk assessments in clinical practice.

  18. Predicting the risk of end-stage renal disease in the population-based setting: a retrospective case-control study

    Directory of Open Access Journals (Sweden)

    Yang Xiuhai

    2011-05-01

    Full Text Available Abstract Background Previous studies of predictors of end-stage renal disease (ESRD have limitations: (1 some focused on patients with clinically recognized chronic kidney disease (CKD; (2 others identified population-based patients who developed ESRD, but lacked earlier baseline clinical measures to predict ESRD. Our study was designed to address these limitations and to identify the strength and precision of characteristics that might predict ESRD pragmatically for decision-makers--as measured by the onset of renal replacement therapy (RRT. Methods We conducted a population-based, retrospective case-control study of patients who developed ESRD and started RRT. We conducted the study in a health maintenance organization, Kaiser Permanente Northwest (KPNW. The case-control study was nested within the adult population of KPNW members who were enrolled during 1999, the baseline period. Cases and their matched controls were identified from January 2000 through December 2004. We evaluated baseline clinical characteristics measured during routine care by calculating the adjusted odds ratios and their 95% confidence intervals after controlling for matching characteristics: age, sex, and year. Results The rate of RRT in the cohort from which we sampled was 58 per 100,000 person-years (95% CI, 53 to 64. After excluding patients with missing data, we analyzed 350 cases and 2,114 controls. We identified the following characteristics that predicted ESRD with odds ratios ≥ 2.0: eGFR2 (OR = 20.5; 95% CI, 11.2 to 37.3, positive test for proteinuria (OR = 5.0; 95% CI, 3.5 to 7.1, hypertension (OR = 4.5; 95% CI, 2.5 to 8.0, gout/positive test for uric acid (OR = 2.5; 95% CI, 1.8 to 3.5, peripheral vascular disease (OR = 2.2; 95% CI, 1.4 to 3.6, congestive heart failure (OR = 2.1; 95% CI, 1.4 to 3.3, and diabetes (OR = 2.1; 95% CI, 1.5 to 2.9. Conclusions The clinical characteristics needed to predict ESRD--for example, to develop a population

  19. Variants of windmill nystagmus.

    Science.gov (United States)

    Choi, Kwang-Dong; Shin, Hae Kyung; Kim, Ji-Soo; Kim, Sung-Hee; Choi, Jae-Hwan; Kim, Hyo-Jung; Zee, David S

    2016-07-01

    Windmill nystagmus is characterized by a clock-like rotation of the beating direction of a jerk nystagmus suggesting separate horizontal and vertical oscillators, usually 90° out of phase. We report oculographic characteristics in three patients with variants of windmill nystagmus in whom the common denominator was profound visual loss due to retinal diseases. Two patients showed a clock-like pattern, while in the third, the nystagmus was largely diagonal (in phase or 180° out of phase) but also periodically changed direction by 180°. We hypothesize that windmill nystagmus is a unique manifestation of "eye movements of the blind." It emerges when the central structures, including the cerebellum, that normally keep eye movements calibrated and gaze steady can no longer perform their task, because they are deprived of the retinal image motion that signals a need for adaptive recalibration.

  20. Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis.

    Science.gov (United States)

    Dinckan, N; Du, R; Petty, L E; Coban-Akdemir, Z; Jhangiani, S N; Paine, I; Baugh, E H; Erdem, A P; Kayserili, H; Doddapaneni, H; Hu, J; Muzny, D M; Boerwinkle, E; Gibbs, R A; Lupski, J R; Uyguner, Z O; Below, J E; Letra, A

    2018-01-01

    Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.

  1. HPRT deficiency as the cause of ESRD in a 24-year-old patient: a very rare presentation of the disorder.

    Science.gov (United States)

    Kassimatis, T I; Simmonds, H A; Goudas, P C; Marinaki, A M; Fairbanks, L D; Diamandopoulos, A A

    2005-01-01

    A 24-year-old male with end-stage renal disease (ESRD) and disproportionately high uric acid plasma concentration was admitted to our unit. After studying the patient's medical history, as well as that of the entire family, hyperuricemia was discovered in his brother, while microscopic examination of his brother's and mother's urine revealed abundant uric acid crystals. After performing purine metabolic studies, it was determined that the two siblings suffered from partial hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency (Kelley-Seegmiller syndrome). This report highlights the importance of clinical awareness and a thorough examination of the patient's medical history for establishing an early diagnosis and commencing treatment for such rare inherited metabolic disorders to prevent renal failure.

  2. Variants affecting exon skipping contribute to complex traits.

    Directory of Open Access Journals (Sweden)

    Younghee Lee

    Full Text Available DNA variants that affect alternative splicing and the relative quantities of different gene transcripts have been shown to be risk alleles for some Mendelian diseases. However, for complex traits characterized by a low odds ratio for any single contributing variant, very few studies have investigated the contribution of splicing variants. The overarching goal of this study is to discover and characterize the role that variants affecting alternative splicing may play in the genetic etiology of complex traits, which include a significant number of the common human diseases. Specifically, we hypothesize that single nucleotide polymorphisms (SNPs in splicing regulatory elements can be characterized in silico to identify variants affecting splicing, and that these variants may contribute to the etiology of complex diseases as well as the inter-individual variability in the ratios of alternative transcripts. We leverage high-throughput expression profiling to 1 experimentally validate our in silico predictions of skipped exons and 2 characterize the molecular role of intronic genetic variations in alternative splicing events in the context of complex human traits and diseases. We propose that intronic SNPs play a role as genetic regulators within splicing regulatory elements and show that their associated exon skipping events can affect protein domains and structure. We find that SNPs we would predict to affect exon skipping are enriched among the set of SNPs reported to be associated with complex human traits.

  3. Genetic profiling using genome-wide significant coronary artery disease risk variants does not improve the prediction of subclinical atherosclerosis: the Cardiovascular Risk in Young Finns Study, the Bogalusa Heart Study and the Health 2000 Survey--a meta-analysis of three independent studies.

    Directory of Open Access Journals (Sweden)

    Jussi A Hernesniemi

    Full Text Available BACKGROUND: Genome-wide association studies (GWASs have identified a large number of variants (SNPs associating with an increased risk of coronary artery disease (CAD. Recently, the CARDIoGRAM consortium published a GWAS based on the largest study population so far. They successfully replicated twelve already known associations and discovered thirteen new SNPs associating with CAD. We examined whether the genetic profiling of these variants improves prediction of subclinical atherosclerosis--i.e., carotid intima-media thickness (CIMT and carotid artery elasticity (CAE--beyond classical risk factors. SUBJECTS AND METHODS: We genotyped 24 variants found in a population of European ancestry and measured CIMT and CAE in 2001 and 2007 from 2,081, and 2,015 subjects (aged 30-45 years in 2007 respectively, participating in the Cardiovascular Risk in Young Finns Study (YFS. The Bogalusa Heart Study (BHS; n = 1179 was used as a replication cohort (mean age of 37.5. For additional replication, a sub-sample of 5 SNPs was genotyped for 1,291 individuals aged 46-76 years participating in the Health 2000 population survey. We tested the impact of genetic risk score (GRS(24SNP/CAD calculated as a weighted (by allelic odds ratios for CAD sum of CAD risk alleles from the studied 24 variants on CIMT, CAE, the incidence of carotid atherosclerosis and the progression of CIMT and CAE during a 6-year follow-up. RESULTS: CIMT or CAE did not significantly associate with GRS(24SNP/CAD before or after adjusting for classical CAD risk factors (p>0.05 for all in YFS or in the BHS. CIMT and CAE associated with only one SNP each in the YFS. The findings were not replicated in the replication cohorts. In the meta-analysis CIMT or CAE did not associate with any of the SNPs. CONCLUSION: Genetic profiling, by using known CAD risk variants, should not improve risk stratification for subclinical atherosclerosis beyond conventional risk factors among healthy young adults.

  4. The value of IgG-uria in predicting renal failure in idiopathic glomerular diseases. A long-term follow-up study.

    Science.gov (United States)

    Tofik, Rafid; Aziz, Rawa; Reda, Ahmed; Rippe, Bengt; Bakoush, Omran

    2011-04-01

    Proteinuria is the hallmark of glomerular disease and non-selective proteinuria is often associated with progression to renal failure. The predictive value of urine IgG excretion was studied comprehensively in patients with nephrotic syndrome. In the present follow-up study, we examine the predictive value of IgG-uria in patients with idiopathic glomerular diseases with a wide range of proteinuia. A total of 189 (113 males and 76 females) patients with idiopathic glomerulonephritis and serum creatinine of less than 150 μmol/L diagnosed between 1993 and 2004 were followed up to their last visit in 2009. Measurement of urine excretion of albumin, IgG, and protein HC were performed in the early morning of spot urine samples collected at the time of the diagnostic renal biopsy. Patients were stratified according to urine protein concentrations and the progression rate to end-stage renal disease (ESRD) calculated using Kaplan-Meier survival analysis. ESRD was defined as the start of renal replacement therapy. During the study follow-up time of 1429 person-years; 26 (13.8%) patients reached ESRD. The overall mean kidney survival time of studied patients with serum creatinine less than 150 were 13.4 years. The incidence rate of ESRD was ∼18 per 1000 person-years. Stratified analysis identified urinary excretion of IgG, but not albuminuria, as predictor of ESRD. The progression rate to ESRD was 36 per 1000 person-years in patients with urine IgG concentration exceeding 5 mg/mmol urine creatinine, compared to a progression rate of 6/1000 person-years for patients with lower levels of urine IgG. The findings of the study suggest that at early stages, the level of IgG-uria is useful to be used in risk stratification of patients with proteinuric glomerular diseases.

  5. Functional characterization of 21 allelic variants of dihydropyrimidinase.

    Science.gov (United States)

    Hishinuma, Eiji; Akai, Fumika; Narita, Yoko; Maekawa, Masamitsu; Yamaguchi, Hiroaki; Mano, Nariyasu; Oda, Akifumi; Hirasawa, Noriyasu; Hiratsuka, Masahiro

    2017-11-01

    Dihydropyrimidinase (DHP, EC 3.5.2.2), encoded by the gene DPYS, is the second enzyme in the catabolic pathway of pyrimidine and of fluoropyrimidine drugs such as 5-fluorouracil, which are commonly used in anticancer treatment; DHP catalyzes the hydrolytic ring opening of dihydrouracil and dihydro-5-fluorouracil. DPYS mutations are known to contribute to interindividual variations in the toxicity of fluoropyrimidine drugs, but the functional characterization of DHP allelic variants remains inadequate. In this study, in vitro analysis was performed on 22 allelic variants of DHP by transiently expressing wild-type DHP and 21 DHP variants in 293FT cells and characterizing their enzymatic activities by using dihydrouracil and dihydro-5-fluorouracil as substrates. DHP expression levels and oligomeric forms were determined using immunoblotting and blue native PAGE, respectively, and the stability of the DHP variants was assessed by examining the proteins in variant-transfected cells treated with cycloheximide or bortezomib. Moreover, three kinetic parameters, Km, Vmax, and intrinsic clearance (Vmax/Km), for the hydrolysis of dihydrouracil and dihydro-5-fluorouracil were determined. We found that 5/21 variants showed significantly decreased intrinsic clearance as compared to wild-type DHP, and that 9/21 variants were expressed at low levels and were inactive due to proteasome-mediated degradation. The band patterns observed in the immunoblotting of blue native gels corresponded to DHP activity, and, notably, 18/21 DHP variants exhibited decreased or null enzymatic activity and these variants also showed a drastically reduced ability to form large oligomers. Thus, detection of DPYS genetic polymorphisms might facilitate the prediction severe adverse effects of fluoropyrimidine-based treatments. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Multisystem altruistic metadynamics—Well-tempered variant

    Science.gov (United States)

    Hošek, Petr; Kříž, Pavel; Toulcová, Daniela; Spiwok, Vojtěch

    2017-03-01

    Metadynamics method has been widely used to enhance sampling in molecular simulations. Its original form suffers two major drawbacks, poor convergence in complex (especially biomolecular) systems and its serial nature. The first drawback has been addressed by introduction of a convergent variant known as well-tempered metadynamics. The second was addressed by introduction of a parallel multisystem metadynamics referred to as altruistic metadynamics. Here, we combine both approaches into well-tempered altruistic metadynamics. We provide mathematical arguments and trial simulations to show that it accurately predicts free energy surfaces.

  7. Multisystem altruistic metadynamics-Well-tempered variant.

    Science.gov (United States)

    Hošek, Petr; Kříž, Pavel; Toulcová, Daniela; Spiwok, Vojtěch

    2017-03-28

    Metadynamics method has been widely used to enhance sampling in molecular simulations. Its original form suffers two major drawbacks, poor convergence in complex (especially biomolecular) systems and its serial nature. The first drawback has been addressed by introduction of a convergent variant known as well-tempered metadynamics. The second was addressed by introduction of a parallel multisystem metadynamics referred to as altruistic metadynamics. Here, we combine both approaches into well-tempered altruistic metadynamics. We provide mathematical arguments and trial simulations to show that it accurately predicts free energy surfaces.

  8. Variants of beta-glucosidase

    Energy Technology Data Exchange (ETDEWEB)

    Fidantsef, Ana; Lamsa, Michael; Gorre-Clancy, Brian

    2015-07-14

    The present invention relates to variants of a parent beta-glucosidase, comprising a substitution at one or more positions corresponding to positions 142, 183, 266, and 703 of amino acids 1 to 842 of SEQ ID NO: 2 or corresponding to positions 142, 183, 266, and 705 of amino acids 1 to 844 of SEQ ID NO: 70, wherein the variant has beta-glucosidase activity. The present invention also relates to nucleotide sequences encoding the variant beta-glucosidases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  9. Variants of beta-glucosidases

    Energy Technology Data Exchange (ETDEWEB)

    Fidantsef, Ana; Lamsa, Michael; Gorre-Clancy, Brian

    2014-10-07

    The present invention relates to variants of a parent beta-glucosidase, comprising a substitution at one or more positions corresponding to positions 142, 183, 266, and 703 of amino acids 1 to 842 of SEQ ID NO: 2 or corresponding to positions 142, 183, 266, and 705 of amino acids 1 to 844 of SEQ ID NO: 70, wherein the variant has beta-glucosidase activity. The present invention also relates to nucleotide sequences encoding the variant beta-glucosidases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  10. Variants of beta-glucosidase

    Science.gov (United States)

    Fidantsef, Ana [Davis, CA; Lamsa, Michael [Davis, CA; Gorre-Clancy, Brian [Elk Grove, CA

    2009-12-29

    The present invention relates to variants of a parent beta-glucosidase, comprising a substitution at one or more positions corresponding to positions 142, 183, 266, and 703 of amino acids 1 to 842 of SEQ ID NO: 2 or corresponding to positions 142, 183, 266, and 705 of amino acids 1 to 844 of SEQ ID NO: 70, wherein the variant has beta-glucosidase activity. The present invention also relates to nucleotide sequences encoding the variant beta-glucosidases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  11. Product Variant Master as a Means to Handle Variant Design

    DEFF Research Database (Denmark)

    Hildre, Hans Petter; Mortensen, Niels Henrik; Andreasen, Mogens Myrup

    1996-01-01

    be implemented in the CAD system I-DEAS. A precondition for high degree of computer support is identification of a product variant master from which new variants can be derived. This class platform defines how a product build up fit certain production methods and rules governing determination of modules......, assemblies, and parts. Implementation in an industrial company shows that considerable rationalisation effects can be achieved...

  12. Massively Parallel Functional Analysis of BRCA1 RING Domain Variants.

    Science.gov (United States)

    Starita, Lea M; Young, David L; Islam, Muhtadi; Kitzman, Jacob O; Gullingsrud, Justin; Hause, Ronald J; Fowler, Douglas M; Parvin, Jeffrey D; Shendure, Jay; Fields, Stanley

    2015-06-01

    Interpreting variants of uncertain significance (VUS) is a central challenge in medical genetics. One approach is to experimentally measure the functional consequences of VUS, but to date this approach has been post hoc and low throughput. Here we use massively parallel assays to measure the effects of nearly 2000 missense substitutions in the RING domain of BRCA1 on its E3 ubiquitin ligase activity and its binding to the BARD1 RING domain. From the resulting scores, we generate a model to predict the capacities of full-length BRCA1 variants to support homology-directed DNA repair, the essential role of BRCA1 in tumor suppression, and show that it outperforms widely used biological-effect prediction algorithms. We envision that massively parallel functional assays may facilitate the prospective interpretation of variants observed in clinical sequencing. Copyright © 2015 by the Genetics Society of America.

  13. Association between cardiac biomarkers and the development of ESRD in patients with type 2 diabetes mellitus, anemia, and CKD

    DEFF Research Database (Denmark)

    Desai, Akshay S; Toto, Robert; Jarolim, Petr

    2011-01-01

    In patients with chronic kidney disease (CKD), as in other populations, elevations in cardiac biomarker levels predict increased risk of cardiovascular events. We examined the value of troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in assessing the risk of developing e...

  14. Variant view: visualizing sequence variants in their gene context.

    Science.gov (United States)

    Ferstay, Joel A; Nielsen, Cydney B; Munzner, Tamara

    2013-12-01

    Scientists use DNA sequence differences between an individual's genome and a standard reference genome to study the genetic basis of disease. Such differences are called sequence variants, and determining their impact in the cell is difficult because it requires reasoning about both the type and location of the variant across several levels of biological context. In this design study, we worked with four analysts to design a visualization tool supporting variant impact assessment for three different tasks. We contribute data and task abstractions for the problem of variant impact assessment, and the carefully justified design and implementation of the Variant View tool. Variant View features an information-dense visual encoding that provides maximal information at the overview level, in contrast to the extensive navigation required by currently-prevalent genome browsers. We provide initial evidence that the tool simplified and accelerated workflows for these three tasks through three case studies. Finally, we reflect on the lessons learned in creating and refining data and task abstractions that allow for concise overviews of sprawling information spaces that can reduce or remove the need for the memory-intensive use of navigation.

  15. A functional variant in NEPH3 gene confers high risk of renal failure in primary hematuric glomerulopathies. Evidence for predisposition to microalbuminuria in the general population.

    Directory of Open Access Journals (Sweden)

    Konstantinos Voskarides

    Full Text Available Recent data emphasize that thin basement membrane nephropathy (TBMN should not be viewed as a form of benign familial hematuria since chronic renal failure (CRF and even end-stage renal disease (ESRD, is a possible development for a subset of patients on long-term follow-up, through the onset of focal and segmental glomerulosclerosis (FSGS. We hypothesize that genetic modifiers may explain this variability of symptoms.We looked in silico for potentially deleterious functional SNPs, using very strict criteria, in all the genes significantly expressed in the slit diaphragm (SD. Two variants were genotyped in a cohort of well-studied adult TBMN patients from 19 Greek-Cypriot families, with a homogeneous genetic background. Patients were categorized as "Severe" or "Mild", based on the presence or not of proteinuria, CRF and ESRD. A larger pooled cohort (HEMATURIA of 524 patients, including IgA nephropathy patients, was used for verification. Additionally, three large general population cohorts [Framingham Heart Study (FHS, KORAF4 and SAPHIR] were used to investigate if the NEPH3-V353M variant has any renal effect in the general population.Genotyping for two high-scored variants in 103 TBMN adult patients with founder mutations who were classified as mildly or severely affected, pointed to an association with variant NEPH3-V353M (filtrin. This promising result prompted testing in the larger pooled cohort (HEMATURIA, indicating an association of the 353M variant with disease severity under the dominant model (p = 3.0x10-3, OR = 6.64 adjusting for gender/age; allelic association: p = 4.2x10-3 adjusting for patients' kinships. Subsequently, genotyping 6,531 subjects of the Framingham Heart Study (FHS revealed an association of the homozygous 353M/M genotype with microalbuminuria (p = 1.0x10-3. Two further general population cohorts, KORAF4 and SAPHIR confirmed the association, and a meta-analysis of all three cohorts (11,258 individuals was highly

  16. Gene Variants Reduce Opioid Risks

    Science.gov (United States)

    ... common variant (A). Text Description of Graphic Genetic Markers for Individualized Treatments Dr. Jamie Biswas, Chief of ... other health and disease indications—such as cancer, heart disease, and opportunistic infections.” The studies were supported by ...

  17. A TSHβ Variant with Impaired Immunoreactivity but Intact Biological Activity and Its Clinical Implications

    DEFF Research Database (Denmark)

    Pappa, Theodora; Johannesen, Jesper; Scherberg, Neal

    2015-01-01

    %) decrease in the TSH measurement with the Siemens platforms. Predictions based on PolyPhen-2 and in silico modeling revealed no functional impairment of the variant TSH. CONCLUSIONS: A TSHβ variant with impaired immunoreactivity, but not bioactivity, is reported, and its biochemical impact in the homo...

  18. New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome

    DEFF Research Database (Denmark)

    Yang, Ren-Qiang; Jabbari, Javad; Cheng, Xiao-Shu

    2014-01-01

    as many of the original studies used low number of controls. To study whether there are possible false-positive variants associated with MFS, four in silico prediction tools (SIFT, Polyphen-2, Grantham score, and conservation across species) were used to predict the pathogenicity of these variant. RESULTS...

  19. MBL2 gene variants coding for mannose-binding lectin deficiency are associated with increased risk of nephritis in Danish patients with systemic lupus erythematosus

    DEFF Research Database (Denmark)

    Tanha, N; Troelsen, L; From Hermansen, M-L

    2014-01-01

    OBJECTIVES: Autoimmunity may in part result from deficiencies in the processing of apoptotic debris. As mannose-binding lectin (MBL) is involved in such processes, we hypothesized that the variants in the MBL2 gene resulting in MBL deficiency confer an increased risk of nephritis in systemic lupus......, respectively. The follow-up period was defined as the time from fulfillment of the ACR 1987 classification criteria for SLE until the occurrence of an event (nephritis, end-stage renal disease (ESRD), or death) or end of follow-up. Cox regression analyses were controlled for gender, age and race. RESULTS......: During a median follow-up of 5.7 years, nephritis developed in 94 patients, and ESRD developed in 16 of these patients. Twenty-seven patients died. The distribution of the MBL2 genotypes A/A, A/O and O/O was 58%, 35% and 7.0%, respectively. Compared to the rest, O/O patients had 2.6 times (95% CI: 1...

  20. Rare variants in known and novel candidate genes predisposing to statin-associated myopathy.

    Science.gov (United States)

    Neřoldová, Magdaléna; Stránecký, Viktor; Hodaňová, Kateřina; Hartmannová, Hana; Piherová, Lenka; Přistoupilová, Anna; Mrázová, Lenka; Vrablík, Michal; Adámková, Věra; Hubáček, Jaroslav A; Jirsa, Milan; Kmoch, Stanislav

    2016-08-01

    Genetic variants affecting statin uptake, metabolism or predisposing to muscular diseases may confer susceptibility to statin-induced myopathy. Besides the SLCO1B1 rs4149056 genotype, common genetic variants do not seem to determine statin-associated myopathy. Here we aimed to address the potential role of rare variants. We performed whole exome sequencing in 88 individuals suffering from statin-associated myopathy and assessed the burden of rare variants using candidate-gene and exome-wide association analysis. In the novel candidate gene CLCN1, we identified a heterozygote truncating mutation p.R894* in four patients. In addition, we detected predictably pathogenic case-specific variants in MYOT, CYP3A5, SH3TC2, FBXO32 and RBM20. These findings support the role of rare variants and nominate loci for follow-up studies.

  1. Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia.

    Science.gov (United States)

    Ylikallio, Emil; Kim, Doyoun; Isohanni, Pirjo; Auranen, Mari; Kim, Eunjoon; Lönnqvist, Tuula; Tyynismaa, Henna

    2015-10-01

    Variants in family 1 kinesin (KIF1A), which encodes a kinesin axonal motor protein, have been described to cause variable neurological manifestations. Recessive missense variants have led to spastic paraplegia, and recessive truncations to sensory and autonomic neuropathy. De novo missense variants cause developmental delay or intellectual disability, cerebellar atrophy and variable spasticity. We describe a family with father-to-son transmission of de novo variant in the KIF1A motor domain, in a phenotype of pure spastic paraplegia. Structural modeling of the predicted p.(Ser69Leu) amino acid change suggested that it impairs the stable binding of ATP to the KIF1A protein. Our study reports the first dominantly inherited KIF1A variant and expands the spectrum of phenotypes caused by heterozygous KIF1A motor domain variants to include pure spastic paraplegia. We conclude that KIF1A should be considered a candidate gene for hereditary paraplegias regardless of inheritance pattern.

  2. Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder.

    Science.gov (United States)

    Kasahara, Takaoki; Ishiwata, Mizuho; Kakiuchi, Chihiro; Fuke, Satoshi; Iwata, Nakao; Ozaki, Norio; Kunugi, Hiroshi; Minabe, Yoshio; Nakamura, Kazuhiko; Iwata, Yasuhide; Fujii, Kumiko; Kanba, Shigenobu; Ujike, Hiroshi; Kusumi, Ichiro; Kataoka, Muneko; Matoba, Nana; Takata, Atsushi; Iwamoto, Kazuya; Yoshikawa, Takeo; Kato, Tadafumi

    2017-08-01

    Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder. We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed. Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls. Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease. © 2016 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.

  3. BreakPoint Surveyor: a pipeline for structural variant visualization.

    Science.gov (United States)

    Wyczalkowski, Matthew A; Wylie, Kristine M; Cao, Song; McLellan, Michael D; Flynn, Jennifer; Huang, Mo; Ye, Kai; Fan, Xian; Chen, Ken; Wendl, Michael C; Ding, Li

    2017-10-01

    BreakPoint Surveyor (BPS) is a computational pipeline for the discovery, characterization, and visualization of complex genomic rearrangements, such as viral genome integration, in paired-end sequence data. BPS facilitates interpretation of structural variants by merging structural variant breakpoint predictions, gene exon structure, read depth, and RNA-sequencing expression into a single comprehensive figure. Source code and sample data freely available for download at https://github.com/ding-lab/BreakPointSurveyor, distributed under the GNU GPLv3 license, implemented in R, Python and BASH scripts, and supported on Unix/Linux/OS X operating systems. lding@wustl.edu. Supplementary data are available at Bioinformatics online.

  4. A genetic variant brain-dervied neurotrophic factor (BDNF) polymorphism interacts with hostile parenting to predict error-related brain activity and thereby risk for internalizing disorders in children.

    Science.gov (United States)

    Meyer, Alexandria; Hajcak, Greg; Hayden, Elizabeth; Sheikh, Haroon I; Singh, Shiva M; Klein, Daniel N

    2017-04-21

    The error-related negativity (ERN) is a negative deflection in the event-related potential occurring when individuals make mistakes, and is increased in children with internalizing psychopathology. We recently found that harsh parenting predicts a larger ERN in children, and recent work has suggested that variation in the brain-derived neurotrophic factor (BDNF) gene may moderate the impact of early life adversity. Parents and children completed measures of parenting when children were 3 years old (N = 201); 3 years later, the ERN was measured and diagnostic interviews as well as dimensional symptom measures were completed. We found that harsh parenting predicted an increased ERN only among children with a methionine allele of the BDNF genotype, and evidence of moderated mediation: the ERN mediated the relationship between parenting and internalizing diagnoses and dimensional symptoms only if children had a methionine allele. We tested this model with externalizing disorders, and found that harsh parenting predicted externalizing outcomes, but the ERN did not mediate this association. These findings suggest that harsh parenting predicts both externalizing and internalizing outcomes in children; however, this occurs through different pathways that uniquely implicate error-related brain activity in the development of internalizing disorders.

  5. SDS, a structural disruption score for assessment of missense variant deleteriousness

    Directory of Open Access Journals (Sweden)

    Thanawadee ePreeprem

    2014-04-01

    Full Text Available We have developed a novel structure-based evaluation for missense variants that explicitly models protein structure and amino acid properties to predict the likelihood that a variant disrupts protein function. A structural disruption score (SDS is introduced as a measure to depict the likelihood that a case variant is functional. The score is constructed using characteristics that distinguish between causal and neutral variants within a group of proteins. The SDS score is correlated with standard sequence-based deleteriousness, but shows promise for improving discrimination between neutral and causal variants at less conserved sites.The prediction was performed on 3-dimentional structures of 57 gene products whose homozygous SNPs were identified as case-exclusive variants in an exome sequencing study of epilepsy disorders. We contrasted the candidate epilepsy variants with scores for likely benign variants found in the EVS database, and for positive control variants in the same genes that are suspected to promote a range of diseases. To derive a characteristic profile of damaging SNPs, we transformed continuous scores into categorical variables based on the score distribution of each measurement, collected from all possible SNPs in this protein set, where extreme measures were assumed to be deleterious. A second epilepsy dataset was used to replicate the findings. Causal variants tend to receive higher sequence-based deleterious scores, induce larger physico-chemical changes between amino acid pairs, locate in protein domains, buried sites or on conserved protein surface clusters, and cause protein destabilization, relative to negative controls. These measures were agglomerated for each variant. A list of nine high-priority putative functional variants for epilepsy was generated. Our newly developed SDS protocol facilitates SNP prioritization for experimental validation.

  6. Classification Models to Predict Survival of Kidney Transplant Recipients Using Two Intelligent Techniques of Data Mining and Logistic Regression.

    Science.gov (United States)

    Nematollahi, M; Akbari, R; Nikeghbalian, S; Salehnasab, C

    2017-01-01

    Kidney transplantation is the treatment of choice for patients with end-stage renal disease (ESRD). Prediction of the transplant survival is of paramount importance. The objective of this study was to develop a model for predicting survival in kidney transplant recipients. In a cross-sectional study, 717 patients with ESRD admitted to Nemazee Hospital during 2008-2012 for renal transplantation were studied and the transplant survival was predicted for 5 years. The multilayer perceptron of artificial neural networks (MLP-ANN), logistic regression (LR), Support Vector Machine (SVM), and evaluation tools were used to verify the determinant models of the predictions and determine the independent predictors. The accuracy, area under curve (AUC), sensitivity, and specificity of SVM, MLP-ANN, and LR models were 90.4%, 86.5%, 98.2%, and 49.6%; 85.9%, 76.9%, 97.3%, and 26.1%; and 84.7%, 77.4%, 97.5%, and 17.4%, respectively. Meanwhile, the independent predictors were discharge time creatinine level, recipient age, donor age, donor blood group, cause of ESRD, recipient hypertension after transplantation, and duration of dialysis before transplantation. SVM and MLP-ANN models could efficiently be used for determining survival prediction in kidney transplant recipients.

  7. Data-variant kernel analysis

    CERN Document Server

    Motai, Yuichi

    2015-01-01

    Describes and discusses the variants of kernel analysis methods for data types that have been intensely studied in recent years This book covers kernel analysis topics ranging from the fundamental theory of kernel functions to its applications. The book surveys the current status, popular trends, and developments in kernel analysis studies. The author discusses multiple kernel learning algorithms and how to choose the appropriate kernels during the learning phase. Data-Variant Kernel Analysis is a new pattern analysis framework for different types of data configurations. The chapters include

  8. Melanocortin 1 receptor variants and skin cancer risk.

    Science.gov (United States)

    Han, Jiali; Kraft, Peter; Colditz, Graham A; Wong, Jason; Hunter, David J

    2006-10-15

    Melanocortin 1 receptor (MC1R) gene variants are associated with red hair and fair skin color. We assessed the associations of common MC1R genotypes with the risks of 3 types of skin cancer simultaneously in a nested case-control study within the Nurses' Health Study (219 melanoma, 286 squamous cell carcinoma (SCC), and 300 basal cell carcinoma (BCC) cases, and 873 controls). We found that the 151Cys, 160Trp and 294His variants were significantly associated with red hair, fair skin color and childhood tanning tendency. The MC1R variants, especially the 151Cys variant, were associated with increased risks of the 3 types of skin cancer, after controlling for hair color, skin color and other skin cancer risk factors. Carriers of the 151Cys variant had an OR of 1.65 (95% CI, 1.04-2.59) for melanoma, 1.67 (1.12-2.49) for SCC and 1.56 (1.03-2.34) for BCC. Women with medium or olive skin color carrying 1 nonred hair color allele and 1 red hair color allele had the highest risk of melanoma. A similar interaction pattern was observed for red hair and carrying at least 1 red hair color allele on melanoma risk. We also observed that the 151Cys variant contributed additional melanoma risk among red-haired women. The information on MC1R status modestly improved the risk prediction; the increase was significant for melanoma and BCC (p, 0.004 and 0.05, respectively). These findings indicated that the effects of the MC1R variants on skin cancer risk were independent from self-reported phenotypic pigmentation. Copyright 2006 Wiley-Liss, Inc.

  9. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy

    Science.gov (United States)

    Holstege, Henne; van der Lee, Sven J; Hulsman, Marc; Wong, Tsz Hang; van Rooij, Jeroen GJ; Weiss, Marjan; Louwersheimer, Eva; Wolters, Frank J; Amin, Najaf; Uitterlinden, André G; Hofman, Albert; Ikram, M Arfan; van Swieten, John C; Meijers-Heijboer, Hanne; van der Flier, Wiesje M; Reinders, Marcel JT; van Duijn, Cornelia M; Scheltens, Philip

    2017-01-01

    Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign. We tested this pathogenicity screen in SORL1 variants reported in two independent published studies. SORL1 variant pathogenicity is defined by the Combined Annotation Dependent Depletion (CADD) score and the minor allele frequency (MAF) reported by the Exome Aggregation Consortium (ExAC) database. Variants predicted strongly damaging (CADD score >30), which are extremely rare (ExAC-MAF <1 × 10−5) increased AD risk by 12-fold (95% CI 4.2–34.3; P=5 × 10−9). Protein-truncating SORL1 mutations were all unknown to ExAC and occurred exclusively in AD cases. More common SORL1 variants (ExAC-MAF≥1 × 10−5) were not associated with increased AD risk, even when predicted strongly damaging. Findings were independent of gender and the APOE-ε4 allele. High-risk SORL1 variants were observed in a substantial proportion of the AD cases analyzed (2%). Based on their effect size, we propose to consider high-risk SORL1 variants next to variants in APOE, PSEN1, PSEN2 and APP for personalized risk assessments in clinical practice. PMID:28537274

  10. Certain variants of multipermutohedron ideals

    Indian Academy of Sciences (India)

    016-0313-4. Certain variants of multipermutohedron ideals. AJAY KUMAR1,2 and CHANCHAL KUMAR1,∗. 1Indian Institute of ... 2010 Mathematics Subject Classification. 05E40 .... eral questions and conjectures from [10] and [5]. In particular ...

  11. Integration of 60 000 exomes and ACMG guidelines question the role of Catecholaminergic Polymorphic Ventricular Tachycardia associated variants

    DEFF Research Database (Denmark)

    Paludan-Müller, Christian; Ahlberg, Gustav; Ghouse, Jonas

    2017-01-01

    Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a highly lethal cardiac arrhythmia disease occurring during exercise or psychological stress. CPVT has an estimated prevalence of 1:10 000 and has mainly been associated with variants in calcium regulating genes. Identification...... of potential false-positive pathogenic variants was conducted by searching The Exome Aggregation Consortium (ExAC) database (n=60 706) for variants reported to be associated with CPVT. The pathogenicity of the interrogated variants was assessed using guidelines from the American College of Medical Genetics...... and Genomics (ACMG) and in silico prediction tools. Thirty-eight out of 246 variants (15%) previously associated with CPVT were identified in the ExAC database. We predicted the CPVT prevalence to be 1:132. The ACMG standards classified 29% of ExAC variants as pathogenic or likely pathogenic. The in silico...

  12. Swine Influenza/Variant Influenza Viruses

    Science.gov (United States)

    ... Address What's this? Submit What's this? Submit Button Influenza Types Seasonal Avian Swine Variant Other Information on Swine Influenza/Variant Influenza Virus Language: English (US) Español Recommend ...

  13. Semantic prioritization of novel causative genomic variants

    OpenAIRE

    Imane Boudellioua; Rozaimi B Mahamad Razali; Maxat Kulmanov; Yasmeen Hashish; Bajic, Vladimir B.; Eva Goncalves-Serra; Nadia Schoenmakers; Gkoutos, Georgios V.; Schofield, Paul N.; Robert Hoehndorf

    2017-01-01

    Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated rea...

  14. DHAD variants and methods of screening

    Energy Technology Data Exchange (ETDEWEB)

    Kelly, Kristen J.; Ye, Rick W.

    2017-02-28

    Methods of screening for dihydroxy-acid dehydratase (DHAD) variants that display increased DHAD activity are disclosed, along with DHAD variants identified by these methods. Such enzymes can result in increased production of compounds from DHAD requiring biosynthetic pathways. Also disclosed are isolated nucleic acids encoding the DHAD variants, recombinant host cells comprising the isolated nucleic acid molecules, and methods of producing butanol.

  15. Variant Humicola grisea CBH1.1

    Energy Technology Data Exchange (ETDEWEB)

    Goedegebuur, Frits; Gualfetti, Peter; Mitchinson, Colin; Larenas, Edmund

    2017-05-09

    Disclosed are variants of Humicola grisea CeI7A (CBH1.1), H. jecorina CBH1 variant or S. thermophilium CBH1, nucleic acids encoding the same and methods for producing the same. The variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted.

  16. Coronary artery anatomy and variants.

    Science.gov (United States)

    Malagò, Roberto; Pezzato, Andrea; Barbiani, Camilla; Alfonsi, Ugolino; Nicolì, Lisa; Caliari, Giuliana; Pozzi Mucelli, Roberto

    2011-12-01

    Variants and congenital anomalies of the coronary arteries are usually asymptomatic, but may present with severe chest pain or cardiac arrest. The introduction of multidetector CT coronary angiography (MDCT-CA) allows the detection of significant coronary artery stenosis. Improved performance with isotropic spatial resolution and higher temporal resolution provides a valid alternative to conventional coronary angiography (CCA) in many patients. MDCT-CA is now considered the ideal tool for three-dimensional visualization of the complex and tortuous anatomy of the coronary arteries. With multiplanar and volume-rendered reconstructions, MDCT-CA may even outperform CCA in determining the relative position of vessels, thus providing a better view of the coronary vascular anatomy. The purpose of this review is to describe the normal anatomy of the coronary arteries and their main variants based on MDCT-CA with appropriate reconstructions.

  17. Coronary artery anatomy and variants

    Energy Technology Data Exchange (ETDEWEB)

    Malago, Roberto; Pezzato, Andrea; Barbiani, Camilla; Alfonsi, Ugolino; Nicoli, Lisa; Caliari, Giuliana; Pozzi Mucelli, Roberto [Policlinico G.B. Rossi, University of Verona, Department of Radiology, Verona (Italy)

    2011-12-15

    Variants and congenital anomalies of the coronary arteries are usually asymptomatic, but may present with severe chest pain or cardiac arrest. The introduction of multidetector CT coronary angiography (MDCT-CA) allows the detection of significant coronary artery stenosis. Improved performance with isotropic spatial resolution and higher temporal resolution provides a valid alternative to conventional coronary angiography (CCA) in many patients. MDCT-CA is now considered the ideal tool for three-dimensional visualization of the complex and tortuous anatomy of the coronary arteries. With multiplanar and volume-rendered reconstructions, MDCT-CA may even outperform CCA in determining the relative position of vessels, thus providing a better view of the coronary vascular anatomy. The purpose of this review is to describe the normal anatomy of the coronary arteries and their main variants based on MDCT-CA with appropriate reconstructions. (orig.)

  18. Clinicopathologic Variants of Mycosis Fungoides.

    Science.gov (United States)

    Muñoz-González, H; Molina-Ruiz, A M; Requena, L

    2017-04-01

    Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. The clinical course of the disease is typically characterized by progression from a nonspecific phase of erythematous macules to the appearance of plaques and ultimately, in some patients, tumors. However, numerous clinical and histopathologic variants of MF with specific therapeutic and prognostic implications have been described in recent decades. Clarification of the differential diagnosis can be frustrated by the wide range of clinical manifestations and histopathologic patterns of cutaneous infiltration, particularly in the early phases of the disease. In this paper, we review the main clinical, histopathologic, and immunohistochemical characteristics of the variants of MF described in the literature in order to facilitate early diagnosis of the disease. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

  19. Impact of MYH6 variants in hypoplastic left heart syndrome

    Science.gov (United States)

    Stamm, Karl D.; Mahnke, Donna K.; Kim, Min-Su; Hidestrand, Pip M.; Liang, Huan Ling; Goetsch, Mary A.; Hidestrand, Mats; Simpson, Pippa; Pelech, Andrew N.; Tweddell, James S.; Benson, D. Woodrow; Lough, John W.; Mitchell, Michael E.

    2016-01-01

    Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P < 1 × 10−5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P < 1 × 10−2). Transcriptome and protein expression analyses with cardiac tissue revealed differential expression of cardiac contractility genes, notably upregulation of the β-myosin heavy chain (MYH7) gene in subjects with MYH6 variants (P < 1 × 10−3). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo (P < 1 × 10−2), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications. PMID:27789736

  20. Functional assays for analysis of variants of uncertain significance in BRCA2

    DEFF Research Database (Denmark)

    Guidugli, Lucia; Carreira, Aura; Caputo, Sandrine M

    2014-01-01

    Missense variants in the BRCA2 gene are routinely detected during clinical screening for pathogenic mutations in patients with a family history of breast and ovarian cancer. These subtle changes frequently remain of unknown clinical significance because of the lack of genetic information that may...... help establish a direct correlation with cancer predisposition. Therefore, alternative ways of predicting the pathogenicity of these variants are urgently needed. Since BRCA2 is a protein involved in important cellular mechanisms such as DNA repair, replication, and cell cycle control, functional...... assays have been developed that exploit these cellular activities to explore the impact of the variants on protein function. In this review, we summarize assays developed and currently utilized for studying missense variants in BRCA2. We specifically depict details of each assay, including variants...

  1. Copy Number Variants Associated with 14 Cases of Self-Injurious Behavior.

    Directory of Open Access Journals (Sweden)

    Matthew D Shirley

    Full Text Available Copy number variants (CNVs were detected and analyzed in 14 probands with autism and intellectual disability with self-injurious behavior (SIB resulting in tissue damage. For each proband we obtained a clinical history and detailed behavioral descriptions. Genetic anomalies were observed in all probands, and likely clinical significance could be established in four cases. This included two cases having novel, de novo copy number variants and two cases having variants likely to have functional significance. These cases included segmental trisomy 14, segmental monosomy 21, and variants predicted to disrupt the function of ZEB2 (encoding a transcription factor and HTR2C (encoding a serotonin receptor. Our results identify variants in regions previously implicated in intellectual disability and suggest candidate genes that could contribute to the etiology of SIB.

  2. Microcystic Variant of Urothelial Carcinoma

    Directory of Open Access Journals (Sweden)

    Anthony Kodzo-Grey Venyo

    2013-01-01

    Full Text Available Background. Microcystic variant of urothelial carcinoma is one of the new variants of urothelial carcinoma that was added to the WHO classification in 2004. Aims. To review the literature on microcystic variant of urothelial carcinoma. Methods. Various internet search engines were used to identify reported cases of the tumour. Results. Microscopic features of the tumour include: (i Conspicuous intracellular and intercellular lumina/microcysts encompassed by malignant urothelial or squamous cells. (ii The lumina are usually empty; may contain granular eosinophilic debris, mucin, or necrotic cells. (iii The cysts may be variable in size; round, or oval, up to 2 mm; lined by urothelium which are either flattened cells or low columnar cells however, they do not contain colonic epithelium or goblet cells; are infiltrative; invade the muscularis propria; mimic cystitis cystica and cystitis glandularis; occasionally exhibit neuroendocrine differentiation. (iv Elongated and irregular branching spaces are usually seen. About 17 cases of the tumour have been reported with only 2 patients who have survived. The tumour tends to be of high-grade and high-stage. There is no consensus opinion on the best option of treatment of the tumour. Conclusions. It would prove difficult at the moment to be dogmatic regarding its prognosis but it is a highly aggressive tumour. New cases of the tumour should be reported in order to document its biological behaviour.

  3. Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers.

    Science.gov (United States)

    Walker, Logan C; Marquart, Louise; Pearson, John F; Wiggins, George A R; O'Mara, Tracy A; Parsons, Michael T; Barrowdale, Daniel; McGuffog, Lesley; Dennis, Joe; Benitez, Javier; Slavin, Thomas P; Radice, Paolo; Frost, Debra; Godwin, Andrew K; Meindl, Alfons; Schmutzler, Rita Katharina; Isaacs, Claudine; Peshkin, Beth N; Caldes, Trinidad; Hogervorst, Frans Bl; Lazaro, Conxi; Jakubowska, Anna; Montagna, Marco; Chen, Xiaoqing; Offit, Kenneth; Hulick, Peter J; Andrulis, Irene L; Lindblom, Annika; Nussbaum, Robert L; Nathanson, Katherine L; Chenevix-Trench, Georgia; Antoniou, Antonis C; Couch, Fergus J; Spurdle, Amanda B

    2017-04-01

    Genome-wide studies of patients carrying pathogenic variants (mutations) in BRCA1 or BRCA2 have reported strong associations between single-nucleotide polymorphisms (SNPs) and cancer risk. To conduct the first genome-wide association analysis of copy-number variants (CNVs) with breast or ovarian cancer risk in a cohort of 2500 BRCA1 pathogenic variant carriers, CNV discovery was performed using multiple calling algorithms and Illumina 610k SNP array data from a previously published genome-wide association study. Our analysis, which focused on functionally disruptive genomic deletions overlapping gene regions, identified a number of loci associated with risk of breast or ovarian cancer for BRCA1 pathogenic variant carriers. Despite only including putative deletions called by at least two or more algorithms, detection of selected CNVs by ancillary molecular technologies only confirmed 40% of predicted common (>1% allele frequency) variants. These include four loci that were associated (unadjusted P<0.05) with breast cancer (GTF2H2, ZNF385B, NAALADL2 and PSG5), and two loci associated with ovarian cancer (CYP2A7 and OR2A1). An interesting finding from this study was an association of a validated CNV deletion at the CYP2A7 locus (19q13.2) with decreased ovarian cancer risk (relative risk=0.50, P=0.007). Genomic analysis found this deletion coincides with a region displaying strong regulatory potential in ovarian tissue, but not in breast epithelial cells. This study highlighted the need to verify CNVs in vitro, but also provides evidence that experimentally validated CNVs (with plausible biological consequences) can modify risk of breast or ovarian cancer in BRCA1 pathogenic variant carriers.

  4. Discriminatory power of common genetic variants in personalized breast cancer diagnosis

    Science.gov (United States)

    Wu, Yirong; Abbey, Craig K.; Liu, Jie; Ong, Irene; Peissig, Peggy; Onitilo, Adedayo A.; Fan, Jun; Yuan, Ming; Burnside, Elizabeth S.

    2016-03-01

    Technology advances in genome-wide association studies (GWAS) has engendered optimism that we have entered a new age of precision medicine, in which the risk of breast cancer can be predicted on the basis of a person's genetic variants. The goal of this study is to evaluate the discriminatory power of common genetic variants in breast cancer risk estimation. We conducted a retrospective case-control study drawing from an existing personalized medicine data repository. We collected variables that predict breast cancer risk: 153 high-frequency/low-penetrance genetic variants, reflecting the state-of-the-art GWAS on breast cancer, mammography descriptors and BI-RADS assessment categories in the Breast Imaging Reporting and Data System (BI-RADS) lexicon. We trained and tested naïve Bayes models by using these predictive variables. We generated ROC curves and used the area under the ROC curve (AUC) to quantify predictive performance. We found that genetic variants achieved comparable predictive performance to BI-RADS assessment categories in terms of AUC (0.650 vs. 0.659, p-value = 0.742), but significantly lower predictive performance than the combination of BI-RADS assessment categories and mammography descriptors (0.650 vs. 0.751, p-value genetic variants and mammography data may benefit clinicians and patients to make appropriate decisions about breast cancer screening, prevention, and treatment in the era of precision medicine.

  5. Listeners' processing of a given reduced word pronunciation variant directly reflects their exposure to this variant: Evidence from native listeners and learners of French.

    Science.gov (United States)

    Brand, Sophie; Ernestus, Mirjam

    2017-04-24

    In casual conversations, words often lack segments. This study investigates whether listeners rely on their experience with reduced word pronunciation variants during the processing of single segment reduction. We tested three groups of listeners in a lexical decision experiment with French words produced either with or without word-medial schwa (e.g., /ʀəvy/ and /ʀvy/ for revue). Participants also rated the relative frequencies of the two pronunciation variants of the words. If the recognition accuracy and reaction times (RTs) for a given listener group correlate best with the frequencies of occurrence holding for that given listener group, recognition is influenced by listeners' exposure to these variants. Native listeners' relative frequency ratings correlated well with their accuracy scores and RTs. Dutch advanced learners' accuracy scores and RTs were best predicted by their own ratings. In contrast, the accuracy and RTs from Dutch beginner learners of French could not be predicted by any relative frequency rating; the rating task was probably too difficult for them. The participant groups showed behaviour reflecting their difference in experience with the pronunciation variants. Our results strongly suggest that listeners store the frequencies of occurrence of pronunciation variants, and consequently the variants themselves.

  6. Common and rare variants of the THBS1 gene associated with the risk for autism.

    Science.gov (United States)

    Lu, Lina; Guo, Hui; Peng, Yu; Xun, Guanglei; Liu, Yanling; Xiong, Zhimin; Tian, Di; Liu, Yalan; Li, Wei; Xu, Xiaojuan; Zhao, Jingping; Hu, Zhengmao; Xia, Kun

    2014-12-01

    Autism is a severe neurodevelopmental disorder. Many susceptible or causative genes have been identified, and most of them are related to synaptogenesis. The THBS1 gene encodes thrombospondin 1, which plays a critical role in synaptogenesis of the central nervous system in the developing brain. However, no study has been carried out revealing that THBS1 is an autism risk gene. We analyzed the whole coding region and the 5'-untranslated region of the THBS1 gene in 313 autistic patients by Sanger sequencing, which was also used to analyze the identified variants in 350 normal controls. Association analysis was carried out using PLINK or R. Haplotype analysis was carried out using Haploview. Functional prediction and conservation analysis of missense variants were carried out using ANNOVAR. Twelve variants, including five common variants and seven rare variants, were identified in the THBS1 coding region and the 5'-untranslated region. Among them, one common variant (c.1567A>G:p.T523A) was significantly associated with autism (PA:p.R810Q, c.3496G>C:p.E1166Q) were absent in the 350 controls and were not reported in the single nucleotide polymorphism database (dbSNP). Combined association analysis of the rare variants (minor allele frequencyautism (P=0.039). Our data revealed that both common and rare variants of the THBS1 gene are associated with risk for autism, suggesting that THBS1 is a novel susceptible gene for autism.

  7. Selection of antigenically advanced variants of seasonal influenza viruses

    Science.gov (United States)

    Ozawa, Makoto; Taft, Andrew S.; Das, Subash C.; Hanson, Anthony P.; Song, Jiasheng; Imai, Masaki; Wilker, Peter R.; Watanabe, Tokiko; Watanabe, Shinji; Ito, Mutsumi; Iwatsuki-Horimoto, Kiyoko; Russell, Colin A.; James, Sarah L.; Skepner, Eugene; Maher, Eileen A.; Neumann, Gabriele; Kelso, Anne; McCauley, John; Wang, Dayan; Shu, Yuelong; Odagiri, Takato; Tashiro, Masato; Xu, Xiyan; Wentworth, David E.; Katz, Jacqueline M.; Cox, Nancy J.; Smith, Derek J.; Kawaoka, Yoshihiro

    2016-01-01

    Influenza viruses mutate frequently, necessitating constant updates of vaccine viruses. To establish experimental approaches that may complement the current vaccine strain selection process, we selected antigenic variants from human H1N1 and H3N2 influenza virus libraries possessing random mutations in the globular head of the haemagglutinin protein (which includes the antigenic sites) by incubating them with human and/or ferret convalescent sera to human H1N1 and H3N2 viruses. Further, we selected antigenic escape variants from human viruses treated with convalescent sera and from mice that had been previously immunized against human influenza viruses. Our pilot studies with past influenza viruses identified escape mutants that were antigenically similar to variants that emerged in nature, establishing the feasibility of our approach. Our studies with contemporary human influenza viruses identified escape mutants before they caused an epidemic in 2014–2015. This approach may aid in the prediction of potential antigenic escape variants and the selection of future vaccine candidates before they become widespread in nature. PMID:27572841

  8. Genetic associations of nonsynonymous exonic variants with psychophysiological endophenotypes

    Science.gov (United States)

    Vrieze, Scott I.; Malone, Stephen M.; Pankratz, Nathan; Vaidyanathan, Uma; Miller, Michael B.; Kang, Hyun Min; McGue, Matt; Abecasis, Gonçalo; Iacono, William G.

    2014-01-01

    We mapped ~85,000 rare nonsynonymous exonic single nucleotide polymorphisms (SNPs) to 17 psychophysiological endophenotypes in 4,905 individuals, including antisaccade eye movements, resting EEG, P300 amplitude, electrodermal activity, affect-modulated startle eye blink. Nonsynonymous SNPs are predicted to directly change or disrupt proteins encoded by genes and are expected to have significant biological consequences. Most such variants are rare, and new technologies can efficiently assay them on a large scale. We assayed 247,870 mostly rare SNPs on an Illumina exome array. Approximately 85,000 of the SNPs were polymorphic, rare (MAF < .05), and nonsynonymous. Single variant association tests identified a SNP in the PARD3 gene associated with theta resting EEG power. The sequence kernel association test, a gene-based test, identified a gene PNPLA7 associated with pleasant difference startle, the difference in startle magnitude between pleasant and neutral images. No other single nonsynonymous variant, or gene-based group of variants, was strongly associated with any endophenotype. PMID:25387709

  9. Affective Differences Between Psychopathy Variants and Genders in Adjudicated Youth.

    Science.gov (United States)

    Gill, Andrew D; Stickle, Timothy R

    2016-02-01

    The present study used Model-Based Cluster analysis to identify primary and secondary psychopathy variants in a mixed-gender sample of 150 adjudicated adolescents (60 % male; M = 15.2 years old). Distinct primary and secondary psychopathy groups emerged and were entered into a structural equation path model for the purpose of predicting group differences in emotional experiences reported between youth assigned to each variant. Youth characterized by secondary psychopathy reported experiencing significantly more frequent and more intense negative affect than their primary psychopathy counterparts. Frequency and intensity of affect also mediated the association between psychopathy variants and symptoms of depression, in which the secondary psychopathy group endorsed significantly more symptoms of major depression than the primary psychopathy group. Overall, these results suggest that different causal processes and affective experiences may underlie distinct trajectories to primary and secondary psychopathy variants in adjudicated adolescents. As such, youths comprising the secondary subtype of psychopathy may be more aptly considered "callous and emotional," compared with the primary subtype who present as prototypically callous and unemotional.

  10. Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy.

    Science.gov (United States)

    Wang, Jizheng; Wang, Yilu; Zou, Yubao; Sun, Kai; Wang, Zhimin; Ding, Hu; Yuan, Jinqing; Wei, Wei; Hou, Qing; Wang, Hu; Liu, Xuan; Zhang, Hongju; Ji, Yun; Zhou, Xianliang; Sharma, Ravi K; Wang, Daowen; Ahmad, Ferhaan; Hui, Rutai; Song, Lei

    2014-09-01

    Although genetic testing has been recommended in patients with hypertrophic cardiomyopathy (HCM) in current clinical practice, its utility in prognostic prediction remains to be ascertained. We assessed the dosage effect of rare variants in sarcomere genes on the long-term outcomes of HCM. A total of 529 unrelated HCM patients were prospectively recruited and followed for 4.7 ± 3.2 years. Eight sarcomere genes were screened with targeted resequencing and identified variants were validated through Sanger sequencing. After polymorphisms and likely neutral rare variants were excluded, the patients were segregated into three groups based on the dosage of rare variants: no rare variant, a single rare variant, and multiple rare variants. Multiple rare variants were identified in 7.2% (38/529) of the study patients. Patients with multiple rare variants were younger at diagnosis, and had greater maximum LV wall thicknesses and larger left atria. The risk for cardiovascular death in patients with multiple rare variants was higher than in those without rare variants (P =10⁻⁵) or in those with a single rare variant (P = 2 × 10⁻⁵). Multivariable analysis revealed that multiple rare variants were a risk factor for cardiovascular death [hazard ratio (HR) 3.74, 95% confidence interval (CI) 1.84-7.58, P = 0.0003], as well as sudden cardiac death (HR 3.57, 95% CI 1.23-10.35, P = 0.019) and heart failure-related death (HR 4.62, 95% CI 1.67-12.76, P = 0.003). The presence of multiple rare variants in sarcomere genes is a risk factor for malignant outcomes in HCM, and may be appropriate to consider as a criterion in the risk stratification of HCM patients. © 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.

  11. Gardner's Minichess Variant is solved

    OpenAIRE

    Mhalla, Mehdi; Prost, Frederic

    2013-01-01

    A 5x5 board is the smallest board on which one can set up all kind of chess pieces as a start position. We consider Gardner's minichess variant in which all pieces are set as in a standard chessboard (from Rook to King). This game has roughly 9x10^{18} legal positions and is comparable in this respect with checkers. We weakly solve this game, that is we prove its game-theoretic value and give a strategy to draw against best play for White and Black sides. Our approach requires surprisingly sm...

  12. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.

    Science.gov (United States)

    Carss, Keren J; Arno, Gavin; Erwood, Marie; Stephens, Jonathan; Sanchis-Juan, Alba; Hull, Sarah; Megy, Karyn; Grozeva, Detelina; Dewhurst, Eleanor; Malka, Samantha; Plagnol, Vincent; Penkett, Christopher; Stirrups, Kathleen; Rizzo, Roberta; Wright, Genevieve; Josifova, Dragana; Bitner-Glindzicz, Maria; Scott, Richard H; Clement, Emma; Allen, Louise; Armstrong, Ruth; Brady, Angela F; Carmichael, Jenny; Chitre, Manali; Henderson, Robert H H; Hurst, Jane; MacLaren, Robert E; Murphy, Elaine; Paterson, Joan; Rosser, Elisabeth; Thompson, Dorothy A; Wakeling, Emma; Ouwehand, Willem H; Michaelides, Michel; Moore, Anthony T; Webster, Andrew R; Raymond, F Lucy

    2017-01-05

    Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease. Copyright © 2017. Published by Elsevier Inc.

  13. Histone variants: emerging players in cancer biology

    Science.gov (United States)

    Vardabasso, Chiara; Hasson, Dan; Ratnakumar, Kajan; Chung, Chi-Yeh; Duarte, Luis F.

    2014-01-01

    Histone variants are key players in shaping chromatin structure, and, thus, in regulating fundamental cellular processes such as chromosome segregation and gene expression. Emerging evidence points towards a role for histone variants in contributing to tumor progression, and, recently, the first cancer-associated mutation in a histone variant-encoding gene was reported. In addition, genetic alterations of the histone chaperones that specifically regulate chromatin incorporation of histone variants are rapidly being uncovered in numerous cancers. Collectively, these findings implicate histone variants as potential drivers of cancer initiation and/or progression, and, therefore, targeting histone deposition or the chromatin remodeling machinery may be of therapeutic value. Here, we review the mammalian histone variants of the H2A and H3 families in their respective cellular functions, and their involvement in tumor biology. PMID:23652611

  14. Nested Variant of Urothelial Carcinoma

    Science.gov (United States)

    Venyo, Anthony Kodzo-Grey

    2014-01-01

    Background. Nested variant of urothelial carcinoma was added to the WHO's classification in 2004. Aims. To review the literature on nested variant of urothelial carcinoma. Results. About 200 cases of the tumour have been reported so far and it has the ensuing morphological features: large numbers of small confluent irregular nests of bland-appearing, closely packed, haphazardly arranged, and poorly defined urothelial cells infiltrating the lamina propria and the muscularis propria. The tumour has a bland histomorphologic appearance, has an aggressive biological behaviour, and has at times been misdiagnosed as a benign lesion which had led to a significant delay in the establishment of the correct diagnosis and contributing to the advanced stage of the disease. Immunohistochemically, the tumour shares some characteristic features with high-risk conventional urothelial carcinomas such as high proliferation index and loss of p27 expression. However, p53, bcl-2, or EGF-r immunoreactivity is not frequently seen. The tumour must be differentiated from a number of proliferative lesions of the urothelium. Conclusions. Correct and early diagnosis of this tumour is essential to provide early curative treatment to avoid diagnosis at an advanced stage. A multicentre trial is required to identify treatment options that would improve the outcome of this tumour. PMID:24587796

  15. Reliably Detecting Clinically Important Variants Requires Both Combined Variant Calls and Optimized Filtering Strategies.

    Directory of Open Access Journals (Sweden)

    Matthew A Field

    Full Text Available A diversity of tools is available for identification of variants from genome sequence data. Given the current complexity of incorporating external software into a genome analysis infrastructure, a tendency exists to rely on the results from a single tool alone. The quality of the output variant calls is highly variable however, depending on factors such as sequence library quality as well as the choice of short-read aligner, variant caller, and variant caller filtering strategy. Here we present a two-part study first using the high quality 'genome in a bottle' reference set to demonstrate the significant impact the choice of aligner, variant caller, and variant caller filtering strategy has on overall variant call quality and further how certain variant callers outperform others with increased sample contamination, an important consideration when analyzing sequenced cancer samples. This analysis confirms previous work showing that combining variant calls of multiple tools results in the best quality resultant variant set, for either specificity or sensitivity, depending on whether the intersection or union, of all variant calls is used respectively. Second, we analyze a melanoma cell line derived from a control lymphocyte sample to determine whether software choices affect the detection of clinically important melanoma risk-factor variants finding that only one of the three such variants is unanimously detected under all conditions. Finally, we describe a cogent strategy for implementing a clinical variant detection pipeline; a strategy that requires careful software selection, variant caller filtering optimizing, and combined variant calls in order to effectively minimize false negative variants. While implementing such features represents an increase in complexity and computation the results offer indisputable improvements in data quality.

  16. The Use of Variant Maps to Explore Domain-Specific Mutations of FGFR1.

    Science.gov (United States)

    Lansdon, L A; Bernabe, H V; Nidey, N; Standley, J; Schnieders, M J; Murray, J C

    2017-10-01

    Here we describe the genotype-phenotype correlations of diseases caused by variants in Fibroblast Growth Factor Receptor 1 ( FGFR1) and report a novel, de novo variant in FGFR1 in an individual with multiple congenital anomalies. The proband presented with bilateral cleft lip and palate, malformed auricles, and bilateral ectrodactyly of his hands and feet at birth. He was later diagnosed with diabetes insipidus, spastic quadriplegia, developmental delay, agenesis of the corpus callosum, and enlargement of the third cerebral ventricle. We noted the substantial phenotypic overlap with individuals with Hartsfield syndrome, the rare combination of holoprosencephaly and ectrodactyly. Sequencing of FGFR1 identified a previously unreported de novo variant in exon 11 (p.Gly487Cys), which we modeled to determine its predicted effect on the protein structure. Although it was not predicted to significantly alter protein folding stability, it is possible this variant leads to the formation of nonnative intra- or intermolecular disulfide bonds. We then mapped this and other disease-associated variants to a 3-dimensional model of FGFR1 to assess which protein domains harbored the highest number of pathogenic changes. We observed the greatest number of variants within the domains involved in FGF binding and FGFR activation. To further explore the contribution of each variant to disease, we recorded the phenotype resulting from each FGFR1 variant to generate a series of phenotype-specific protein maps and compared our results to benign variants appearing in control databases. It is our hope that the use of phenotypic maps such as these will further the understanding of genetic disease in general and diseases caused by variation in FGFR1 specifically.

  17. Global inference of disease-causing single nucleotide variants from exome sequencing data.

    Science.gov (United States)

    Wu, Mengmeng; Chen, Ting; Jiang, Rui

    2016-12-23

    Whole exome sequencing (WES) has recently emerged as an effective approach for identifying genetic variants underlying human diseases. However, considerable time and labour is needed for careful investigation of candidate variants. Although filtration based on population frequencies and functional prediction scores could effectively remove common and neutral variants, hundreds or even thousands of rare deleterious variants still remain. In addition, current WES platforms also provide variant information in flanking noncoding regions, such as promoters, introns and splice sites. Despite of being recognized to harbour causal variants, these regions are usually ignored by current analysis pipelines. We present a novel computational method, called Glints, to overcome the above limitations. Glints is capable of identifying disease-causing SNVs in both coding and flanking noncoding regions from exome sequencing data. The principle behind Glints is that disease-causing variants should manifest their effect at both variant and gene levels. Specifically, Glints integrates 14 types of functional scores, including predictions for both coding and noncoding variants, and 9 types of association scores, which help identifying disease relevant genes. We conducted a large-scale simulation studies based on 1000 Genomes Project data and demonstrated the effectiveness of our method in both coding and flanking noncoding regions. We also applied Glints in two real exome sequencing and demonstrated its effectiveness for uncovering disease-causing SNVs. Both standalone software and web server are available at our website http://bioinfo.au.tsinghua.edu.cn/jianglab/glints . Glints is effective for uncovering disease-causing SNVs in coding and flanking noncoding regions, which is supported by both simulation and real case studies. Glints is expected to be a useful tool for human genetics research based on exome sequencing data.

  18. Predictive value of testing for multiple genetic variants in multifactorial

    NARCIS (Netherlands)

    A.C.J.W. Janssens (Cécile); M.J. Khoury (Muin Joseph)

    2009-01-01

    textabstractMultifactorial diseases such as type 2 diabetes, osteoporosis, and cardiovascular disease are caused by a complex interplay of many genetic and nongenetic factors, each of which conveys a minor increase in the risk of disease. Unraveling the genetic origins of these diseases is

  19. New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants

    DEFF Research Database (Denmark)

    Andreasen, Charlotte Hartig; Nielsen, Jonas B; Refsgaard, Lena

    2013-01-01

    Cardiomyopathies are a heterogeneous group of diseases with various etiologies. We focused on three genetically determined cardiomyopathies: hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Eighty-four genes have so far been associated...... with these cardiomyopathies, but the disease-causing effect of reported variants is often dubious. In order to identify possible false-positive variants, we investigated the prevalence of previously reported cardiomyopathy-associated variants in recently published exome data. We searched for reported missense and nonsense....... These findings correspond to a genotype prevalence of 1:4 for HCM, 1:6 for DCM, and 1:5 for ARVC. PolyPhen-2 predictions were conducted on all previously published cardiomyopathy-associated missense variants. We found significant overrepresentation of variants predicted as being benign among those present in ESP...

  20. A Protein Domain and Family Based Approach to Rare Variant Association Analysis.

    Science.gov (United States)

    Richardson, Tom G; Shihab, Hashem A; Rivas, Manuel A; McCarthy, Mark I; Campbell, Colin; Timpson, Nicholas J; Gaunt, Tom R

    2016-01-01

    It has become common practice to analyse large scale sequencing data with statistical approaches based around the aggregation of rare variants within the same gene. We applied a novel approach to rare variant analysis by collapsing variants together using protein domain and family coordinates, regarded to be a more discrete definition of a biologically functional unit. Using Pfam definitions, we collapsed rare variants (Minor Allele Frequency ≤ 1%) together in three different ways 1) variants within single genomic regions which map to individual protein domains 2) variants within two individual protein domain regions which are predicted to be responsible for a protein-protein interaction 3) all variants within combined regions from multiple genes responsible for coding the same protein domain (i.e. protein families). A conventional collapsing analysis using gene coordinates was also undertaken for comparison. We used UK10K sequence data and investigated associations between regions of variants and lipid traits using the sequence kernel association test (SKAT). We observed no strong evidence of association between regions of variants based on Pfam domain definitions and lipid traits. Quantile-Quantile plots illustrated that the overall distributions of p-values from the protein domain analyses were comparable to that of a conventional gene-based approach. Deviations from this distribution suggested that collapsing by either protein domain or gene definitions may be favourable depending on the trait analysed. We have collapsed rare variants together using protein domain and family coordinates to present an alternative approach over collapsing across conventionally used gene-based regions. Although no strong evidence of association was detected in these analyses, future studies may still find value in adopting these approaches to detect previously unidentified association signals.

  1. A Protein Domain and Family Based Approach to Rare Variant Association Analysis

    Science.gov (United States)

    Richardson, Tom G.; Shihab, Hashem A.; Rivas, Manuel A.; McCarthy, Mark I.; Campbell, Colin; Timpson, Nicholas J.; Gaunt, Tom R.

    2016-01-01

    Background It has become common practice to analyse large scale sequencing data with statistical approaches based around the aggregation of rare variants within the same gene. We applied a novel approach to rare variant analysis by collapsing variants together using protein domain and family coordinates, regarded to be a more discrete definition of a biologically functional unit. Methods Using Pfam definitions, we collapsed rare variants (Minor Allele Frequency ≤ 1%) together in three different ways 1) variants within single genomic regions which map to individual protein domains 2) variants within two individual protein domain regions which are predicted to be responsible for a protein-protein interaction 3) all variants within combined regions from multiple genes responsible for coding the same protein domain (i.e. protein families). A conventional collapsing analysis using gene coordinates was also undertaken for comparison. We used UK10K sequence data and investigated associations between regions of variants and lipid traits using the sequence kernel association test (SKAT). Results We observed no strong evidence of association between regions of variants based on Pfam domain definitions and lipid traits. Quantile-Quantile plots illustrated that the overall distributions of p-values from the protein domain analyses were comparable to that of a conventional gene-based approach. Deviations from this distribution suggested that collapsing by either protein domain or gene definitions may be favourable depending on the trait analysed. Conclusion We have collapsed rare variants together using protein domain and family coordinates to present an alternative approach over collapsing across conventionally used gene-based regions. Although no strong evidence of association was detected in these analyses, future studies may still find value in adopting these approaches to detect previously unidentified association signals. PMID:27128313

  2. A Protein Domain and Family Based Approach to Rare Variant Association Analysis.

    Directory of Open Access Journals (Sweden)

    Tom G Richardson

    Full Text Available It has become common practice to analyse large scale sequencing data with statistical approaches based around the aggregation of rare variants within the same gene. We applied a novel approach to rare variant analysis by collapsing variants together using protein domain and family coordinates, regarded to be a more discrete definition of a biologically functional unit.Using Pfam definitions, we collapsed rare variants (Minor Allele Frequency ≤ 1% together in three different ways 1 variants within single genomic regions which map to individual protein domains 2 variants within two individual protein domain regions which are predicted to be responsible for a protein-protein interaction 3 all variants within combined regions from multiple genes responsible for coding the same protein domain (i.e. protein families. A conventional collapsing analysis using gene coordinates was also undertaken for comparison. We used UK10K sequence data and investigated associations between regions of variants and lipid traits using the sequence kernel association test (SKAT.We observed no strong evidence of association between regions of variants based on Pfam domain definitions and lipid traits. Quantile-Quantile plots illustrated that the overall distributions of p-values from the protein domain analyses were comparable to that of a conventional gene-based approach. Deviations from this distribution suggested that collapsing by either protein domain or gene definitions may be favourable depending on the trait analysed.We have collapsed rare variants together using protein domain and family coordinates to present an alternative approach over collapsing across conventionally used gene-based regions. Although no strong evidence of association was detected in these analyses, future studies may still find value in adopting these approaches to detect previously unidentified association signals.

  3. Polymorphism of the Transcription Factor 7-Like 2 Gene (TCF7L2 Interacts with Obesity on Type-2 Diabetes in the PREDIMED Study Emphasizing the Heterogeneity of Genetic Variants in Type-2 Diabetes Risk Prediction: Time for Obesity-Specific Genetic Risk Scores

    Directory of Open Access Journals (Sweden)

    Dolores Corella

    2016-12-01

    Full Text Available Nutrigenetic studies analyzing gene–diet interactions of the TCF7L2-rs7903146 C > T polymorphism on type-2 diabetes (T2D have shown controversial results. A reason contributing to this may be the additional modulation by obesity. Moreover, TCF7L2-rs7903146 is one of the most influential variants in T2D-genetic risk scores (GRS. Therefore, to increase the predictive value (PV of GRS it is necessary to first see whether the included polymorphisms have heterogeneous effects. We comprehensively investigated gene-obesity interactions between the TCF7L2-rs7903146 C > T polymorphism on T2D (prevalence and incidence and analyzed other T2D-polymorphisms in a sub-sample. We studied 7018 PREDIMED participants at baseline and longitudinally (8.7 years maximum follow-up. Obesity significantly interacted with the TCF7L2-rs7903146 on T2D prevalence, associations being greater in non-obese subjects. Accordingly, we prospectively observed in non-T2D subjects (n = 3607 that its association with T2D incidence was stronger in non-obese (HR: 1.81; 95% CI: 1.13–2.92, p = 0.013 for TT versus CC than in obese subjects (HR: 1.01; 95% CI: 0.61–1.66; p = 0.979; p-interaction = 0.048. Accordingly, TCF7L2-PV was higher in non-obese subjects. Additionally, we created obesity-specific GRS with ten T2D-polymorphisms and demonstrated for the first time their higher strata-specific PV. In conclusion, we provide strong evidence supporting the need for considering obesity when analyzing the TCF7L2 effects and propose the use of obesity-specific GRS for T2D.

  4. Deep sequencing of Danish Holstein dairy cattle for variant detection and insight into potential loss-of-function variants in protein coding genes.

    Science.gov (United States)

    Das, Ashutosh; Panitz, Frank; Gregersen, Vivi Raundahl; Bendixen, Christian; Holm, Lars-Erik

    2015-12-09

    1000 bull genomes data set. Deep sequencing of Danish Holstein genomes enabled us to identify 12.1 million variants. An investigation into LoF variants discovered a set of variants predicted to disrupt protein-coding genes. This catalog of variants will be a resource for future studies to understand variation underlying important phenotypes, particularly recessively inherited lethal phenotypes.

  5. Mitochondrial DNA variants in obesity.

    Directory of Open Access Journals (Sweden)

    Nadja Knoll

    Full Text Available Heritability estimates for body mass index (BMI variation are high. For mothers and their offspring higher BMI correlations have been described than for fathers. Variation(s in the exclusively maternally inherited mitochondrial DNA (mtDNA might contribute to this parental effect. Thirty-two to 40 mtDNA single nucleotide polymorphisms (SNPs were available from genome-wide association study SNP arrays (Affymetrix 6.0. For discovery, we analyzed association in a case-control (CC sample of 1,158 extremely obese children and adolescents and 435 lean adult controls. For independent confirmation, 7,014 population-based adults were analyzed as CC sample of n = 1,697 obese cases (BMI ≥ 30 kg/m2 and n = 2,373 normal weight and lean controls (BMI<25 kg/m2. SNPs were analyzed as single SNPs and haplogroups determined by HaploGrep. Fisher's two-sided exact test was used for association testing. Moreover, the D-loop was re-sequenced (Sanger in 192 extremely obese children and adolescents and 192 lean adult controls. Association testing of detected variants was performed using Fisher's two-sided exact test. For discovery, nominal association with obesity was found for the frequent allele G of m.8994G/A (rs28358887, p = 0.002 located in ATP6. Haplogroup W was nominally overrepresented in the controls (p = 0.039. These findings could not be confirmed independently. For two of the 252 identified D-loop variants nominal association was detected (m.16292C/T, p = 0.007, m.16189T/C, p = 0.048. Only eight controls carried the m.16292T allele, five of whom belonged to haplogroup W that was initially enriched among these controls. m.16189T/C might create an uninterrupted poly-C tract located near a regulatory element involved in replication of mtDNA. Though follow-up of some D-loop variants still is conceivable, our hypothesis of a contribution of variation in the exclusively maternally inherited mtDNA to the observed larger correlations for BMI between mothers and

  6. Classifying Variants of Undetermined Significance in BRCA2 with Protein Likelihood Ratios

    Directory of Open Access Journals (Sweden)

    Mary S. Beattie

    2008-01-01

    Full Text Available Background: Missense (amino-acid changing variants found in cancer predisposition genes often create difficulties when clinically interpreting genetic testing results. Although bioinformatics has developed approaches to predicting the impact of these variants, many of these approaches have not been readily applicable in the clinical setting. Bioinformatics approaches for predicting the impact of these variants have not yet found their footing in clinical practice because 1 interpreting the medical relevance of predictive scores is difficult; 2 the relationship between bioinformatics “predictors” (sequence conservation, protein structure and cancer susceptibility is not understood.Methodology/Principal Findings: We present a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function. We apply the method to a tumor suppressor gene, BRCA2, whose loss of function is important to cancer susceptibility. Protein likelihood ratios are computed for 229 unclassified variants found in individuals from high-risk breast/ovarian cancer families. We map the variants onto a protein structure model, and suggest that a cluster of predicted deleterious variants in the BRCA2 OB1 domain may destabilize BRCA2 and a protein binding partner, the small acidic protein DSS1. We compare our predictions with variant “re-classifications” provided by Myriad Genetics, a biotechnology company that holds the patent on BRCA2 genetic testing in the U.S., and with classifications made by an established medical genetics model [1]. Our approach uses bioinformatics data that is independent of these genetics-based classifications and yet shows significant agreement with them. Preliminary results indicate that our method is less likely to make false positive errors than other bioinformatics methods, which were designed to predict the impact of missense mutations in general

  7. Resistance of Abaca Somaclonal Variant Against Fusarium

    Directory of Open Access Journals (Sweden)

    RULLY DYAH PURWATI

    2007-12-01

    Full Text Available The objectives of this study were (i to evaluate responses against F. oxysporum f.sp. cubense (Foc infection of abaca variants regenerated using four different methods, (ii to determine initial root length and plant height effects on survival of inoculated abaca variants, and (iii to identify Foc resistance abaca variants. In the previous experiment, four abaca variant lines were regenerated from (i embryogenic calli (TC line, (ii ethyl methyl sulphonate (EMS treated embryogenic calli (EMS line, (iii EMS treated embryogenic calli, followed by in vitro selection on Foc culture filtrate (EMS+CF line, and (iv EMS treated embryogenic calli, followed by in vitro selection on fusaric acid (EMS+FA line. All abaca variants were grown in a glasshouse and inoculated with Banyuwangi isolate of Foc (Foc Bw. Initial root length (RL and plant height (PH of the abaca variants were recorded before inoculation, while scores of plant damage (SPD, and their survival were recorded at 60 days after inoculation (DAI. The results showed that the initial RL and PH did not affect survival of the tested abaca variants. Regardless of their initial RL and PH, susceptible abaca variants died before 60 DAI while resistance ones still survived. Abaca variants regenerated from single clump of embryogenic callus showed an array of responses against Foc Bw infection, indicating the existence of a mix cells population. The Foc Bw resistance abaca variants were successfully identified from four tested abaca variant lines, although with different frequencies. However, more Foc Bw resistance abaca plants were identified from EMS+CF line than the others. Using the developed procedures, 8 resistance abaca plants were identified from abaca cv. Tangongon and 12 from abaca cv. Sangihe-1.

  8. Detection of variants in SLC6A8 and functional analysis of unclassified missense variants

    NARCIS (Netherlands)

    Betsalel, Ofir T; Pop, Ana; Rosenberg, Efraim H; Fernandez-Ojeda, Matilde; Jakobs, Cornelis; Salomons, Gajja S; Koning, Klaziena

    Creatine transporter deficiency is an X-linked disorder caused by mutations in the SLC6A8 gene. Currently, 38 pathogenic, including 15 missense variants, are reported. In this study, we report 33 novel, including 6 missense variants. To classify all known missense variants, we transfected creatine

  9. Detection of variants in SLC6A8 and functional analysis of unclassified missense variants

    NARCIS (Netherlands)

    Betsalel, O.T.; Pop, A.; Rosenberg, E.H.; Fernandez-Ojeda, M.; Jakobs, C.; Salomons, G.S.; Brouwer, A.P. de; Wevers, R.A.; Yntema, H.G.

    2012-01-01

    Creatine transporter deficiency is an X-linked disorder caused by mutations in the SLC6A8 gene. Currently, 38 pathogenic, including 15 missense variants, are reported. In this study, we report 33 novel, including 6 missense variants. To classify all known missense variants, we transfected creatine

  10. A rare myelin protein zero (MPZ variant alters enhancer activity in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Anthony Antonellis

    2010-12-01

    Full Text Available Myelin protein zero (MPZ is a critical structural component of myelin in the peripheral nervous system. The MPZ gene is regulated, in part, by the transcription factors SOX10 and EGR2. Mutations in MPZ, SOX10, and EGR2 have been implicated in demyelinating peripheral neuropathies, suggesting that components of this transcriptional network are candidates for harboring disease-causing mutations (or otherwise functional variants that affect MPZ expression.We utilized a combination of multi-species sequence comparisons, transcription factor-binding site predictions, targeted human DNA re-sequencing, and in vitro and in vivo enhancer assays to study human non-coding MPZ variants.Our efforts revealed a variant within the first intron of MPZ that resides within a previously described SOX10 binding site is associated with decreased enhancer activity, and alters binding of nuclear proteins. Additionally, the genomic segment harboring this variant directs tissue-relevant reporter gene expression in zebrafish.This is the first reported MPZ variant within a cis-acting transcriptional regulatory element. While we were unable to implicate this variant in disease onset, our data suggests that similar non-coding sequences should be screened for mutations in patients with neurological disease. Furthermore, our multi-faceted approach for examining the functional significance of non-coding variants can be readily generalized to study other loci important for myelin structure and function.

  11. Genetic Load of Loss-of-Function Polymorphic Variants in Great Apes.

    Science.gov (United States)

    de Valles-Ibáñez, Guillem; Hernandez-Rodriguez, Jessica; Prado-Martinez, Javier; Luisi, Pierre; Marquès-Bonet, Tomàs; Casals, Ferran

    2016-03-26

    Loss of function (LoF) genetic variants are predicted to disrupt gene function, and are therefore expected to substantially reduce individual's viability. Knowing the genetic burden of LoF variants in endangered species is of interest for a better understanding of the effects of declining population sizes on species viability. In this study, we have estimated the number of LoF polymorphic variants in six great ape populations, based on whole-genome sequencing data in 79 individuals. Our results show that although the number of functional variants per individual is conditioned by the effective population size, the number of variants with a drastic phenotypic effect is very similar across species. We hypothesize that for those variants with high selection coefficients, differences in effective population size are not important enough to affect the efficiency of natural selection to remove them. We also describe that mostly CpG LoF mutations are shared across species, and an accumulation of LoF variants at olfactory receptor genes in agreement with its pseudogenization in humans and other primate species. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  12. Quantifying the Impact of Non-coding Variants on Transcription Factor-DNA Binding.

    Science.gov (United States)

    Zhao, Jingkang; Li, Dongshunyi; Seo, Jungkyun; Allen, Andrew S; Gordân, Raluca

    2017-05-01

    Many recent studies have emphasized the importance of genetic variants and mutations in cancer and other complex human diseases. The overwhelming majority of these variants occur in non-coding portions of the genome, where they can have a functional impact by disrupting regulatory interactions between transcription factors (TFs) and DNA. Here, we present a method for assessing the impact of non-coding mutations on TF-DNA interactions, based on regression models of DNA-binding specificity trained on high-throughput in vitro data. We use ordinary least squares (OLS) to estimate the parameters of the binding model for each TF, and we show that our predictions of TF-binding changes due to DNA mutations correlate well with measured changes in gene expression. In addition, by leveraging distributional results associated with OLS estimation, for each predicted change in TF binding we also compute a normalized score (z-score) and a significance value (p-value) reflecting our confidence that the mutation affects TF binding. We use this approach to analyze a large set of pathogenic non-coding variants, and we show that these variants lead to significant differences in TF binding between alleles, compared to a control set of common variants. Thus, our results indicate that there is a strong regulatory component to the pathogenic non-coding variants identified thus far.

  13. Semantic prioritization of novel causative genomic variants

    KAUST Repository

    Boudellioua, Imene

    2017-04-17

    Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

  14. Cryptanalysis of SIMON Variants with Connections

    DEFF Research Database (Denmark)

    Alizadeh, Javad; Alkhzaimi, Hoda A.; Aref, Mohammad Reza

    2014-01-01

    attacks extend to all variants of SIMON covering more rounds compared to any known results using linear cryptanalysis. We present a key recovery attack against SIMON128/256 which covers 35 out of 72 rounds with data complexity 2123. We have implemented our attacks for small scale variants of SIMON and our...

  15. Beta-glucosidase I variants with improved properties

    Science.gov (United States)

    Bott, Richard R.; Kaper, Thijs; Kelemen, Bradley; Goedegebuur, Frits; Hommes, Ronaldus Wilhelmus; Kralj, Slavko; Kruithof, Paulien; Nikolaev, Igor; Van Der Kley, Wilhelmus Antonious Hendricus; Van Lieshout, Johannes Franciscus Thomas; Van Stigt Thans, Sander

    2016-09-20

    The present disclosure is generally directed to enzymes and in particular beta-glucosidase variants. Also described are nucleic acids encoding beta-glucosidase variants, compositions comprising beta-glucosidase variants, methods of using beta-glucosidase variants, and methods of identifying additional useful beta-glucosidase variants.

  16. Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance

    Directory of Open Access Journals (Sweden)

    Claire Jackson

    2013-01-01

    Full Text Available Overexpression of human epidermal growth factor receptor (HER-2 occurs in 20–30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin. Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology. For example, the splice variant 16HER-2 (results from exon 16 skipping increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention and p100 (results from intron 15 retention inhibit tumour cell proliferation. This review focuses on the potential clinical implications of the expression and coexistence of HER-2 splice variants in cancer cells in relation to breast cancer progression and drug resistance. “Individualised” strategies currently guide breast cancer management; in accordance, HER-2 splice variants may prove valuable as future prognostic and predictive factors, as well as potential therapeutic targets.

  17. Local binary patterns new variants and applications

    CERN Document Server

    Jain, Lakhmi; Nanni, Loris; Lumini, Alessandra

    2014-01-01

    This book introduces Local Binary Patterns (LBP), arguably one of the most powerful texture descriptors, and LBP variants. This volume provides the latest reviews of the literature and a presentation of some of the best LBP variants by researchers at the forefront of textual analysis research and research on LBP descriptors and variants. The value of LBP variants is illustrated with reported experiments using many databases representing a diversity of computer vision applications in medicine, biometrics, and other areas. There is also a chapter that provides an excellent theoretical foundation for texture analysis and LBP in particular. A special section focuses on LBP and LBP variants in the area of face recognition, including thermal face recognition. This book will be of value to anyone already in the field as well as to those interested in learning more about this powerful family of texture descriptors.

  18. Somatic cancer variant curation and harmonization through consensus minimum variant level data

    Directory of Open Access Journals (Sweden)

    Deborah I. Ritter

    2016-11-01

    Full Text Available Abstract Background To truly achieve personalized medicine in oncology, it is critical to catalog and curate cancer sequence variants for their clinical relevance. The Somatic Working Group (WG of the Clinical Genome Resource (ClinGen, in cooperation with ClinVar and multiple cancer variant curation stakeholders, has developed a consensus set of minimal variant level data (MVLD. MVLD is a framework of standardized data elements to curate cancer variants for clinical utility. With implementation of MVLD standards, and in a working partnership with ClinVar, we aim to streamline the somatic variant curation efforts in the community and reduce redundancy and time burden for the interpretation of cancer variants in clinical practice. Methods We developed MVLD through a consensus approach by i reviewing clinical actionability interpretations from institutions participating in the WG, ii conducting extensive literature search of clinical somatic interpretation schemas, and iii survey of cancer variant web portals. A forthcoming guideline on cancer variant interpretation, from the Association of Molecular Pathology (AMP, can be incorporated into MVLD. Results Along with harmonizing standardized terminology for allele interpretive and descriptive fields that are collected by many databases, the MVLD includes unique fields for cancer variants such as Biomarker Class, Therapeutic Context and Effect. In addition, MVLD includes recommendations for controlled semantics and ontologies. The Somatic WG is collaborating with ClinVar to evaluate MVLD use for somatic variant submissions. ClinVar is an open and centralized repository where sequencing laboratories can report summary-level variant data with clinical significance, and ClinVar accepts cancer variant data. Conclusions We expect the use of the MVLD to streamline clinical interpretation of cancer variants, enhance interoperability among multiple redundant curation efforts, and increase submission of

  19. Biomarkers: a new approach to behavioural variant frontotemporal dementia.

    Science.gov (United States)

    Fernández-Matarrubia, M; Matías-Guiu, J A; Moreno-Ramos, T; Matías-Guiu, J

    2015-01-01

    Lobar frontotemporal degeneration (FTLD) encompasses a group of molecular disease defined by the deposition of an abnormal protein in the central nervous system. Behavioural variant frontotemporal dementia (bvFTD) is the most frequent clinical presentation of FTLD. The past two decades of research have contributed to a better understanding of this entity, which may be the first manifestation in many different neurodegenerative disorders. We reviewed correlations between clinical, pathological, and genetic findings and the main disease biomarkers of FTLD, with particular interest in bvFTD. Anatomical pathology findings in FTLD are heterogeneous and the syndrome is not associated with any one specific histopathological type. Promising available biomarkers include structural and functional neuroimaging techniques and biochemical and genetic biomarkers. Disease-modifying drugs designed for specific molecular targets that are implicated in FTLD pathogenesis are being developed. BvFTD is a frequent cause of dementia. Of all the clinical variants of FTLD, behavioural variant is the one in which establishing a correlation between clinical and pathological signs is the most problematic. A biomarker evaluation may help predict the underlying pathology; this approach, in conjunction with the development of disease-modifying drugs, offers new therapeutic possibilities. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  20. Improving adequacy of hemodialysis in Northern California ESRD patients: a final project report. Provider Participants and Medical Review Board of the TransPacific Renal Network.

    Science.gov (United States)

    Brown, J; Josephson, M

    2000-10-01

    The National Core Indicators Project, initiated in 1994, has brought progressive changes in adequacy of dialysis for end-stage renal disease (ESRD) patients in the TransPacific Renal Network and across the United States. The 1998 Core Indicator Project showed each Network's standing for percentage of patients with urea reduction ratio (URR) > or = 0.65 and average URR. The TransPacific Renal Network ranked 12(th) among the 18 Networks for this adequacy measure. The goals of this project were to improve the Network standing in the United States for the percent of patients with URR > or = 0.65, eliminate or reduce the barriers to achieving adequate dialysis, and evaluate URR versus KT/V data and the variances occurring with these measures. In January 1999, data were collected from all 113 Northern California hemodialysis facilities for quarter 4, 1998, to evaluate adequacy. Each facility provided patient population (N) for KT/V and URR samples, facility averages for KT/V and URR, number of patients with KT/V > or = 1.2 and URR > or = 0.65, and data on post-blood-urea-nitrogen (BUN) sampling methods. A random selection of 10% (12) providers with data below the US and Network standards was selected for an intensive assessment. Using baseline measurements, on-site data were collected from a random selection of the patient population. Chart data were reviewed, analyzed, and discussed in an exit interview with the facility management. On-site visits were performed in July/June 1999. The primary focus included adequacy data and process of care that affect adequacy outcomes, concurrent review of patients receiving treatment at the time of the site visit, and general medical record review. In Phase I, only 12 facilities showed an average URR below 0.65. All facilities reported an average KT/V greater than the DOQI target of 1.2. Forty-two facilities had their percentage of patients with a URR below the national benchmark; only 18 facilities had their percentage of patients

  1. Computational approaches to identify functional genetic variants in cancer genomes

    DEFF Research Database (Denmark)

    Gonzalez-Perez, Abel; Mustonen, Ville; Reva, Boris

    2013-01-01

    The International Cancer Genome Consortium (ICGC) aims to catalog genomic abnormalities in tumors from 50 different cancer types. Genome sequencing reveals hundreds to thousands of somatic mutations in each tumor but only a minority of these drive tumor progression. We present the result of discu...... of discussions within the ICGC on how to address the challenge of identifying mutations that contribute to oncogenesis, tumor maintenance or response to therapy, and recommend computational techniques to annotate somatic variants and predict their impact on cancer phenotype....

  2. Variability extraction and modeling for product variants.

    Science.gov (United States)

    Linsbauer, Lukas; Lopez-Herrejon, Roberto Erick; Egyed, Alexander

    2017-01-01

    Fast-changing hardware and software technologies in addition to larger and more specialized customer bases demand software tailored to meet very diverse requirements. Software development approaches that aim at capturing this diversity on a single consolidated platform often require large upfront investments, e.g., time or budget. Alternatively, companies resort to developing one variant of a software product at a time by reusing as much as possible from already-existing product variants. However, identifying and extracting the parts to reuse is an error-prone and inefficient task compounded by the typically large number of product variants. Hence, more disciplined and systematic approaches are needed to cope with the complexity of developing and maintaining sets of product variants. Such approaches require detailed information about the product variants, the features they provide and their relations. In this paper, we present an approach to extract such variability information from product variants. It identifies traces from features and feature interactions to their implementation artifacts, and computes their dependencies. This work can be useful in many scenarios ranging from ad hoc development approaches such as clone-and-own to systematic reuse approaches such as software product lines. We applied our variability extraction approach to six case studies and provide a detailed evaluation. The results show that the extracted variability information is consistent with the variability in our six case study systems given by their variability models and available product variants.

  3. Novel oxytocin receptor variants in laboring women requiring high doses of oxytocin.

    Science.gov (United States)

    Reinl, Erin L; Goodwin, Zane A; Raghuraman, Nandini; Lee, Grace Y; Jo, Erin Y; Gezahegn, Beakal M; Pillai, Meghan K; Cahill, Alison G; de Guzman Strong, Cristina; England, Sarah K

    2017-08-01

    Although oxytocin commonly is used to augment or induce labor, it is difficult to predict its effectiveness because oxytocin dose requirements vary significantly among women. One possibility is that women requiring high or low doses of oxytocin have variations in the oxytocin receptor gene. To identify oxytocin receptor gene variants in laboring women with low and high oxytocin dosage requirements. Term, nulliparous women requiring oxytocin doses of ≤4 mU/min (low-dose-requiring, n = 83) or ≥20 mU/min (high-dose-requiring, n = 104) for labor augmentation or induction provided consent to a postpartum blood draw as a source of genomic DNA. Targeted-amplicon sequencing (coverage >30×) with MiSeq (Illumina) was performed to discover variants in the coding exons of the oxytocin receptor gene. Baseline relevant clinical history, outcomes, demographics, and oxytocin receptor gene sequence variants and their allele frequencies were compared between low-dose-requiring and high-dose-requiring women. The Scale-Invariant Feature Transform algorithm was used to predict the effect of variants on oxytocin receptor function. The Fisher exact or χ 2 tests were used for categorical variables, and Student t tests or Wilcoxon rank sum tests were used for continuous variables. A P value oxytocin receptor gene in the total cohort (n = 187) revealed 30 distinct coding variants: 17 nonsynonymous, 11 synonymous, and 2 small structural variants. One novel variant (A243T) was found in both the low- and high-dose-requiring groups. Three novel variants (Y106H, A240_A249del, and P197delfs*206) resulting in an amino acid substitution, loss of 9 amino acids, and a frameshift stop mutation, respectively, were identified only in low-dose-requiring women. Nine nonsynonymous variants were unique to the high-dose-requiring group. These included 3 known variants (R151C, G221S, and W228C) and 6 novel variants (M133V, R150L, H173R, A248V, G253R, and I266V). Of these, R150L, R151C, and H173

  4. LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Alyssa Florwick

    2017-06-01

    Full Text Available Mutations in LMNA, encoding nuclear intermediate filament proteins lamins A and C, cause multiple diseases (‘laminopathies’ including muscular dystrophy, dilated cardiomyopathy, familial partial lipodystrophy (FPLD2, insulin resistance syndrome and progeria. To assess the prevalence of LMNA missense mutations (‘variants’ in a broad, ethnically diverse population, we compared missense alleles found among 60,706 unrelated individuals in the ExAC cohort to those identified in 1,404 individuals in the laminopathy database (UMD-LMNA. We identified 169 variants in the ExAC cohort, of which 37 (∼22% are disease-associated including p.I299V (allele frequency 0.0402%, p.G602S (allele frequency 0.0262% and p.R644C (allele frequency 0.124%, suggesting certain LMNA mutations are more common than previously recognized. Independent analysis of LMNA variants via the type 2 diabetes (T2D Knowledge Portal showed that variant p.G602S associated significantly with type 2 diabetes (p = 0.02; odds ratio = 4.58, and was more frequent in African Americans (allele frequency 0.297%. The FPLD2-associated variant I299V was most prevalent in Latinos (allele frequency 0.347%. The ExAC cohort also revealed 132 novel LMNA missense variants including p.K108E (limited to individuals with psychiatric disease; predicted to perturb coil-1B, p.R397C and p.R427C (predicted to perturb filament biogenesis, p.G638R and p.N660D (predicted to perturb prelamin A processing, and numerous Ig-fold variants predicted to perturb phenotypically characteristic protein–protein interactions. Overall, this two-pronged strategy— mining a large database for missense variants in a single gene (LMNA, coupled to knowledge about the structure, biogenesis and functions of A-type lamins— revealed an unexpected number of LMNA variants, including novel variants predicted to perturb lamin assembly or function. Interestingly, this study also correlated novel variant p.K108E with psychiatric

  5. Ultrasonographic imaging of papillary thyroid carcinoma variants

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Jung Hee [Dept. of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2017-04-15

    Ultrasonography (US) is routinely used to evaluate thyroid nodules. The US features of papillary thyroid carcinoma (PTC), the most common thyroid malignancy, include hypoechogenicity, spiculated/microlobulated margins, microcalcifications, and a nonparallel orientation. However, many PTC variants have been identified, some of which differ from the classic type of PTC in terms of biological behavior and clinical outcomes. This review describes the US features and clinical implications of the variants of PTC. With the introduction of active surveillance replacing immediate biopsy or surgical treatment of indolent, small PTCs, an understanding of the US characteristics of PTC variants will facilitate the individualized management of patients with PTC.

  6. Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels

    Science.gov (United States)

    van Leeuwen, Elisabeth M.; Karssen, Lennart C.; Deelen, Joris; Isaacs, Aaron; Medina-Gomez, Carolina; Mbarek, Hamdi; Kanterakis, Alexandros; Trompet, Stella; Postmus, Iris; Verweij, Niek; van Enckevort, David J.; Huffman, Jennifer E.; White, Charles C.; Feitosa, Mary F.; Bartz, Traci M.; Manichaikul, Ani; Joshi, Peter K.; Peloso, Gina M.; Deelen, Patrick; van Dijk, Freerk; Willemsen, Gonneke; de Geus, Eco J.; Milaneschi, Yuri; Penninx, Brenda W.J.H.; Francioli, Laurent C.; Menelaou, Androniki; Pulit, Sara L.; Rivadeneira, Fernando; Hofman, Albert; Oostra, Ben A.; Franco, Oscar H.; Leach, Irene Mateo; Beekman, Marian; de Craen, Anton J.M.; Uh, Hae-Won; Trochet, Holly; Hocking, Lynne J.; Porteous, David J.; Sattar, Naveed; Packard, Chris J.; Buckley, Brendan M.; Brody, Jennifer A.; Bis, Joshua C.; Rotter, Jerome I.; Mychaleckyj, Josyf C.; Campbell, Harry; Duan, Qing; Lange, Leslie A.; Wilson, James F.; Hayward, Caroline; Polasek, Ozren; Vitart, Veronique; Rudan, Igor; Wright, Alan F.; Rich, Stephen S.; Psaty, Bruce M.; Borecki, Ingrid B.; Kearney, Patricia M.; Stott, David J.; Adrienne Cupples, L.; Neerincx, Pieter B.T.; Elbers, Clara C.; Francesco Palamara, Pier; Pe'er, Itsik; Abdellaoui, Abdel; Kloosterman, Wigard P.; van Oven, Mannis; Vermaat, Martijn; Li, Mingkun; Laros, Jeroen F.J.; Stoneking, Mark; de Knijff, Peter; Kayser, Manfred; Veldink, Jan H.; van den Berg, Leonard H.; Byelas, Heorhiy; den Dunnen, Johan T.; Dijkstra, Martijn; Amin, Najaf; Joeri van der Velde, K.; van Setten, Jessica; Kattenberg, Mathijs; van Schaik, Barbera D.C.; Bot, Jan; Nijman, Isaäc J.; Mei, Hailiang; Koval, Vyacheslav; Ye, Kai; Lameijer, Eric-Wubbo; Moed, Matthijs H.; Hehir-Kwa, Jayne Y.; Handsaker, Robert E.; Sunyaev, Shamil R.; Sohail, Mashaal; Hormozdiari, Fereydoun; Marschall, Tobias; Schönhuth, Alexander; Guryev, Victor; Suchiman, H. Eka D.; Wolffenbuttel, Bruce H.; Platteel, Mathieu; Pitts, Steven J.; Potluri, Shobha; Cox, David R.; Li, Qibin; Li, Yingrui; Du, Yuanping; Chen, Ruoyan; Cao, Hongzhi; Li, Ning; Cao, Sujie; Wang, Jun; Bovenberg, Jasper A.; Jukema, J. Wouter; van der Harst, Pim; Sijbrands, Eric J.; Hottenga, Jouke-Jan; Uitterlinden, Andre G.; Swertz, Morris A.; van Ommen, Gert-Jan B.; de Bakker, Paul I.W.; Eline Slagboom, P.; Boomsma, Dorret I.; Wijmenga, Cisca; van Duijn, Cornelia M.

    2015-01-01

    Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of the Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10−4), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR. PMID:25751400

  7. Hemilaryngeal Microsomia: An Anatomic Variant.

    Science.gov (United States)

    Urban, Matthew J; Mattioni, Jillian; Jaworek, Aaron; Potigailo, Valeria; Sataloff, Robert T

    2017-09-01

    This study aims to describe a congenital laryngeal structural variant, hemilaryngeal microsomia (HLM), and to correlate identification on physical examination with computerized tomography scan (CT) and laryngoscopy findings. The study was conducted at a tertiary care center. Six patients presenting with hoarseness were admitted to a tertiary care otolaryngology office. These patients had asymmetrical thyroid cartilage prominence on palpation during physical examination. A diagnosis of HLM was made. All patients underwent laryngostroboscopy and CT scan. Four control patients with normal thyroid cartilage anatomy on physical examination, CT, and stroboscopy results were included for comparison. Disparities in thyroid cartilage angles correlated with documented physical examination findings for six out of six HLM patients. On CT scan, the average difference in left and right thyroid laminar angles was 30.2° ± 18.3° in HLM patients vs 4.00° ± 1.63° in control patients (P = 0.023). Strobosocopic findings also correlated with HLM. The arytenoid cartilage was anteriorly or medially displaced on the microsomic side in all six HLM patients. Three patients had anterior placement of the vocal process resulting in shortening of the vocal fold on the microsomic side of the larynx. HLM is a congenital structural anomaly of the larynx that may be palpated on physical examination. HLM found on physical examination can be correlated with asymmetries found on CT scan and endoscopy. There is no evidence that the structural features of HLM were causally related to voice symptoms, but the findings on HLM may lead to misdiagnosis. A larger study is indicated to confirm laryngeal structural differences between patients with HLM on physical examination and the general population. Whether or not HLM affects clinical or surgical outcomes remains to be studied. Copyright © 2017. Published by Elsevier Inc.

  8. Histone variants in plant transcriptional regulation.

    Science.gov (United States)

    Jiang, Danhua; Berger, Frédéric

    2017-01-01

    Chromatin based organization of eukaryotic genome plays a profound role in regulating gene transcription. Nucleosomes form the basic subunits of chromatin by packaging DNA with histone proteins, impeding the access of DNA to transcription factors and RNA polymerases. Exchange of histone variants in nucleosomes alters the properties of nucleosomes and thus modulates DNA exposure during transcriptional regulation. Growing evidence indicates the important function of histone variants in programming transcription during developmental transitions and stress response. Here we review how histone variants and their deposition machineries regulate the nucleosome stability and dynamics, and discuss the link between histone variants and transcriptional regulation in plants. This article is part of a Special Issue entitled: Plant Gene Regulatory Mechanisms and Networks, edited by Dr. Erich Grotewold and Dr. Nathan Springer. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Variant (Swine Origin) Influenza Viruses in Humans

    Science.gov (United States)

    ... at Commercial Swine Farms Fair Organizers & Exhibitors In Humans Key Facts about Human Infections with Variant Viruses Interim Guidance for Clinicians on Human Infections Background, Risk Assessment & Reporting Reported Infections with ...

  10. Splicing variants of porcine synphilin-1

    DEFF Research Database (Denmark)

    Larsen, Knud Erik; Madsen, Lone Bruhn; Farajzadeh, Leila

    2015-01-01

    %) and to mouse (84%) synphilin-1. Three shorter transcript variants of the synphilin-1 gene were identified, all lacking one or more exons. SNCAIP transcripts were detected in most examined organs and tissues and the highest expression was found in brain tissues and lung. Conserved splicing variants and a novel......RNA was investigated by RNAseq. The presented work reports the molecular cloning and characterization of the porcine (Sus scrofa) synphilin-1 cDNA (SNCAIP) and three splice variants hereof. The porcine SNCAIP cDNA codes for a protein (synphilin-1) of 919 amino acids which shows a high similarity to human (90...... splice form of synhilin-1 were found in this study. All synphilin-1 isoforms encoded by the identified transcript variants lack functional domains important for protein degradation....

  11. Identification of an APC Variant in a Patient with Clinical Attenuated Familial Adenomatous Polyposis

    Directory of Open Access Journals (Sweden)

    Andrew T. Schlussel

    2014-01-01

    Full Text Available Introduction. The objective of this case report is to discuss an unclassified germline variant of the adenomatous polyposis coli (APC gene identified in an older patient with attenuated familial adenomatous polyposis syndrome (AFAP. Methods. We present a case report of a 66-year-old man diagnosed with AFAP. Colonoscopy found multiple polyps and invasive adenocarcinoma arising in the transverse colon. Samples were tested for mutations in the APC gene. Results. DNA sequencing of germline DNA identified a cytosine (C to thymine (T transition at nucleotide 1240, heterozygous. The C to T transition at codon 414 is predicted to convert an arginine residue to a cysteine that is possibly pathogenic. Analysis of the patient’s colon tumor DNA indicated that the tumor had lost the mutant variant allele and retained only the normal allele, suggesting that the variant may not be significant. Conclusions. The p.R414C variant has been described previously as a germline mutation of probable pathogenicity. This substitution should be considered an unclassified variant and possibly not pathogenic. These findings support the need for further genetic testing of tissue, as well as for developing a mechanism for testing all variants, as this could significantly impact the lives of patients and their family members.

  12. Neutralization-resistant variants of infectious hematopoietic necrosis virus have altered virulence and tissue tropism

    Science.gov (United States)

    Kim, C.H.; Winton, J.R.; Leong, J.C.

    1994-01-01

    Infectious hematopoietic necrosis virus (IHNV) is a rhabdovirus that causes an acute disease in salmon and trout. In this study, a correlation between changes in tissue tropism and specific changes in the virus genome appeared to be made by examining four IHNV neutralization-resistant variants (RB-1, RB-2, RB-3, and RB-4) that had been selected with the glycoprotein (G)-specific monoclonal antibody RB/B5. These variants were compared with the parental strain (RB-76) for their virulence and pathogenicity in rainbow trout after waterborne challenge. Variants RB-2, RB-3, and RB-4 were only slightly attenuated and showed distributions of viral antigen in the livers and hematopoietic tissues of infected fish similar to those of the parental strain. Variant RB-1, however, was highly attenuated and the tissue distribution of viral antigen in RB-1-infected fish was markedly different, with more viral antigen in brain tissue. The sequences of the G genes of all four variants and RB-76 were determined. No significant changes were found for the slightly attenuated variants, but RB-1 G had two changes at amino acids 78 and 218 that dramatically altered its predicted secondary structure. These changes are thought to be responsible for the altered tissue tropism of the virus. Thus, IHNV G, like that of rabies virus and vesicular stomatitis virus, plays an integral part in the pathogenesis of viral infection.

  13. Improving bioinformatic pipelines for exome variant calling

    OpenAIRE

    Ji, Hanlee P.

    2012-01-01

    Exome sequencing analysis is a cost-effective approach for identifying variants in coding regions. However, recognizing the relevant single nucleotide variants, small insertions and deletions remains a challenge for many researchers and diagnostic laboratories typically do not have access to the bioinformatic analysis pipelines necessary for clinical application. The Atlas2 suite, recently released by Baylor Genome Center, is designed to be widely accessible, runs on desktop computers but is ...

  14. Rare hemoglobin variants in Tunisian population.

    Science.gov (United States)

    Zorai, A; Moumni, I; Mosbahi, I; Douzi, K; Chaouachi, D; Guemira, F; Abbes, S

    2015-04-01

    During the last 30 years, many studies concerning hemoglobinopathies were realized among Tunisians. More than twenty different thalassemic alleles were detected on the β-globin gene, and less are affecting the α-globin genes. Unusual hemoglobin (Hb) variants other than Hb S, Hb C, and Hb O-arab, which are the most frequent variants in Tunisia, were also detected. Eight Tunisian subjects were studied at phenotypic and molecular levels. Hematological indices and hemoglobin (Hb) pattern were performed by alkaline electrophoresis and isoelectric focusing (IEF),and the Hb fractions were quantitated by cation exchange HPLC. On genomic level, coding regions were amplified by polymerase chain reaction (PCR) followed by a sequencing of the purified PCR products using the dye terminator method. Seven uncommon Hb variants were detected and described for the first time among Tunisians. HbA2-Tunis [δ46(CD5), Gly → Glu, GGG → GAG] is the newly described δ-chain variant in our laboratory, and some other variants (Hb Constant Spring, G San Jose, and Hb J-Bangkok) are very uncommon in the Mediterranean region. We present here an updated review of the Hb variants detected among Tunisians. Twenty-one rare Hb variants were detected affecting the α1-, α2-, δ-, γ-, and β-globin genes, leading in some cases to a severe phenotype especially when the stability is completely altered. The ethnical history of Tunisia could explain this important variability of the observed rare Hb variants. © 2014 John Wiley & Sons Ltd.

  15. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

    DEFF Research Database (Denmark)

    Scott, Robert A; Freitag, Daniel F; Li, Li

    2016-01-01

    . We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict...

  16. Systematic TOR1A non-c.907_909delGAG variant analysis in isolated dystonia and controls.

    Science.gov (United States)

    Zech, Michael; Jochim, Angela; Boesch, Sylvia; Weber, Sandrina; Meindl, Tobias; Peters, Annette; Gieger, Christian; Mueller, Joerg; Messner, Michael; Ceballos-Baumann, Andres; Poewe, Werner; Haslinger, Bernhard; Winkelmann, Juliane

    2016-10-01

    An increasing number of rare, functionally relevant non-c.907_909delGAG (non-ΔGAG) variants in TOR1A have been recognized, associated with phenotypic expressions different from classic DYT1 childhood-onset generalized dystonia. Only recently, DYT1 genotype-phenotype correlations have been proposed, awaiting further elucidation in independent cohorts. We screened the entire coding sequence and the 5'-UTR region of TOR1A for rare non-ΔGAG sequence variants in a large series of 940 individuals with various forms of isolated dystonia as well as in 376 ancestry-matched controls. The frequency of rare, predicted deleterious non-ΔGAG TOR1A variants was assessed in the European sample of the Exome Aggregation Consortium (ExAC) dataset. In the case cohort, we identified a rare 5'-UTR variant (c.-39G > T), a rare splice-region variant (c.445-8T > C), as well as one novel (p.Ile231Asn) and two rare (p.Ala163Val, p.Thr321Met) missense variants, each in a single patient with adult-onset focal/segmental isolated dystonia. Of these variants, only p.Thr321Met qualified as possibly disease-related according to variant interpretation criteria. One novel, predicted deleterious missense substitution (p.Asn208Ser) was detected in the control cohort. Among European ExAC individuals, the carrier rate of rare, predicted deleterious non-ΔGAG variants was 0.4%. Our study does not allow the establishment of genotype-specific clinical correlations for DYT1. Further large-scale genetic screening accompanied by comprehensive segregation and functional studies is required to conclusively define the contribution of TOR1A whole-gene variation to the pathogenesis of isolated dystonia. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Demography and the age of rare variants.

    Science.gov (United States)

    Mathieson, Iain; McVean, Gil

    2014-08-01

    Large whole-genome sequencing projects have provided access to much rare variation in human populations, which is highly informative about population structure and recent demography. Here, we show how the age of rare variants can be estimated from patterns of haplotype sharing and how these ages can be related to historical relationships between populations. We investigate the distribution of the age of variants occurring exactly twice (ƒ(2) variants) in a worldwide sample sequenced by the 1000 Genomes Project, revealing enormous variation across populations. The median age of haplotypes carrying ƒ(2) variants is 50 to 160 generations across populations within Europe or Asia, and 170 to 320 generations within Africa. Haplotypes shared between continents are much older with median ages for haplotypes shared between Europe and Asia ranging from 320 to 670 generations. The distribution of the ages of ƒ(2) haplotypes is informative about their demography, revealing recent bottlenecks, ancient splits, and more modern connections between populations. We see the effect of selection in the observation that functional variants are significantly younger than nonfunctional variants of the same frequency. This approach is relatively insensitive to mutation rate and complements other nonparametric methods for demographic inference.

  18. Hemoglobin Variant Profiles among Brazilian Quilombola Communities.

    Science.gov (United States)

    Santiago, Rayra P; Oliveira, Rodrigo M; Soares, Leonardo F; Figueiredo, Camylla V B; Silva, Denise Oliveira; Hurtado-Guerrero, Ana F; Fiuza, Luciana M; Guarda, Caroline C; Adorno, Elisângela V; Barbosa, Cynara G; Gonçalves, Marilda S

    2017-03-01

    Brazilian Quilombolas are communities composed of African-derived populations that have their territories guaranteed by the Brazilian Constitution. The present study investigated the hemoglobin (Hb) variants among these population groups. This study was conducted in a total of 2843 individuals of Brazilian Quilombola communities of the Bahia, Pará, and Piauí states. All the participants had their Hb profiles evaluated. The Hb S (HBB: c.20A>T) variant was described in all the studied localities. However, the individuals in Bahia State had the highest frequency of the Hb C (HBB: c.19G>A) variant; individuals from Piauí State had a higher frequency of the Hb D-Punjab (HBB: c.364G>C) variant compared to the other states, and individuals from Pará State only carried the Hb S variant. The present study revealed a specific distribution of Hb variants that could represent different waves of African influence in these Brazilian populations.

  19. Detection of variants in SLC6A8 and functional analysis of unclassified missense variants.

    Science.gov (United States)

    Betsalel, Ofir T; Pop, Ana; Rosenberg, Efraim H; Fernandez-Ojeda, Matilde; Jakobs, Cornelis; Salomons, Gajja S

    2012-04-01

    Creatine transporter deficiency is an X-linked disorder caused by mutations in the SLC6A8 gene. Currently, 38 pathogenic, including 15 missense variants, are reported. In this study, we report 33 novel, including 6 missense variants. To classify all known missense variants, we transfected creatine deficient fibroblasts with the SLC6A8 ORF containing one of the unique variants and tested their ability to restore creatine uptake. This resulted in the definitive classification of 2 non-disease associated and 19 pathogenic variants of which 3 have residual activity. Furthermore, we report the development and validation of a novel DHPLC method for the detection of heterozygous SLC6A8 variants. The method was validated by analysis of DNAs that in total contained 67 unique variants of which 66 could be detected. Therefore, this rapid screening method may prove valuable for the analysis of large cohorts of females with mild intellectual disability of unknown etiology, since in this group heterozygous SLC6A8 mutations may be detected. DHPLC proved also to be important for the detection of somatic mosaicism in mothers of patients who have a pathogenic mutation in SLC6A8. All variants reported in the present and previous studies are included in the Leiden Open Source Variant Database (LOVD) of SLC6A8 (www.LOVD.nl/SLC6A8). Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Signatures of natural selection on genetic variants affecting complex human traits.

    Science.gov (United States)

    Zhang, Ge; Muglia, Louis J; Chakraborty, Ranajit; Akey, Joshua M; Williams, Scott M

    2013-12-01

    It has recently been hypothesized that polygenic adaptation, resulting in modest allele frequency changes at many loci, could be a major mechanism behind the adaptation of complex phenotypes in human populations. Here we leverage the large number of variants that have been identified through genome-wide association (GWA) studies to comprehensively study signatures of natural selection on genetic variants associated with complex traits. Using population differentiation based methods, such as F ST and phylogenetic branch length analyses, we systematically examined nearly 1300 SNPs associated with 38 complex phenotypes. Instead of detecting selection signatures at individual variants, we aimed to identify combined evidence of natural selection by aggregating signals across many trait associated SNPs. Our results have revealed some general features of polygenic selection on complex traits associated variants. First, natural selection acting on standing variants associated with complex traits is a common phenomenon. Second, characteristics of selection for different polygenic traits vary both temporarily and geographically. Third, some studied traits (e.g. height and urate level) could have been the primary targets of selection, as indicated by the significant correlation between the effect sizes and the estimated strength of selection in the trait associated variants; however, for most traits, the allele frequency changes in trait associated variants might have been driven by the selection on other correlated phenotypes. Fourth, the changes in allele frequencies as a result of selection can be highly stochastic, such that, polygenic adaptation may accelerate differentiation in allele frequencies among populations, but generally does not produce predictable directional changes. Fifth, multiple mechanisms (pleiotropy, hitchhiking, etc) may act together to govern the changes in allele frequencies of genetic variants associated with complex traits.

  1. Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene.

    Science.gov (United States)

    Mercimek-Mahmutoglu, Saadet; Ndika, Joseph; Kanhai, Warsha; de Villemeur, Thierry Billette; Cheillan, David; Christensen, Ernst; Dorison, Nathalie; Hannig, Vickie; Hendriks, Yvonne; Hofstede, Floris C; Lion-Francois, Laurence; Lund, Allan M; Mundy, Helen; Pitelet, Gaele; Raspall-Chaure, Miquel; Scott-Schwoerer, Jessica A; Szakszon, Katalin; Valayannopoulos, Vassili; Williams, Monique; Salomons, Gajja S

    2014-04-01

    Guanidinoacetate methyltransferase deficiency (GAMT-D) is an autosomal recessively inherited disorder of creatine biosynthesis. Creatine deficiency on cranial proton magnetic resonance spectroscopy, and elevated guanidinoacetate levels in body fluids are the biomarkers of GAMT-D. In 74 patients, 50 different mutations in the GAMT gene have been identified with missense variants being the most common. Clinical and biochemical features of the patients with missense variants were obtained from their physicians using a questionnaire. In 20 patients, 17 missense variants, 25% had a severe, 55% a moderate, and 20% a mild phenotype. The effect of these variants on GAMT enzyme activity was overexpressed using primary GAMT-D fibroblasts: 17 variants retained no significant activity and are therefore considered pathogenic. Two additional variants, c.22C>A (p.Pro8Thr) and c.79T>C (p.Tyr27His) (the latter detected in control cohorts) are in fact not pathogenic as these alleles restored GAMT enzyme activity, although both were predicted to be possibly damaging by in silico analysis. We report 13 new patients with GAMT-D, six novel mutations and functional analysis of 19 missense variants, all being included in our public LOVD database. Our functional assay is important for the confirmation of the pathogenicity of identified missense variants in the GAMT gene. © 2014 WILEY PERIODICALS, INC.

  2. Catching hidden variation: systematic correction of reference minor allele annotation in clinical variant calling.

    Science.gov (United States)

    Barbitoff, Yury A; Bezdvornykh, Igor V; Polev, Dmitrii E; Serebryakova, Elena A; Glotov, Andrey S; Glotov, Oleg S; Predeus, Alexander V

    2017-10-26

    PurposeWe comprehensively assessed the influence of reference minor alleles (RMAs), one of the inherent problems of the human reference genome sequence.MethodsThe variant call format (VCF) files provided by the 1000 Genomes and Exome Aggregation Consortium (ExAC) consortia were used to identify RMA sites. All coding RMA sites were checked for concordance with UniProt and the presence of same codon variants. RMA-corrected predictions of functional effect were obtained with SIFT, PolyPhen-2, and PROVEAN standalone tools and compared with dbNSFP v2.9 for consistency.ResultsWe systematically characterized the problem of RMAs and identified several possible ways in which RMA could interfere with accurate variant discovery and annotation. We have discovered a systematic bias in the automated variant effect prediction at the RMA loci, as well as widespread switching of functional consequences for variants located in the same codon as the RMA. As a convenient way to address the problem of RMAs we have developed a simple bioinformatic tool that identifies variation at RMA sites and provides correct annotations for all such substitutions. The tool is available free of charge at http://rmahunter.bioinf.me.ConclusionCorrection of RMA annotation enhances the accuracy of next-generation sequencing-based methods in clinical practice.Genetics in Medicine advance online publication, 26 October 2017; doi:10.1038/gim.2017.168.

  3. Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes.

    Science.gov (United States)

    Akbari, Mohammad R; Zhang, Shiyu; Fan, Isabel; Royer, Robert; Li, Song; Risch, Harvey; McLaughlin, John; Rosen, Barry; Sun, Ping; Narod, Steven A

    2011-11-01

    Women who carry a pathogenic mutation in BRCA1 or BRCA2 have high risks of developing breast and ovarian cancers. The functional effect of many missense variants on BRCA1 and BRCA2 protein function is not known. Here, the authors construct a historical cohort of 4030 female first-degree relatives of 1345 unselected patients with ovarian cancer who have been screened for BRCA1 and BRCA2 mutations. The authors compared the risks by the age of 80 years for all cancers combined in female first-degree relatives of women with a pathogenic mutation, women with a variant of unknown significance (unclassified variant) and non-carriers. The cumulative risk of cancer among the relatives of patients with a pathogenic mutation was much higher than the risk in relatives of non-carriers (50.2% vs 28.5%; HR=2.87, pcancer among relatives of patients carrying an unclassified variant was similar to the risk of cancer for relatives of non-carriers (27.6% vs 28.5%; HR=1.08, p=0.79). The authors used three different algorithms to predict the pathogenicity of unclassified variants and compared their penetrance with non-carriers. In this sample, only Align Grantham Variation Grantham Deviation appeared to predict penetrance based on first-degree relatives.

  4. A novel RAD21 variant associated with intrafamilial phenotypic variation in Cornelia de Lange syndrome - review of the literature

    DEFF Research Database (Denmark)

    Boyle, M I; Jespersgaard, C; Nazaryan-Petersen, Lusine

    2017-01-01

    In a patient with CdLS (IV.16) we identifed a novel single basepair deletion (c.704delG) in RAD21, which encodes a cohesin pathway protein. The variant is predicted to result in a premature stop codon [p.(Ser235Ilefs*19)] and hereby would have a deleterious effect. RAD21 variants have previously......LS, but the other family members do not fulfill the diagnostic criteria of CdLS. This study together with previous reports suggests incomplete penetrance associated with RAD21 variants and these individuals may therefore be underdiagnosed....

  5. Improved imputation accuracy of rare and low-frequency variants using population-specific high-coverage WGS-based imputation reference panel.

    Science.gov (United States)

    Mitt, Mario; Kals, Mart; Pärn, Kalle; Gabriel, Stacey B; Lander, Eric S; Palotie, Aarno; Ripatti, Samuli; Morris, Andrew P; Metspalu, Andres; Esko, Tõnu; Mägi, Reedik; Palta, Priit

    2017-06-01

    Genetic imputation is a cost-efficient way to improve the power and resolution of genome-wide association (GWA) studies. Current publicly accessible imputation reference panels accurately predict genotypes for common variants with minor allele frequency (MAF)≥5% and low-frequency variants (0.5≤MAFWGS) based reference panel, comprising of 2244 Estonian individuals (0.25% of adult Estonians). Although the Estonian-specific panel contains fewer haplotypes and variants, the imputation confidence and accuracy of imputed low-frequency and rare variants was significantly higher. The results indicate the utility of population-specific reference panels for human genetic studies.

  6. [Frequency of chromosome variants in human populations].

    Science.gov (United States)

    Kuleshov, N P; Kulieva, L M

    1979-01-01

    Chromosome variants were analyzed in the course of the population chromosome investigation of 6000 newborns and clinical cytogenetic studies of 403 married couples with recurrent spontaneous abortions, stillbirths or offsprings having congenital malformations or Down's syndrome. The following variants were determined: 1) Igh+, 9gh+, 16gh+ - the enlargement of the secondary constrictions of the size, more than 1/4 of the long arm of the chromosome; 2) Dp+ or Gp+ - the enlargement of the short arms of acrocentrics, their size being more than the short arm of the chromosome 18; 3) Ds+ or Gs - large satellites of the acrocentrics which are equal or more than the thickness of the chromatids of the long arms; 4) Es+ - satellites on the short arms of the chromosomes 17 or 18; 5) Dss of Gss - double satellites; 6) Yq+ - the enlargement of the long arm of Y chromosome, the size of which being more than G chromosome; 7) Yq- - deletion of the long arm of Y chromosome, the size of the long arm being less than chromosomes 21--22. The total frequency of variants in newborns was 12.8/1000 births. The incidence of different types of variants per 1000 births was as follows: Igh+ - 0.33; 9gh+ - 0.17; 16gh+ - 0.50; Ds+ - 2.33; Dp+ - 1.50; Dp- - 0.17; Gs+ - 0.83; Gp+ - 2.17; Yq+ - 6.91/1000 males; Yg- - 0.99/1000 males; double variants - 0.33; other variants - 0.33. 4.0% of married couples with recurrent spontaneous abortions had major chromosome aberrations, 14.6% - extreme variants of chromosomes. Among 113 couples with the history of congenital malformations in their offsprings major chromosome abnormalities were found in 4.4%, chromosome variants - 13.3%. The frequency of chromosome variants among 139 patients with Down's syndrome was 7.2%. In one case Robertsonian translocation t(DqGa) was determined. The most frequent types of variant chromosomes were Ds+, Dp+, Es+, Yq+.

  7. A novel nonsense ATP7A pathogenic variant in a family exhibiting a variable occipital horn syndrome phenotype

    Directory of Open Access Journals (Sweden)

    Maria Teresa Bonati

    2017-12-01

    Full Text Available We report on a family with occipital horn syndrome (OHS diagnosed in the proband's late fifties. A novel ATP7A pathogenic variant (c.4222A>T, p.(Lys1408*, representing the first nonsense variant and the second late truncation causing OHS rather than classic Menkes disease, was found to segregate in the family. The predicted maintenance of transmembrane domains is consistent with a residual protein activity, which may explain the mild clinical presentation.

  8. Beta-glucosidase variants and polynucleotides encoding same

    Energy Technology Data Exchange (ETDEWEB)

    Wogulis, Mark; Harris, Paul; Osborn, David

    2017-06-27

    The present invention relates to beta-glucosidase variants, e.g. beta-glucosidase variants of a parent Family GH3A beta-glucosidase from Aspergillus fumigatus. The present invention also relates to polynucleotides encoding the beta-glucosidase variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the beta-glucosidase variants.

  9. Modeling and Validation of the Ecological Behavior of Wild-Type Listeria monocytogenes and Stress-Resistant Variants.

    Science.gov (United States)

    Metselaar, Karin I; Abee, Tjakko; Zwietering, Marcel H; den Besten, Heidy M W

    2016-09-01

    Listeria monocytogenes exhibits a heterogeneous response upon stress exposure which can be partially attributed to the presence of stable stress-resistant variants. This study aimed to evaluate the impact of the presence of stress-resistant variants of Listeria monocytogenes and their corresponding trade-offs on population composition under different environmental conditions. A set of stress robustness and growth parameters of the wild type (WT) and an rpsU deletion variant was obtained and used to model their growth behavior under combined mild stress conditions and to model their kinetics under single- and mixed-strain conditions in a simulated food chain. Growth predictions for the WT and the rpsU deletion variant matched the experimental data generally well, although some deviations from the predictions were observed. The data highlighted the influence of the environmental conditions on the ratio between the WT and variant. Prediction of performance in the simulated food chain proved to be challenging. The trend of faster growth and lower stress robustness for the WT than for the rpsU variant in the different steps of the chain was confirmed, but especially for the inactivation steps and the time needed to resume growth after an inactivation step, the experimental data deviated from the model predictions. This report provides insights into the conditions which can select for stress-resistant variants in industrial settings and discusses their potential persistence in food processing environments. Listeria monocytogenes exhibits a heterogeneous stress response which can partially be attributed to the presence of genetic variants. These stress-resistant variants survive better under severe conditions but have, on the other hand, a reduced growth rate. To date, the ecological behavior and potential impact of the presence of stress-resistant variants is not fully understood. In this study, we quantitatively assessed growth and inactivation behavior of wild-type L

  10. Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy: The RENAAL study

    NARCIS (Netherlands)

    Keane, W.F.; Zhang, Z.X.; Lyle, P.A.; Cooper, M.E.; Grunfeld, J.P.; Lash, J.P.; McGill, J.B.; Mitch, W.E.; Remuzzi, G.; Shahinfar, S.; Snapinn, S.M.; Toto, R.; Brenner, B.M.; de Zeeuw, Dick

    2006-01-01

    Diabetic nephropathy is the most important cause of ESRD. The aim of this study was to develop a risk score from risk predictors for ESRD, with and without death, in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study and to compare ability of the ESRD risk

  11. Frequency of thermostability variants: estimation of total rare variant frequency in human populations

    Energy Technology Data Exchange (ETDEWEB)

    Mohrenweiser, H.W.; Neel, J.V.

    1981-09-01

    Eight erythrocyte enzymes were examine for thermostability in an unselected sample of 100 newborn infants. Three thermolabile variants, one each of lactate dehydrogenase, glucosephosphate isomerase, and glucose-6-phosphate dehydrogenase, were identified, none of which was detectable as a variant by standard electrophoretic techniques. All were inherited. This frequency of 3.8 heritable thermostability variants per 1000 determinations is to be compared with a frequency of electrophoretically detectable variants of 1.1 per 1000 determinations, a frequency of 2.4 enzyme-deficiency variants per 1000 determinations, and a frequency of individuals with rare enzyme deficiency or electrophoretic or thermostability (or both) variants at these loci is 8.4 per 1000 determinations. A similar distribution and frequency is seen when the comparison is limited to the seven loci studied by all techniques. it is clear that not all of the electrophoretic and thermostability variants present in the population are detected by the techniques used in this study. Accordingly, it is estimated that the true frequency of carriers of a rare variant for each of these enzyme-coding loci averages greater than 10/1000. Some implications of these frequencies for human disease are discussed.

  12. The effects of common genetic variants in oncogenes on ovarian cancer survival

    DEFF Research Database (Denmark)

    Quaye, L.; Gayther, S.A.; Ramus, S.J.

    2008-01-01

    of this study was to evaluate associations between common germline genetic variants in the oncogenes BRAF, ERBB2, KRAS, NMI, and PIK3CA, and survival after a diagnosis of epithelial ovarian cancer. EXPERIMENTAL DESIGN: We evaluated the association between 34 tagging single nucleotide polymorphisms and survival...... subtype, the rare allele rs10842513 in KRAS, was associated with poor survival (HR, 1.40; 95% CI, 1.10-1.78; P = 0.007). CONCLUSION: Common genetic variants in the BRAF and KRAS oncogenes may be important in the prediction of survival in patients with invasive epithelial ovarian cancer Udgivelsesdato...

  13. Determination of quantitative trait variants by concordance via application of the a posteriori granddaughter design to the U.S. Holstein population

    Science.gov (United States)

    Experimental designs that exploit family information can provide substantial predictive power in quantitative trait variant discovery projects. Concordance between quantitative trait locus genotype as determined by the a posteriori granddaughter design and marker genotype was determined for 29 trai...

  14. Word Variant Identification in Old French

    Directory of Open Access Journals (Sweden)

    Peter Willett

    1997-01-01

    Full Text Available Increasing numbers of historical texts are available in machine-readable form, which retain the original spelling, which can be very different from the modern-day equivalents due to the natural evolution of a language, and because the concept of standardisation in spelling is comparatively modern. Among medieval vernacular writers, the same word could be spelled in different ways and the same author (or scribe might even use several alternative spellings in the same passage. Thus, we do not know,a priori, how many variant forms of a particular word there are in such texts, let alone what these variants might be. Searching on the modern equivalent, or even the commonest historical variant, of a particular word may thus fail to retrieve an appreciable number of occurrences unless the searcher already has an extensive knowledge of the language of the documents. Moreover, even specialist scholars may be unaware of some idiosyncratic variants. Here, we consider the use of computer methods to retrieve variant historical spellings.

  15. Simulation model for overloaded monoclonal antibody variants separations in ion-exchange chromatography.

    Science.gov (United States)

    Guélat, Bertrand; Ströhlein, Guido; Lattuada, Marco; Delegrange, Lydia; Valax, Pascal; Morbidelli, Massimo

    2012-08-31

    A model was developed for the design of a monoclonal antibody charge variants separation process based on ion-exchange chromatography. In order to account for a broad range of operating conditions in the simulations, an explicit pH and salt concentration dependence has been included in the Langmuir adsorption isotherm. The reliability of this model was tested using experimental chromatographic retention times as well as information about the structural characteristics of the different charge variants, e.g. C-terminal lysine groups and deamidated groups. Next, overloaded isocratic elutions at various pH and salt concentrations have been performed to determine the saturation capacity of the ion-exchanger. Furthermore, the column simulation model was applied for the prediction of monoclonal antibody variants separations with both pH and salt gradient elutions. A good prediction of the elution times and peak shapes was observed, even though none of the model parameters was adjusted to fit the experimental data. The trends in the separation performance obtained through the simulations were generally sufficient to identify the most promising operating conditions. The predictive column simulation model thus developed in this work, including a set of parameters determined through specific independent experiments, was experimentally validated and offers a useful basis for a rational optimization of monoclonal antibody variants separation processes on ion-exchange chromatography. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. Rare ATAD5 missense variants in breast and ovarian cancer patients.

    Science.gov (United States)

    Maleva Kostovska, Ivana; Wang, Jing; Bogdanova, Natalia; Schürmann, Peter; Bhuju, Sabin; Geffers, Robert; Dürst, Matthias; Liebrich, Clemens; Klapdor, Rüdiger; Christiansen, Hans; Park-Simon, Tjoung-Won; Hillemanns, Peter; Plaseska-Karanfilska, Dijana; Dörk, Thilo

    2016-06-28

    ATAD5/ELG1 is a protein crucially involved in replication and maintenance of genome stability. ATAD5 has recently been identified as a genomic risk locus for both breast and ovarian cancer through genome-wide association studies. We aimed to investigate the spectrum of coding ATAD5 germ-line mutations in hospital-based series of patients with triple-negative breast cancer or serous ovarian cancer compared with healthy controls. The ATAD5 coding and adjacent splice site regions were analyzed by targeted next-generation sequencing of DNA samples from 273 cancer patients, including 114 patients with triple-negative breast cancer and 159 patients with serous epithelial ovarian cancer, and from 276 healthy females. Among 42 different variants identified, twenty-two were rare missense substitutions, of which 14 were classified as pathogenic by at least one in silico prediction tool. Three of four novel missense substitutions (p.S354I, p.H974R and p.K1466N) were predicted to be pathogenic and were all identified in ovarian cancer patients. Overall, rare missense variants with predicted pathogenicity tended to be enriched in ovarian cancer patients (14/159) versus controls (11/276) (p = 0.05, 2df). While truncating germ-line variants in ATAD5 were not detected, it remains possible that several rare missense variants contribute to genetic susceptibility toward epithelial ovarian carcinomas. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Which Genetics Variants in DNase-Seq Footprints Are More Likely to Alter Binding?

    Directory of Open Access Journals (Sweden)

    Gregory A Moyerbrailean

    2016-02-01

    Full Text Available Large experimental efforts are characterizing the regulatory genome, yet we are still missing a systematic definition of functional and silent genetic variants in non-coding regions. Here, we integrated DNaseI footprinting data with sequence-based transcription factor (TF motif models to predict the impact of a genetic variant on TF binding across 153 tissues and 1,372 TF motifs. Each annotation we derived is specific for a cell-type condition or assay and is locally motif-driven. We found 5.8 million genetic variants in footprints, 66% of which are predicted by our model to affect TF binding. Comprehensive examination using allele-specific hypersensitivity (ASH reveals that only the latter group consistently shows evidence for ASH (3,217 SNPs at 20% FDR, suggesting that most (97% genetic variants in footprinted regulatory regions are indeed silent. Combining this information with GWAS data reveals that our annotation helps in computationally fine-mapping 86 SNPs in GWAS hit regions with at least a 2-fold increase in the posterior odds of picking the causal SNP. The rich meta information provided by the tissue-specificity and the identity of the putative TF binding site being affected also helps in identifying the underlying mechanism supporting the association. As an example, the enrichment for LDL level-associated SNPs is 9.1-fold higher among SNPs predicted to affect HNF4 binding sites than in a background model already including tissue-specific annotation.

  18. Resequencing three candidate genes discovers seven potentially deleterious variants susceptibility to major depressive disorder and suicide attempts in Chinese.

    Science.gov (United States)

    Rao, Shitao; Leung, Cherry She Ting; Lam, Macro Hb; Wing, Yun Kwok; Waye, Mary Miu Yee; Tsui, Stephen Kwok Wing

    2017-03-01

    To date almost 200 genes were found to be associated with major depressive disorder (MDD) or suicide attempts (SA), but very few genes were reported for their molecular mechanisms. This study aimed to find out whether there were common or rare variants in three candidate genes altering the risk for MDD and SA in Chinese. Three candidate genes (HOMER1, SLC6A4 and TEF) were chosen for resequencing analysis and association studies as they were reported to be involved in the etiology of MDD and SA. Following that, bioinformatics analyses were applied on those variants of interest. After resequencing analysis and alignment for the amplicons, a total of 34 common or rare variants were found in the randomly selected 36 Hong Kong Chinese patients with both MDD and SA. Among those, seven variants show potentially deleterious features. Rs60029191 and a rare variant located in regulatory region of the HOMER1 gene may affect the promoter activities through interacting with predicted transcription factors. Two missense mutations existed in the SLC6A4 coding regions were firstly reported in Hong Kong Chinese MDD and SA patients, and both of them could affect the transport efficiency of SLC6A4 to serotonin. Moreover, a common variant rs6354 located in the untranslated region of this gene may affect the expression level or exonic splicing of serotonin transporter. In addition, both of a most studied polymorphism rs738499 and a low-frequency variant in the promoter region of the TEF gene were found to be located in potential transcription factor binding sites, which may let the two variants be able to influence the promoter activities of the gene. This study elucidated the potentially molecular mechanisms of the three candidate genes altering the risk for MDD and SA. These findings implied that not only common variants but rare variants could make contributions to the genetic susceptibility to MDD and SA in Chinese. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Rapid functional analysis of computationally complex rare human IRF6 gene variants using a novel zebrafish model.

    Directory of Open Access Journals (Sweden)

    Edward B Li

    2017-09-01

    Full Text Available Large-scale sequencing efforts have captured a rapidly growing catalogue of genetic variations. However, the accurate establishment of gene variant pathogenicity remains a central challenge in translating personal genomics information to clinical decisions. Interferon Regulatory Factor 6 (IRF6 gene variants are significant genetic contributors to orofacial clefts. Although approximately three hundred IRF6 gene variants have been documented, their effects on protein functions remain difficult to interpret. Here, we demonstrate the protein functions of human IRF6 missense gene variants could be rapidly assessed in detail by their abilities to rescue the irf6 -/- phenotype in zebrafish through variant mRNA microinjections at the one-cell stage. The results revealed many missense variants previously predicted by traditional statistical and computational tools to be loss-of-function and pathogenic retained partial or full protein function and rescued the zebrafish irf6 -/- periderm rupture phenotype. Through mRNA dosage titration and analysis of the Exome Aggregation Consortium (ExAC database, IRF6 missense variants were grouped by their abilities to rescue at various dosages into three functional categories: wild type function, reduced function, and complete loss-of-function. This sensitive and specific biological assay was able to address the nuanced functional significances of IRF6 missense gene variants and overcome many limitations faced by current statistical and computational tools in assigning variant protein function and pathogenicity. Furthermore, it unlocked the possibility for characterizing yet undiscovered human IRF6 missense gene variants from orofacial cleft patients, and illustrated a generalizable functional genomics paradigm in personalized medicine.

  20. Emergence of CXCR4-tropic HIV-1 variants followed by rapid disease progression in hemophiliac slow progressors.

    Directory of Open Access Journals (Sweden)

    Tsunefusa Hayashida

    Full Text Available The association between emergence of CXCR4-tropic HIV-1 variants (X4 variants and disease progression of HIV-1 infection has been reported. However, it is not known whether the emergence of X4 variants is the cause or result of HIV-1 disease progression. We tried to answer this question.HIV-1 env sequences around the V3 region were analyzed in serially stocked samples in order to determine whether X4 variants emerged before or after the fall in CD4+ T-cell count.The study subjects were five HIV-1-infected hemophiliac slow progressors. Deep sequencing around the HIV-1 env V3 region was conducted in duplicate. Tropism was predicted by geno2pheno [coreceptor] 2.5 with cutoff value of false positive ratio at <5%. When X4 variant was identified in the latest stocked sample before the introduction of antiretroviral therapy, we checked viral genotype in previously stocked samples to determine the time of emergence of X4 variants.Emergence of X4 variants was noted in two of the five patients when their CD4+ T-cell counts were still high. The rate of decrease of CD4+ T-cell count or of rise of HIV-1 load accelerated significantly after the emergence of X4 variants in these two cases. Phylogenetic analysis showed that these X4 variants emerged from CCR5-tropic HIV-1 viruses with several amino acid changes in the V3 region.The emergence of X4 variants preceded HIV-1 disease progression in two hemophiliac slow progressors.

  1. The hypomorphic TERT A1062T variant is associated with increased treatment-related toxicity in acute myeloid leukemia.

    Science.gov (United States)

    Both, Anna; Krauter, Jürgen; Damm, Frederik; Thol, Felicitas; Göhring, Gudrun; Heuser, Michael; Ottmann, Oliver; Lübbert, Michael; Wattad, Mohammed; Kanz, Lothar; Schlimok, Günter; Raghavachar, Aruna; Fiedler, Walter; Kirchner, Hartmut; Brugger, Wolfram; Schlegelberger, Brigitte; Heil, Gerhard; Ganser, Arnold; Wagner, Katharina

    2017-06-01

    Hypomorphic germline variants in TERT, the gene encoding the reverse transcriptase component of the human telomerase complex, occur with a frequency of 3-5% in acute myeloid leukemia. We analyzed the clinical and prognostic impact of the most common TERT A1062T variant in younger patients with acute myeloid leukemia intensively treated within two prospective multicenter trials. Four hundred and twenty patients (age 17-60 years) were analyzed for the TERT A1062T variant by direct sequencing. Fifteen patients (3.6%) carried the TERT A1062T variant. Patients with the TERT A1062T variant had a trend towards less favorable and more intermediate 2/adverse karyotypes/genotypes according to the European Leukemia Net classification. In univariate and multivariate analysis, patients with the TERT A1062T variant had a significantly inferior overall survival compared to wild-type patients (6-year overall survival 20 vs. 41%, p = 0.005). Patients with the TERT A1062T variant showed a high rate of treatment-related mortality: 5/15 (33%) died during induction therapy or in complete remission as compared to 62/405 (15%) of the wild-type patients. In patients with the TERT variant, 14/15 (93%) suffered from non-hematological/non-infectious grade 3/4 adverse events (mostly hepatic and/or mucosal) as compared to 216/405 (53%) wild-type patients (p = 0.006). In multivariate analysis, the TERT A1062T variant was an independent risk factor predicting for adverse events during induction chemotherapy. In conclusion, the TERT A1062T variant is an independent negative prognostic factor in younger patients with acute myeloid leukemia and seems to predispose those patients to treatment-related toxicity.

  2. A Weighted Polygenic Risk Score Using 14 Known Susceptibility Variants to Estimate Risk and Age Onset of Psoriasis in Han Chinese

    OpenAIRE

    Yin, Xianyong; Cheng, Hui; Lin, Yan; Wineinger, Nathan E.; Zhou, Fusheng; Sheng, Yujun; Yang, Chao; Li, Pan; Li, Feng; Shen, Changbing; Yang, Sen; Schork, Nicholas J.; Zhang, Xuejun

    2015-01-01

    With numbers of common variants identified mainly through genome-wide association studies (GWASs), there is great interest in incorporating the findings into screening individuals at high risk of psoriasis. The purpose of this study is to establish genetic prediction models and evaluate its discriminatory ability in psoriasis in Han Chinese population. We built the genetic prediction models through weighted polygenic risk score (PRS) using 14 susceptibility variants in 8,819 samples. We found...

  3. Hemoglobin Variants: Biochemical Properties and Clinical Correlates

    Science.gov (United States)

    Thom, Christopher S.; Dickson, Claire F.; Gell, David A.; Weiss, Mitchell J.

    2013-01-01

    Diseases affecting hemoglobin synthesis and function are extremely common worldwide. More than 1000 naturally occurring human hemoglobin variants with single amino acid substitutions throughout the molecule have been discovered, mainly through their clinical and/or laboratory manifestations. These variants alter hemoglobin structure and biochemical properties with physiological effects ranging from insignificant to severe. Studies of these mutations in patients and in the laboratory have produced a wealth of information on hemoglobin biochemistry and biology with significant implications for hematology practice. More generally, landmark studies of hemoglobin performed over the past 60 years have established important paradigms for the disciplines of structural biology, genetics, biochemistry, and medicine. Here we review the major classes of hemoglobin variants, emphasizing general concepts and illustrative examples. PMID:23388674

  4. Genetics in psychiatry: common variant association studies

    Directory of Open Access Journals (Sweden)

    Buxbaum Joseph D

    2010-03-01

    Full Text Available Abstract Many psychiatric conditions and traits are associated with significant heritability. Genetic risk for psychiatric conditions encompass rare variants, identified due to major effect, as well as common variants, the latter analyzed by association analyses. We review guidelines for common variant association analyses, undertaking after assessing evidence of heritability. We highlight the importance of: suitably large sample sizes; an experimental design that controls for ancestry; careful data cleaning; correction for multiple testing; small P values for positive findings; assessment of effect size for positive findings; and, inclusion of an independent replication sample. We also note the importance of a critical discussion of any prior findings, biological follow-up where possible, and a means of accessing the raw data.

  5. Warty Carcinoma Penis: An Uncommon Variant.

    Science.gov (United States)

    Thapa, Sushma; Ghosh, Arnab; Shrestha, Santosh; Ghartimagar, Dilasma; Narasimhan, Raghavan; Talwar, O P

    2017-01-01

    Penile carcinoma frequency varies widely in different parts of the world and comprises 1-10% of all the malignancies in males. Majority of the cases of penile carcinoma are squamous cell carcinoma of penis comprising 60% to 70% of all cases. Warty carcinoma of penis is an unusual neoplasm and a variant of penile squamous cell carcinoma comprising 5%-10% of all the variants. The other histological variants include basaloid, verrucous, papillary, sarcomatous, mixed, and adenosquamous carcinoma. The various histological entities with an exophytic papillary lesions including warty carcinoma are together referred to as the "verruciform" group of neoplasms. The warty carcinoma has to be differentiated from these lesions and is typically distinguished by histological features of hyperkeratosis, arborescent papillomatosis, acanthosis, and prominent koilocytosis with nuclear pleomorphism. We present a case of 65-year-old male with growth measuring 6 × 4 cm in the penis who underwent total penectomy and was diagnosed as warty carcinoma penis.

  6. Variants of Monteggia Type Injury: Case Reports

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    Kamudin NAF

    2015-03-01

    Full Text Available Background: Monteggia fracture-dislocation is rare in children. Various reports attest to its rarity, while recording the many variant of this injury. It is, therefore, easy to miss the diagnosis in the absence of proper clinical examination and radiographs. Case Report : This report highlights two rare variants of Monteggia fracture-dislocation seen in children. The first case was a 12-year old girl alleged to have fallen from a 15-feet tall tree and sustaining a combined type III Monteggia injury with ipsilateral Type II Salter-Harris injury of distal end radius with a metaphyseal fracture of the distal third of the ulna. The second case was a 13-year old who had sustained a closed fracture of atypical Type I Monteggia hybrid lesion, in a road traffic accident. Conclusion: This report highlights the rare variants of Monteggia fracture dislocation which could have been missed without proper clinical examinations and radiographs.

  7. Development of industrial variant specification systems

    DEFF Research Database (Denmark)

    Hansen, Benjamin Loer

    With globalisation and increased competition industrial companies must be prepared to satisfy individual customer needs and still stay competitive with regards to lead times, quality, and prices. These factors require companies to be better prepared to handle specification activities during order...... and the challenge of understanding the variant specification tasks and the connections between variant specification, product development, sales, manufacturing, and information technology. The present thesis seeks to meet this challenge with a procedure, concepts and tools. This is done through an extensive answer...... acquisition and order fulfilment, i.e. the creation of drawings, bill-of-materials, routings, product descriptions, quote letters etc. The present thesis is rooted in the assumption that variant specification systems supporting the cross-functional processes of order acquisition and order fulfilment must...

  8. A case of reninoma with variant angina

    Directory of Open Access Journals (Sweden)

    Hyung Ah Jo

    2014-06-01

    Full Text Available Reninoma is a tumor of the renal juxtaglomerular cell apparatus that causes hypertension and hypokalemia because of hypersecretion of renin. We present a case of a 29-year-old female patient with reninoma and concomitant variant angina. The patient had uncontrolled hypertension and elevated plasma renin activity and aldosterone levels. Imaging studies revealed a mass in the left kidney, which was further confirmed as a renin-producing lesion via selective venous catheterization. During the evaluation, the patient had acute-onset chest pain that was diagnosed as variant angina after a provocation test. After partial nephrectomy, the plasma renin activity and plasma aldosterone levels decreased and blood pressure normalized. We report a case of reninoma with variant angina.

  9. A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk.

    Science.gov (United States)

    Blair, David R; Lyttle, Christopher S; Mortensen, Jonathan M; Bearden, Charles F; Jensen, Anders Boeck; Khiabanian, Hossein; Melamed, Rachel; Rabadan, Raul; Bernstam, Elmer V; Brunak, Søren; Jensen, Lars Juhl; Nicolae, Dan; Shah, Nigam H; Grossman, Robert L; Cox, Nancy J; White, Kevin P; Rzhetsky, Andrey

    2013-09-26

    Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes to complex disease risk. We detect thousands of associations between Mendelian and complex diseases, revealing a nondegenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this "Mendelian code." Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute nonadditively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Variantes estruturalistas no ensino de Lacan

    OpenAIRE

    Riaviz, Eduardo

    2005-01-01

    Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Comunicação e Expressão. Programa de Pós-Graduação em Literatura A presente tese estuda as variantes estruturalistas no ensino de Lacan. Para introduzir estas variantes, parte dos antecedentes desse ensino, i.e., dos textos de Lacan que ainda não são lacanianos. Mostra, nestes antecedentes, uma intuição estruturalista em Lacan, um estruturalismo em estado prático. Será justamente este proto-estruturalismo a permitir que L...

  11. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease

    Science.gov (United States)

    2014-01-01

    Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer's disease in seven independent case-control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer's disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer's disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer's disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex

  12. CYP2D6 gene variants and their association with breast cancer susceptibility.

    Science.gov (United States)

    Abraham, Jean E; Maranian, Mel J; Driver, Kristy E; Platte, Radka; Kalmyrzaev, Bolot; Baynes, Caroline; Luccarini, Craig; Earl, Helena M; Dunning, Alison M; Pharoah, Paul D P; Caldas, Carlos

    2011-06-01

    The gene encoding the phase I enzyme cytochrome P4502D6 (CYP2D6) has been previously investigated for its potential predictive role in the efficacy of breast cancer treatments such as tamoxifen, but its role in breast cancer susceptibility is unclear. This study aims to evaluate the association between germ line variations in CYP2D6 and breast cancer susceptibility. DNA samples from 13,472 cases and controls were genotyped for seven known functional variants [minor allele frequency (MAF) ≥ 0.01] and five single nucleotide polymorphisms (SNP) that tag common genetic variation (MAF > 0.05) in CYP2D6. One relatively rare functional variant, CYP2D6*6, (MAF = 0.01) showed a modest increased association with breast cancer susceptibility (P(trend) = 0.02; OR = 1.32; 95% CI = 1.04-1.68). All other functional and tagSNPs showed no association with breast cancer susceptibility. Common variants of CYP2D6 do not play a significant role in breast cancer susceptibility. However, this study raises questions regarding the role of rare variants, such as CYP2D6*6, in breast cancer susceptibility which merit further investigation. This large case-control study, involving 13,472 women, found no evidence of any association between common CYP2D6 gene variants and breast cancer susceptibility. However, one relatively rare functional variant CYP2D6*6 showed a modest association with breast cancer susceptibility, indicating that the role of rare CYP2D6 variants in breast cancer risk is unclear and requires further investigation in an adequately powered study. ©2011 AACR.

  13. Analysis of stop-gain and frameshift variants in human innate immunity genes.

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    Antonio Rausell

    2014-07-01

    Full Text Available Loss-of-function variants in innate immunity genes are associated with Mendelian disorders in the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts are collectively prevalent in humans and could be responsible for some of the inter-individual variability in innate immune response. Current computational approaches evaluating loss-of-function in genes carrying these variants rely on gene-level characteristics such as evolutionary conservation and functional redundancy across the genome. However, innate immunity genes represent a particular case because they are more likely to be under positive selection and duplicated. To create a ranking of severity that would be applicable to innate immunity genes we evaluated 17,764 stop-gain and 13,915 frameshift variants from the NHLBI Exome Sequencing Project and 1,000 Genomes Project. Sequence-based features such as loss of functional domains, isoform-specific truncation and nonsense-mediated decay were found to correlate with variant allele frequency and validated with gene expression data. We integrated these features in a Bayesian classification scheme and benchmarked its use in predicting pathogenic variants against Online Mendelian Inheritance in Man (OMIM disease stop-gains and frameshifts. The classification scheme was applied in the assessment of 335 stop-gains and 236 frameshifts affecting 227 interferon-stimulated genes. The sequence-based score ranks variants in innate immunity genes according to their potential to cause disease, and complements existing gene-based pathogenicity scores. Specifically, the sequence-based score improves measurement of functional gene impairment, discriminates across different variants in a given gene and appears particularly useful for analysis of less conserved genes.

  14. Isolation and characterization of alternatively spliced variants of the mouse sigma1 receptor gene, Sigmar1.

    Directory of Open Access Journals (Sweden)

    Ling Pan

    Full Text Available The sigma1 receptor acts as a chaperone at the endoplasmic reticulum, associates with multiple proteins in various cellular systems, and involves in a number of diseases, such as addiction, pain, cancer and psychiatric disorders. The sigma1 receptor is encoded by the single copy SIGMAR1 gene. The current study identifies five alternatively spliced variants of the mouse sigma1 receptor gene using a polymerase chain reaction cloning approach. All the splice variants are generated by exon skipping or alternative 3' or 5' splicing, producing the truncated sigma1 receptor. Similar alternative splicing has been observed in the human SIGMAR1 gene based on the molecular cloning or genome sequence prediction, suggesting conservation of alternative splicing of SIGMAR1 gene. Using quantitative polymerase chain reactions, we demonstrate differential expression of several splice variants in mouse tissues and brain regions. When expressed in HEK293 cells, all the splice variants fail to bind sigma ligands, implicating that each truncated region in these splice variants is important for ligand binding. However, co-immunoprecipitation (Co-IP study in HEK293 cells co-transfected with tagged constructs reveals that all the splice variants maintain their ability to physically associate with a mu opioid receptor (mMOR-1, providing useful information to correlate the motifs/sequences necessary for their physical association. Furthermore, a competition Co-IP study showed that all the variants can disrupt in a dose-dependent manner the dimerization of the original sigma1 receptor with mMOR-1, suggesting a potential dominant negative function and providing significant insights into their function.

  15. Genomic variants in the FTO gene are associated with sporadic amyotrophic lateral sclerosis in Greek patients.

    Science.gov (United States)

    Mitropoulos, Konstantinos; Merkouri Papadima, Eleni; Xiromerisiou, Georgia; Balasopoulou, Angeliki; Charalampidou, Kyriaki; Galani, Vasiliki; Zafeiri, Krystallia-Vassiliki; Dardiotis, Efthymios; Ralli, Styliani; Deretzi, Georgia; John, Anne; Kydonopoulou, Kyriaki; Papadopoulou, Elpida; di Pardo, Alba; Akcimen, Fulya; Loizedda, Annalisa; Dobričić, Valerija; Novaković, Ivana; Kostić, Vladimir S; Mizzi, Clint; Peters, Brock A; Basak, Nazli; Orrù, Sandro; Kiskinis, Evangelos; Cooper, David N; Gerou, Spyridon; Drmanac, Radoje; Bartsakoulia, Marina; Tsermpini, Evangelia-Eirini; Hadjigeorgiou, Georgios M; Ali, Bassam R; Katsila, Theodora; Patrinos, George P

    2017-12-08

    Amyotrophic lateral sclerosis (ALS) is a devastating disease whose complex pathology has been associated with a strong genetic component in the context of both familial and sporadic disease. Herein, we adopted a next-generation sequencing approach to Greek patients suffering from sporadic ALS (together with their healthy counterparts) in order to explore further the genetic basis of sporadic ALS (sALS). Whole-genome sequencing analysis of Greek sALS patients revealed a positive association between FTO and TBC1D1 gene variants and sALS. Further, linkage disequilibrium analyses were suggestive of a specific disease-associated haplotype for FTO gene variants. Genotyping for these variants was performed in Greek, Sardinian, and Turkish sALS patients. A lack of association between FTO and TBC1D1 variants and sALS in patients of Sardinian and Turkish descent may suggest a founder effect in the Greek population. FTO was found to be highly expressed in motor neurons, while in silico analyses predicted an impact on FTO and TBC1D1 mRNA splicing for the genomic variants in question. To our knowledge, this is the first study to present a possible association between FTO gene variants and the genetic etiology of sALS. In addition, the next-generation sequencing-based genomics approach coupled with the two-step validation strategy described herein has the potential to be applied to other types of human complex genetic disorders in order to identify variants of clinical significance.

  16. LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure.

    Science.gov (United States)

    Riley, Lisa G; Rudinger-Thirion, Joëlle; Schmitz-Abe, Klaus; Thorburn, David R; Davis, Ryan L; Teo, Juliana; Arbuckle, Susan; Cooper, Sandra T; Campagna, Dean R; Frugier, Magali; Markianos, Kyriacos; Sue, Carolyn M; Fleming, Mark D; Christodoulou, John

    2016-01-01

    Pathogenic variants in mitochondrial aminoacyl-tRNA synthetases result in a broad range of mitochondrial respiratory chain disorders despite their shared role in mitochondrial protein synthesis. LARS2 encodes the mitochondrial leucyl-tRNA synthetase, which attaches leucine to its cognate tRNA. Sequence variants in LARS2 have previously been associated with Perrault syndrome, characterized by premature ovarian failure and hearing loss (OMIM #615300). In this study, we report variants in LARS2 that are associated with a severe multisystem metabolic disorder. The proband was born prematurely with severe lactic acidosis, hydrops, and sideroblastic anemia. She had multisystem complications with hyaline membrane disease, impaired cardiac function, a coagulopathy, pulmonary hypertension, and progressive renal disease and succumbed at 5 days of age. Whole exome sequencing of patient DNA revealed compound heterozygous variants in LARS2 (c.1289C>T; p.Ala430Val and c.1565C>A; p.Thr522Asn). The c.1565C>A (p.Thr522Asn) LARS2 variant has previously been associated with Perrault syndrome and both identified variants are predicted to be damaging (SIFT, PolyPhen). Muscle and liver samples from the proband did not display marked mitochondrial respiratory chain enzyme deficiency. Immunoblotting of patient muscle and liver showed LARS2 levels were reduced in liver and complex I protein levels were reduced in patient muscle and liver. Aminoacylation assays revealed p.Ala430Val LARS2 had an 18-fold loss of catalytic efficiency and p.Thr522Asn a 9-fold loss compared to wild-type LARS2. We suggest that the identified LARS2 variants are responsible for the severe multisystem clinical phenotype seen in this baby and that mutations in LARS2 can result in variable phenotypes.

  17. Complete functional characterization of disease-associated genetic variants in the complement factor H gene.

    Science.gov (United States)

    Merinero, Héctor Martín; García, Sheila Pinto; García-Fernández, Jesús; Arjona, Emilia; Tortajada, Agustín; Rodríguez de Córdoba, Santiago

    2017-09-20

    Genetic analyses in atypical hemolytic uremic syndrome (aHUS) and C3-glomerulopathy (C3G) patients have provided an excellent understanding of the genetic component of the disease and informed genotype-phenotype correlations supporting an individualized approach to patient management and treatment. In this context, a correct categorization of the disease-associated gene variants is critical to avoid detrimental consequences for patients and their relatives. Here we describe a comprehensive procedure to measure levels and functional activity of complement regulator factor H (FH) encoded by CFH, the commonest genetic factor associated with aHUS and C3G, and present the results of the analysis of 28 uncharacterized, disease-associated, FH variants. Sixteen variants were not expressed in plasma and eight had significantly reduced functional activities that impact on complement regulation. In total, 24 of 28 CFH variants were unambiguously categorized as pathogenic and the nature of the pathogenicity fully documented for each. The data also reinforce the genotype-phenotype correlations that associate specific FH functional alterations with either aHUS or C3G and illustrate important drawbacks of the prediction algorithms dealing with variants located in FH functional regions. We also report that the novel aHUS-associated M823T variant is functionally impaired. This was unexpected and uncovered the important contribution of regions outside the N-terminal and C-terminal functional domains to FH regulatory activities on surfaces. Thus, our work significantly advances knowledge towards a complete functional understanding of the CFH genetic variability and highlights the importance of functional analysis of the disease-associated CFH variants. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  18. Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members.

    Science.gov (United States)

    Thomassen, Mads; Blanco, Ana; Montagna, Marco; Hansen, Thomas V O; Pedersen, Inge S; Gutiérrez-Enríquez, Sara; Menéndez, Mireia; Fachal, Laura; Santamariña, Marta; Steffensen, Ane Y; Jønson, Lars; Agata, Simona; Whiley, Phillip; Tognazzo, Silvia; Tornero, Eva; Jensen, Uffe B; Balmaña, Judith; Kruse, Torben A; Goldgar, David E; Lázaro, Conxi; Diez, Orland; Spurdle, Amanda B; Vega, Ana

    2012-04-01

    Mutations in BRCA1 and BRCA2 predispose carriers to early onset breast and ovarian cancer. A common problem in clinical genetic testing is interpretation of variants with unknown clinical significance. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium was initiated to evaluate and implement strategies to characterize the clinical significance of BRCA1 and BRCA2 variants. As an initial project of the ENIGMA Splicing Working Group, we report splicing and multifactorial likelihood analysis of 25 BRCA1 and BRCA2 variants from seven different laboratories. Splicing analysis was performed by reverse transcriptase PCR or mini gene assay, and sequencing to identify aberrant transcripts. The findings were compared to bioinformatic predictions using four programs. The posterior probability of pathogenicity was estimated using multifactorial likelihood analysis, including co-occurrence with a deleterious mutation, segregation and/or report of family history. Abnormal splicing patterns expected to lead to a non-functional protein were observed for 7 variants (BRCA1 c.441+2T>A, c.4184_4185+2del, c.4357+1G>A, c.4987-2A>G, c.5074G>C, BRCA2 c.316+5G>A, and c.8754+3G>C). Combined interpretation of splicing and multifactorial analysis classified an initiation codon variant (BRCA2 c.3G>A) as likely pathogenic, uncertain clinical significance for 7 variants, and indicated low clinical significance or unlikely pathogenicity for another 10 variants. Bioinformatic tools predicted disruption of consensus donor or acceptor sites with high sensitivity, but cryptic site usage was predicted with low specificity, supporting the value of RNA-based assays. The findings also provide further evidence that clinical RNA-based assays should be extended from analysis of invariant dinucleotides to routinely include all variants located within the donor and acceptor consensus splicing sites. Importantly, this study demonstrates the added value of

  19. Diagnosis, prognosis, and management of leiomyosarcoma: recognition of anatomic variants.

    Science.gov (United States)

    Bathan, Andrew J; Constantinidou, Anastasia; Pollack, Seth M; Jones, Robin L

    2013-07-01

    The purpose of this review is to present the most recent advances in the diagnosis of the more common leiomyosarcoma (LMS) anatomic variants, potentially useful prognostic markers that have recently been identified and the systemic approaches currently used or under evaluation to improve the outcome of patients with this disease. Over the last few years emphasis has been placed on incorporating effective imaging tools and using pathological biomarkers in the diagnostic workup of LMS. Moreover, efforts are being made to identify meaningful prognostic and predictive parameters that will aid the development of effective novel therapeutics. The number of systemic therapies available to treat LMS has increased over the last decade, but the selection of systemic therapy is not based on the anatomic origin of LMS. Currently, the only curative option in LMS is surgery and despite progress in systemic therapy the outcome of patients with advanced/metastatic disease remains poor. Better understanding of the underlying biology of the LMS variants, improved diagnostics and more effective, less toxic therapeutic agents are required.

  20. Variants in the vitamin D receptor gene and asthma

    Directory of Open Access Journals (Sweden)

    Wjst Matthias

    2005-01-01

    Full Text Available Abstract Background Early lifetime exposure to dietary or supplementary vitamin D has been predicted to be a risk factor for later allergy. Twin studies suggest that response to vitamin D exposure might be influenced by genetic factors. As these effects are primarily mediated through the vitamin D receptor (VDR, single base variants in this gene may be risk factors for asthma or allergy. Results 951 individuals from 224 pedigrees with at least 2 asthmatic children were analyzed for 13 SNPs in the VDR. There was no preferential transmission to children with asthma. In their unaffected sibs, however, one allele in the 5' region was 0.5-fold undertransmitted (p = 0.049, while two other alleles in the 3' terminal region were 2-fold over-transmitted (p = 0.013 and 0.018. An association was also seen with bronchial hyperreactivity against methacholine and with specific immunoglobulin E serum levels. Conclusion The transmission disequilibrium in unaffected sibs of otherwise multiple-affected families seem to be a powerful statistical test. A preferential transmission of vitamin D receptor variants to children with asthma could not be confirmed but raises the possibility of a protective effect for unaffected children.

  1. Germline genetic variants with implications for disease risk and therapeutic outcomes.

    Science.gov (United States)

    Pasternak, Amy L; Ward, Kristen M; Luzum, Jasmine A; Ellingrod, Vicki L; Hertz, Daniel L

    2017-10-01

    Genetic testing has multiple clinical applications including disease risk assessment, diagnosis, and pharmacogenomics. Pharmacogenomics can be utilized to predict whether a pharmacologic therapy will be effective or to identify patients at risk for treatment-related toxicity. Although genetic tests are typically ordered for a distinct clinical purpose, the genetic variants that are found may have additional implications for either disease or pharmacology. This review will address multiple examples of germline genetic variants that are informative for both disease and pharmacogenomics. The discussed relationships are diverse. Some of the agents are targeted for the disease-causing genetic variant, while others, although not targeted therapies, have implications for the disease they are used to treat. It is also possible that the disease implications of a genetic variant are unrelated to the pharmacogenomic implications. Some of these examples are considered clinically actionable pharmacogenes, with evidence-based, pharmacologic treatment recommendations, while others are still investigative as areas for additional research. It is important that clinicians are aware of both the disease and pharmacogenomic associations of these germline genetic variants to ensure patients are receiving comprehensive personalized care. Copyright © 2017 the American Physiological Society.

  2. A Novel Pathogenic BRCA1 Splicing Variant Produces Partial Intron Retention in the Mature Messenger RNA

    Directory of Open Access Journals (Sweden)

    Maria Valeria Esposito

    2016-12-01

    Full Text Available About 10% of all breast cancers arise from hereditary mutations that increase the risk of breast and ovarian cancers; and about 25% of these are associated with the BRCA1 or BRCA2 genes. The identification of BRCA1/BRCA2 mutations can enable physicians to better tailor the clinical management of patients; and to initiate preventive measures in healthy carriers. The pathophysiological significance of newly identified variants poses challenges for genetic counseling. We characterized a new BRCA1 variant discovered in a breast cancer patient during BRCA1/2 screening by next-generation sequencing. Bioinformatic predictions; indicating that the variant is probably pathogenetic; were verified using retro-transcription of the patient’s RNA followed by PCR amplifications performed on the resulting cDNA. The variant causes the loss of a canonic donor splice site at position +2 in BRCA1 intron 21; and consequently the partial retention of 156 bp of intron 21 in the patient’s transcript; which demonstrates that this novel BRCA1 mutation plays a pathogenetic role in breast cancer. These findings enabled us to initiate appropriate counseling and to tailor the clinical management of this family. Lastly; these data reinforce the importance of studying the effects of sequence variants at the RNA level to verify their potential role in disease onset.

  3. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

    Science.gov (United States)

    Milne, Roger L; Kuchenbaecker, Karoline B; Michailidou, Kyriaki; Beesley, Jonathan; Kar, Siddhartha; Lindström, Sara; Hui, Shirley; Lemaçon, Audrey; Soucy, Penny; Dennis, Joe; Jiang, Xia; Rostamianfar, Asha; Finucane, Hilary; Bolla, Manjeet K; McGuffog, Lesley; Wang, Qin; Aalfs, Cora M; Adams, Marcia; Adlard, Julian; Agata, Simona; Ahmed, Shahana; Ahsan, Habibul; Aittomäki, Kristiina; Al-Ejeh, Fares; Allen, Jamie; Ambrosone, Christine B; Amos, Christopher I; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Arndt, Volker; Arnold, Norbert; Aronson, Kristan J; Auber, Bernd; Auer, Paul L; Ausems, Margreet G E M; Azzollini, Jacopo; Bacot, François; Balmaña, Judith; Barile, Monica; Barjhoux, Laure; Barkardottir, Rosa B; Barrdahl, Myrto; Barnes, Daniel; Barrowdale, Daniel; Baynes, Caroline; Beckmann, Matthias W; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Bignon, Yves-Jean; Blazer, Kathleen R; Blok, Marinus J; Blomqvist, Carl; Blot, William; Bobolis, Kristie; Boeckx, Bram; Bogdanova, Natalia V; Bojesen, Anders; Bojesen, Stig E; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Bozsik, Aniko; Bradbury, Angela R; Brand, Judith S; Brauch, Hiltrud; Brenner, Hermann; Bressac-de Paillerets, Brigitte; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Brunet, Joan; Brüning, Thomas; Burwinkel, Barbara; Buys, Saundra S; Byun, Jinyoung; Cai, Qiuyin; Caldés, Trinidad; Caligo, Maria A; Campbell, Ian; Canzian, Federico; Caron, Olivier; Carracedo, Angel; Carter, Brian D; Castelao, J Esteban; Castera, Laurent; Caux-Moncoutier, Virginie; Chan, Salina B; Chang-Claude, Jenny; Chanock, Stephen J; Chen, Xiaoqing; Cheng, Ting-Yuan David; Chiquette, Jocelyne; Christiansen, Hans; Claes, Kathleen B M; Clarke, Christine L; Conner, Thomas; Conroy, Don M; Cook, Jackie; Cordina-Duverger, Emilie; Cornelissen, Sten; Coupier, Isabelle; Cox, Angela; Cox, David G; Cross, Simon S; Cuk, Katarina; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Damiola, Francesca; Darabi, Hatef; Davidson, Rosemarie; De Leeneer, Kim; Devilee, Peter; Dicks, Ed; Diez, Orland; Ding, Yuan Chun; Ditsch, Nina; Doheny, Kimberly F; Domchek, Susan M; Dorfling, Cecilia M; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dubois, Stéphane; Dugué, Pierre-Antoine; Dumont, Martine; Dunning, Alison M; Durcan, Lorraine; Dwek, Miriam; Dworniczak, Bernd; Eccles, Diana; Eeles, Ros; Ehrencrona, Hans; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B; Eliassen, A Heather; Engel, Christoph; Eriksson, Mikael; Fachal, Laura; Faivre, Laurence; Fasching, Peter A; Faust, Ulrike; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Foulkes, William D; Friedman, Eitan; Fritschi, Lin; Frost, Debra; Gabrielson, Marike; Gaddam, Pragna; Gammon, Marilie D; Ganz, Patricia A; Gapstur, Susan M; Garber, Judy; Garcia-Barberan, Vanesa; García-Sáenz, José A; Gaudet, Mia M; Gauthier-Villars, Marion; Gehrig, Andrea; Georgoulias, Vassilios; Gerdes, Anne-Marie; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Goodfellow, Paul; Greene, Mark H; Alnæs, Grethe I Grenaker; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Gschwantler-Kaulich, Daphne; Guénel, Pascal; Guo, Qi; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A; Håkansson, Niclas; Hallberg, Emily; Hamann, Ute; Hamel, Nathalie; Hankinson, Susan; Hansen, Thomas V O; Harrington, Patricia; Hart, Steven N; Hartikainen, Jaana M; Healey, Catherine S; Hein, Alexander; Helbig, Sonja; Henderson, Alex; Heyworth, Jane; Hicks, Belynda; Hillemanns, Peter; Hodgson, Shirley; Hogervorst, Frans B; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Bob; Hopper, John L; Hu, Chunling; Huang, Guanmengqian; Hulick, Peter J; Humphreys, Keith; Hunter, David J; Imyanitov, Evgeny N; Isaacs, Claudine; Iwasaki, Motoki; Izatt, Louise; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Janni, Wolfgang; Jensen, Uffe Birk; John, Esther M; Johnson, Nichola; Jones, Kristine; Jones, Michael; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kang, Daehee; Kast, Karin; Keeman, Renske; Kerin, Michael J; Kets, Carolien M; Keupers, Machteld; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I; Kim, Sung-Won; Knight, Julia A; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela N; Kruse, Torben A; Kwong, Ava; Lænkholm, Anne-Vibeke; Laitman, Yael; Lalloo, Fiona; Lambrechts, Diether; Landsman, Keren; Lasset, Christine; Lazaro, Conxi; Le Marchand, Loic; Lecarpentier, Julie; Lee, Andrew; Lee, Eunjung; Lee, Jong Won; Lee, Min Hyuk; Lejbkowicz, Flavio; Lesueur, Fabienne; Li, Jingmei; Lilyquist, Jenna; Lincoln, Anne; Lindblom, Annika; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Long, Jirong; Loud, Jennifer T; Lubinski, Jan; Luccarini, Craig; Lush, Michael; MacInnis, Robert J; Maishman, Tom; Makalic, Enes; Kostovska, Ivana Maleva; Malone, Kathleen E; Manoukian, Siranoush; Manson, JoAnn E; Margolin, Sara; Martens, John W M; Martinez, Maria Elena; Matsuo, Keitaro; Mavroudis, Dimitrios; Mazoyer, Sylvie; McLean, Catriona; Meijers-Heijboer, Hanne; Menéndez, Primitiva; Meyer, Jeffery; Miao, Hui; Miller, Austin; Miller, Nicola; Mitchell, Gillian; Montagna, Marco; Muir, Kenneth; Mulligan, Anna Marie; Mulot, Claire; Nadesan, Sue; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nevelsteen, Ines; Niederacher, Dieter; Nielsen, Sune F; Nordestgaard, Børge G; Norman, Aaron; Nussbaum, Robert L; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Olswold, Curtis; Ong, Kai-Ren; Oosterwijk, Jan C; Orr, Nick; Osorio, Ana; Pankratz, V Shane; Papi, Laura; Park-Simon, Tjoung-Won; Paulsson-Karlsson, Ylva; Lloyd, Rachel; Pedersen, Inge Søkilde; Peissel, Bernard; Peixoto, Ana; Perez, Jose I A; Peterlongo, Paolo; Peto, Julian; Pfeiler, Georg; Phelan, Catherine M; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Poppe, Bruce; Porteous, Mary E; Prentice, Ross; Presneau, Nadege; Prokofieva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rennert, Hedy S; Rhenius, Valerie; Rhiem, Kerstin; Richardson, Andrea; Rodriguez, Gustavo C; Romero, Atocha; Romm, Jane; Rookus, Matti A; Rudolph, Anja; Ruediger, Thomas; Saloustros, Emmanouil; Sanders, Joyce; Sandler, Dale P; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Daniel F; Schoemaker, Minouk J; Schumacher, Fredrick; Schürmann, Peter; Schwentner, Lukas; Scott, Christopher; Scott, Rodney J; Seal, Sheila; Senter, Leigha; Seynaeve, Caroline; Shah, Mitul; Sharma, Priyanka; Shen, Chen-Yang; Sheng, Xin; Shimelis, Hermela; Shrubsole, Martha J; Shu, Xiao-Ou; Side, Lucy E; Singer, Christian F; Sohn, Christof; Southey, Melissa C; Spinelli, John J; Spurdle, Amanda B; Stegmaier, Christa; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Surowy, Harald; Sutter, Christian; Swerdlow, Anthony; Szabo, Csilla I; Tamimi, Rulla M; Tan, Yen Y; Taylor, Jack A; Tejada, Maria-Isabel; Tengström, Maria; Teo, Soo H; Terry, Mary B; Tessier, Daniel C; Teulé, Alex; Thöne, Kathrin; Thull, Darcy L; Tibiletti, Maria Grazia; Tihomirova, Laima; Tischkowitz, Marc; Toland, Amanda E; Tollenaar, Rob A E M; Tomlinson, Ian; Tong, Ling; Torres, Diana; Tranchant, Martine; Truong, Thérèse; Tucker, Kathy; Tung, Nadine; Tyrer, Jonathan; Ulmer, Hans-Ulrich; Vachon, Celine; van Asperen, Christi J; Van Den Berg, David; van den Ouweland, Ans M W; van Rensburg, Elizabeth J; Varesco, Liliana; Varon-Mateeva, Raymonda; Vega, Ana; Viel, Alessandra; Vijai, Joseph; Vincent, Daniel; Vollenweider, Jason; Walker, Lisa; Wang, Zhaoming; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weinberg, Clarice R; Weitzel, Jeffrey N; Wendt, Camilla; Wesseling, Jelle; Whittemore, Alice S; Wijnen, Juul T; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Wu, Anna H; Xia, Lucy; Yang, Xiaohong R; Yannoukakos, Drakoulis; Zaffaroni, Daniela; Zheng, Wei; Zhu, Bin; Ziogas, Argyrios; Ziv, Elad; Zorn, Kristin K; Gago-Dominguez, Manuela; Mannermaa, Arto; Olsson, Håkan; Teixeira, Manuel R; Stone, Jennifer; Offit, Kenneth; Ottini, Laura; Park, Sue K; Thomassen, Mads; Hall, Per; Meindl, Alfons; Schmutzler, Rita K; Droit, Arnaud; Bader, Gary D; Pharoah, Paul D P; Couch, Fergus J; Easton, Douglas F; Kraft, Peter; Chenevix-Trench, Georgia; García-Closas, Montserrat; Schmidt, Marjanka K; Antoniou, Antonis C; Simard, Jacques

    2017-12-01

    Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

  4. A Large French Case-Control Study Emphasizes the Role of Rare Mc1R Variants in Melanoma Risk

    Directory of Open Access Journals (Sweden)

    Hui-Han Hu

    2014-01-01

    Full Text Available Background. The MC1R gene implicated in melanogenesis and skin pigmentation is highly polymorphic. Several alleles are associated with red hair and fair skin phenotypes and contribute to melanoma risk. Objective. This work aims to assess the effect of different classes of MC1R variants, notably rare variants, on melanoma risk. Methods. MC1R coding region was sequenced in 1131 melanoma patients and 869 healthy controls. MC1R variants were classified as RHC (R and non-RHC (r. Rare variants (frequency < 1% were subdivided into two subgroups, predicted to be damaging (D or not (nD. Results. Both R and r alleles were associated with melanoma (OR = 2.66 [2.20–3.23] and 1.51 [1.32–1.73] and had similar population attributable risks (15.8% and 16.6%. We also identified 69 rare variants, of which 25 were novel. D variants were strongly associated with melanoma (OR = 2.38 [1.38–4.15] and clustered in the same MC1R domains as R alleles (intracellular 2, transmembrane 2 and 7. Conclusion. This work confirms the role of R and r alleles in melanoma risk in the French population and proposes a novel class of rare D variants as important melanoma risk factors. These findings may improve the definition of high-risk subjects that could be targeted for melanoma prevention and screening.

  5. Structural and functional insights into thermostable and organic solvent stable variant Pro247-Ser of Bacillus lipase.

    Science.gov (United States)

    Chopra, Nisha; Kumar, Arbind; Kaur, Jagdeep

    2017-10-31

    Thermostability of enzymes is an important issue in protein engineering and has been studied in detail. Still there is no hard and fast rule to define the conditions which will provide thermal stability. Understanding the various factors and mechanism responsible for thermal stability will add on new insights into our present knowledge in this area. Pro247-Ser variant was constructed based on homology modelling and rational design. It exhibited 60 fold increase in thermal stability at 60°C and+0.7M shift in C1/2 value for urea denaturation as compared to WT. Variant displayed noticeable tolerance to organic solvents. With decrease in Km, catalytic efficiency of Pro247-Ser variant was increased by 12 fold. The activity and stability assay including circular dichroism and fluorescence spectroscopy favoured increased thermal performance of variant. Hydrolytic activity of variant was found to be high in comparison to control for all p-nitrophenol esters investigated. The immobilized variant enzyme demonstrated nearly two fold enhanced conversion of methyl oleate than WT enzyme. The additional molecular interactions of variant residue might contribute to increased thermostability of lipase. The homology modeling predicted formation of additional hydrogen bonds between Ser247/O-Thr251/OG1 as well as Ser247/O-Glu250/N. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Nutritional Status Predicts 10-Year Mortality in Patients with End-Stage Renal Disease on Hemodialysis.

    Science.gov (United States)

    Kang, Shin Sook; Chang, Jai Won; Park, Yongsoon

    2017-04-18

    Protein-energy wasting (PEW) is associated with mortality in patients with end-stage renal disease (ESRD) on maintenance hemodialysis. The correct diagnosis of PEW is extremely important in order to predict clinical outcomes. However, it is unclear which parameters should be used to diagnose PEW. Therefore, this retrospective observational study investigated the relationship between mortality and nutritional parameters in ESRD patients on maintenance hemodialysis. A total of 144 patients were enrolled. Nutritional parameters, including body mass index, serum albumin, dietary intake, normalized protein catabolic rate (nPCR), and malnutrition inflammation score (MIS), were measured at baseline. Fifty-three patients died during the study. Survivors had significantly higher nPCR (1.10 ± 0.24 g/kg/day vs. 1.01 ± 0.21 g/kg/day; p = 0.048), energy intake (26.7 ± 5.8 kcal/kg vs. 24.3 ± 4.2 kcal/kg; p = 0.009) and protein intake (0.91 ± 0.21 g/kg vs. 0.82 ± 0.24 g/kg; p = 0.020), and lower MIS (5.2 ± 2.3 vs. 6.1 ± 2.1, p = 0.039). In multivariable analysis, energy intake 5 (HR 2.146, 95% CI 1.173-3.928; p = 0.013) were independent variables associated with all-cause mortality. These results suggest that higher MIS and lower energy intake are harmful to ESRD patients on maintenance hemodialysis. Optimal energy intake could reduce mortality in these patients.

  7. Mining business process variants: Challenges, scenarios, algorithms

    NARCIS (Netherlands)

    Li, C.; Reichert, M.U.; Wombacher, Andreas

    During the last years a new generation of process-aware information systems has emerged, which enables process model configurations at buildtime as well as process instance changes during runtime. Respective model adaptations result in a large number of model variants that are derived from the same

  8. Probabilistic Transcriptome Assembly and Variant Graph Genotyping

    DEFF Research Database (Denmark)

    Sibbesen, Jonas Andreas

    that this approach outperforms existing state-of-the-art methods measured using sensitivity and precision on both simulated and real data. The second is a novel probabilistic method that uses exact alignment of k-mers to a set of variants graphs to provide unbiased estimates of genotypes in a population...

  9. HLogo: a parallel Haskell variant of Netlogo

    NARCIS (Netherlands)

    N. Bezirgiannis (Nikolaos); Prasetya, I.S.W.B.; Sakellariou, I.

    2016-01-01

    textabstractAgent-based Modeling (ABM) has become quite popular to the simulation community for its usability and wide area of applicability. However, speed is not usually a trait that ABM tools are characterized of attaining. This paper presents HLogo, a parallel variant of the NetLogo ABM

  10. XVCL: XML-based Variant Configuration Language

    DEFF Research Database (Denmark)

    Jarzabek, Stan; Basset, Paul; Zhang, Hongyu

    2003-01-01

    XVCL (XML-based Variant Configuration Language) is a meta-programming technique and tool that provides effective reuse mechanisms. XVCL is an open source software developed at the National University of Singapore. Being a modern and versatile version of Bassett's frames, a technology that has...

  11. Variants of the left aortic arch branches

    African Journals Online (AJOL)

    ORIGINAL ARTICLE. Variants of the left aortic arch branches. N Z Makhanya. MB ChB. R T Mamogale. MB 0113. N Khan. FCRaD (0). Department of Diagnostic Radiology. Medical University of Southern Africa. Abstract. The normal aorta has three branches from its arch, but variations in this pattern are not uncommon. Our.

  12. New genetic variants associated with prostate cancer

    Science.gov (United States)

    Researchers have newly identified 23 common genetic variants -- one-letter changes in DNA known as single-nucleotide polymorphisms or SNPs -- that are associated with risk of prostate cancer. These results come from an analysis of more than 10 million SNP

  13. Psychiatric misdiagnoses in Dandy-Walker variant.

    Science.gov (United States)

    Blaettner, C; Pfaffenberger, N M; Cartes-Zumelzu, F; Hofer, A

    2015-01-01

    Cases of intellectual impairment and aberrant behavior in patients with cerebellar diseases have been described since the early nineteenth century. Here, we report on a patient suffering from Dandy-Walker variant who presented with symptoms of obsessive compulsive disorder and delusional disorder. The current findings emphasize the potential relevance of focal cerebellar lesions as organic correlates of these disorders.

  14. Developing consistent pronunciation models for phonemic variants

    CSIR Research Space (South Africa)

    Davel, M

    2006-09-01

    Full Text Available from a lexicon containing variants. In this paper we (the authors) address both these issues by creating ‘pseudo-phonemes’ associated with sets of ‘generation restriction rules’ to model those pronunciations that are consistently realised as two or more...

  15. Mining Process Model Variants: Challenges, Techniques, Examples

    NARCIS (Netherlands)

    Li, C.

    2010-01-01

    During the last years a new generation of process-aware information systems has emerged, which enables process model configurations at buildtime as well as process instance changes during runtime. Respective model adaptations result in large collections of process model variants that are derived

  16. Cellobiohydrolase I gene and improved variants

    Science.gov (United States)

    Adney, William S [Golden, CO; Decker, Stephen R [Berthoud, CO; Mc Carter, Suzanne [San Carlos, CA; Baker, John O [Golden, CO; Nieves, Raphael [Lakewood, CO; Himmel, Michael E [Littleton, CO; Vinzant, Todd B [Golden, CO

    2008-05-20

    The disclosure provides a method for preparing an active exoglucanase in a heterologous host of eukaryotic origin. The method includes mutagenesis to reduce glycosylation of the exoglucanase when expressed in a heterologous host. It is further disclosed a method to produce variant cellobiohydrolase that is stable at high temperature through mutagenesis.

  17. Report of a rare anatomic variant

    DEFF Research Database (Denmark)

    De Brucker, Y; Ilsen, B; Muylaert, C

    2015-01-01

    We report the CT findings in a case of partial anomalous pulmonary venous return (PAPVR) from the left upper lobe in an adult. PAPVR is an anatomic variant in which one to three pulmonary veins drain into the right atrium or its tributaries, rather than into the left atrium. This results in a lef...

  18. PIN1 gene variants in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Siedlecki Janusz

    2009-11-01

    Full Text Available Abstract Background Peptidyl-prolyl isomerase, NIMA-interacting 1 (PIN1 plays a significant role in the brain and is implicated in numerous cellular processes related to Alzheimer's disease (AD and other neurodegenerative conditions. There are confounding results concerning PIN1 activity in AD brains. Also PIN1 genetic variation was inconsistently associated with AD risk. Methods We performed analysis of coding and promoter regions of PIN1 in early- and late-onset AD and frontotemporal dementia (FTD patients in comparison with healthy controls. Results Analysis of eighteen PIN1 common polymorphisms and their haplotypes in EOAD, LOAD and FTD individuals in comparison with the control group did not reveal their contribution to disease risk. In six unrelated familial AD patients four novel PIN1 sequence variants were detected. c.58+64C>T substitution that was identified in three patients, was located in an alternative exon. In silico analysis suggested that this variant highly increases a potential affinity for a splicing factor and introduces two intronic splicing enhancers. In the peripheral leukocytes of one living patient carrying the variant, a 2.82 fold decrease in PIN1 expression was observed. Conclusion Our data does not support the role of PIN1 common polymorphisms as AD risk factor. However, we suggest that the identified rare sequence variants could be directly connected with AD pathology, influencing PIN1 splicing and/or expression.

  19. Identification and annotation of genetic variants (SNP/Indel) in Danish Jutland cattle

    DEFF Research Database (Denmark)

    Das, Ashutosh; Panitz, Frank; Holm, Lars-Erik

    We sequenced the whole-genome of a Danish Jutland bull to identify genetic variants (SNP/indel). Using UnifiedGenotyper from the Genome Analysis Toolkit (GATK), we identified 6,812,198 SNPs and 804,453 indels. There were 2,598,000 (38.1%) novel SNPs and 607,923(75.6%) novel indels while the remai......,122 indels in coding sequences, 832 predicted to cause frame shift, 89 predicted to be inframe insertion and 115 to be inframe deletion. We detected a higher level of genetic variation in the Jutland bull compared to similar data from Holstein cattle......We sequenced the whole-genome of a Danish Jutland bull to identify genetic variants (SNP/indel). Using UnifiedGenotyper from the Genome Analysis Toolkit (GATK), we identified 6,812,198 SNPs and 804,453 indels. There were 2,598,000 (38.1%) novel SNPs and 607,923(75.6%) novel indels while...... the remaining was annotated in dbSNP build 133. In-depth annotation of the variants revealed that 45,776 SNPs affected the coding sequences of 11,538 genes, 221 SNPs predicted to cause a premature stop codon, 17 to cause a gain in coding sequence and 20,828 predicted to be non-synonymous. We identified 1...

  20. Interleukin‑1 gene cluster variants in hemodialysis patients with end stage renal disease: An association and meta‑analysis

    Directory of Open Access Journals (Sweden)

    G Tripathi

    2015-01-01

    Full Text Available We evaluated whether polymorphisms in interleukin (IL-1 gene cluster (IL-1 alpha [IL-1A], IL-1 beta [IL-1B], and IL-1 receptor antagonist [IL-1RN] are associated with end stage renal disease (ESRD. A total of 258 ESRD patients and 569 ethnicity matched controls were examined for IL-1 gene cluster. These were genotyped for five single-nucleotide gene polymorphisms in the IL-1A, IL-1B and IL-1RN genes and a variable number of tandem repeats (VNTR in the IL-1RN. The IL-1B − 3953 and IL-1RN + 8006 polymorphism frequencies were significantly different between the two groups. At IL-1B, the T allele of − 3953C/T was increased among ESRD (P = 0.0001. A logistic regression model demonstrated that two repeat (240 base pair [bp] of the IL-1Ra VNTR polymorphism was associated with ESRD (P = 0.0001. The C/C/C/C/C/1 haplotype was more prevalent in ESRD = 0.007. No linkage disequilibrium (LD was observed between six loci of IL-1 gene. We further conducted a meta-analysis of existing studies and found that there is a strong association of IL-1 RN VNTR 86 bp repeat polymorphism with susceptibility to ESRD (odds ratio = 2.04, 95% confidence interval = 1.48-2.82; P = 0.000. IL-1B − 5887, +8006 and the IL-1RN VNTR polymorphisms have been implicated as potential risk factors for ESRD. The meta-analysis showed a strong association of IL-1RN 86 bp VNTR polymorphism with susceptibility to ESRD.

  1. Allele Variants of Enterotoxigenic Escherichia coli Heat-Labile Toxin Are Globally Transmitted and Associated with Colonization Factors

    KAUST Repository

    Joffré, Enrique

    2015-01-15

    Enterotoxigenic Escherichia coli (ETEC) is a significant cause of morbidity and mortality in the developing world. ETEC-mediated diarrhea is orchestrated by heat-labile toxin (LT) and heat-stable toxins (STp and STh), acting in concert with a repertoire of more than 25 colonization factors (CFs). LT, the major virulence factor, induces fluid secretion after delivery of a monomeric ADP-ribosylase (LTA) and its pentameric carrier B subunit (LTB). A study of ETEC isolates from humans in Brazil reported the existence of natural LT variants. In the present study, analysis of predicted amino acid sequences showed that the LT amino acid polymorphisms are associated with a geographically and temporally diverse set of 192 clinical ETEC strains and identified 12 novel LT variants. Twenty distinct LT amino acid variants were observed in the globally distributed strains, and phylogenetic analysis showed these to be associated with different CF profiles. Notably, the most prevalent LT1 allele variants were correlated with major ETEC lineages expressing CS1 + CS3 or CS2 + CS3, and the most prevalent LT2 allele variants were correlated with major ETEC lineages expressing CS5 + CS6 or CFA/I. LTB allele variants generally exhibited more-stringent amino acid sequence conservation (2 substitutions identified) than LTA allele variants (22 substitutions identified). The functional impact of LT1 and LT2 polymorphisms on virulence was investigated by measuring total-toxin production, secretion, and stability using GM1-enzyme-linked immunosorbent assays (GM1-ELISA) and in silico protein modeling. Our data show that LT2 strains produce 5-fold more toxin than LT1 strains (P < 0.001), which may suggest greater virulence potential for this genetic variant. Our data suggest that functionally distinct LT-CF variants with increased fitness have persisted during the evolution of ETEC and have spread globally.

  2. Rare variant density across the genome and across populations

    OpenAIRE

    Raska Paola; Zhu Xiaofeng

    2011-01-01

    Abstract Next-generation sequencing allows for a new focus on rare variant density for conducting analyses of association to disease and for narrowing down the genomic regions that show evidence of functionality. In this study we use the 1000 Genomes Project pilot data as distributed by Genetic Analysis Workshop 17 to compare rare variant densities across seven populations. We made the comparisons using regressions of rare variants on total variant counts per gene for each population and Taji...

  3. Dietary intake, FTO genetic variants and adiposity

    DEFF Research Database (Denmark)

    Qi, Qibin; Downer, Mary K; Oskari Kilpeläinen, Tuomas

    2015-01-01

    between the FTO rs9939609 variant (or a proxy) and total energy and macronutrient intake; and 2) the interaction between the FTO variant and dietary intake, and the effect on BMI. We found that the BMI-increasing allele (minor allele) of the FTO variant was associated with increased total energy intake...

  4. Processing of No-Release Variants in Connected Speech

    Science.gov (United States)

    LoCasto, Paul C.; Connine, Cynthia M.

    2011-01-01

    The cross modal repetition priming paradigm was used to investigate how potential lexically ambiguous no-release variants are processed. In particular we focus on segmental regularities that affect the variant's frequency of occurrence (voicing of the critical segment) and phonological context in which the variant occurs (status of the following…

  5. The power of multiplexed functional analysis of genetic variants.

    Science.gov (United States)

    Gasperini, Molly; Starita, Lea; Shendure, Jay

    2016-10-01

    New technologies have recently enabled saturation mutagenesis and functional analysis of nearly all possible variants of regulatory elements or proteins of interest in single experiments. Here we discuss the past, present, and future of such multiplexed (functional) assays for variant effects (MAVEs). MAVEs provide detailed insight into sequence-function relationships, and they may prove critical for the prospective clinical interpretation of genetic variants.

  6. GAVIN : Gene-Aware Variant INterpretation for medical sequencing

    NARCIS (Netherlands)

    van der Velde, K Joeri; de Boer, Eddy N; van Diemen, Cleo C; Sikkema-Raddatz, Birgit; Abbott, Kristin M; Knopperts, Alain; Franke, Lude; Sijmons, Rolf H; de Koning, Tom J; Wijmenga, Cisca; Sinke, Richard J; Swertz, Morris A

    2017-01-01

    We present Gene-Aware Variant INterpretation (GAVIN), a new method that accurately classifies variants for clinical diagnostic purposes. Classifications are based on gene-specific calibrations of allele frequencies from the ExAC database, likely variant impact using SnpEff, and estimated

  7. Variant of Rett syndrome and CDKL5 gene

    DEFF Research Database (Denmark)

    Pini, Giorgio; Bigoni, Stefania; Engerström, Ingegerd Witt

    2012-01-01

    UNLABELLED: Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS: In recent years more than 60 patients with mutations in the CDKL5 gene have...... the general Rett population, suggesting a specific behavioral and cardiorespiratory phenotype of the RTT the Hanefeld variant....

  8. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

    Directory of Open Access Journals (Sweden)

    Mengmeng Du

    Full Text Available Genome-wide association studies (GWAS have identified many common single nucleotide polymorphisms (SNPs associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs. We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33. We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s.

  9. Unusual variant of Cantrell′s pentalogy?

    Directory of Open Access Journals (Sweden)

    Kumar Basant

    2008-01-01

    Full Text Available A 12-hour-old male infant presented with prolapsed abdominal content through a defect on left side of chest wall with respiratory distress. A thorough clinical examination suggested absence of ectopia cordis, abdominal wall defect, and any bony anomaly. The child expired after 6 hours of admission because of respiratory distress and electrolyte imbalance. Is congenital defect of chest wall associated with diaphragmatic hernia without ectopia cordis and omphalocele, an unusual variant of Cantrell′s pentalogy?

  10. A Splice Variant of Bardet-Biedl Syndrome 5 (BBS5 Protein that Is Selectively Expressed in Retina.

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    Susan N Bolch

    Full Text Available Bardet-Biedl syndrome is a complex ciliopathy that usually manifests with some form of retinal degeneration, amongst other ciliary-related deficiencies. One of the genetic causes of this syndrome results from a defect in Bardet-Biedl Syndrome 5 (BBS5 protein. BBS5 is one component of the BBSome, a complex of proteins that regulates the protein composition in cilia. In this study, we identify a smaller molecular mass form of BBS5 as a variant formed by alternative splicing and show that expression of this splice variant is restricted to the retina.Reverse transcription PCR from RNA was used to isolate and identify potential alternative transcripts of Bbs5. A peptide unique to the C-terminus of the BBS5 splice variant was synthesized and used to prepare antibodies that selectively recognized the BBS5 splice variant. These antibodies were used on immunoblots of tissue extracts to determine the extent of expression of the alternative transcript and on tissue slices to determine the localization of expressed protein. Pull-down of fluorescently labeled arrestin1 by immunoprecipitation of the BBS5 splice variant was performed to assess functional interaction between the two proteins.PCR from mouse retinal cDNA using Bbs5-specific primers amplified a unique cDNA that was shown to be a splice variant of BBS5 resulting from the use of cryptic splicing sites in Intron 7. The resulting transcript codes for a truncated form of the BBS5 protein with a unique 24 amino acid C-terminus, and predicted 26.5 kD molecular mass. PCR screening of RNA isolated from various ciliated tissues and immunoblots of protein extracts from these same tissues showed that this splice variant was expressed in retina, but not brain, heart, kidney, or testes. Quantitative PCR showed that the splice variant transcript is 8.9-fold (+/- 1.1-fold less abundant than the full-length transcript. In the retina, the splice variant of BBS5 appears to be most abundant in the connecting cilium

  11. wKinMut-2: Identification and Interpretation of Pathogenic Variants in Human Protein Kinases

    DEFF Research Database (Denmark)

    Vazquez, Miguel; Pons, Tirso; Brunak, Søren

    2016-01-01

    forest approach. To understand the biological mechanisms causative of human diseases and cancer, information from pertinent reference knowledgebases and the literature is automatically mined, digested and homogenized. Variants are visualized in their structural contexts and residues affecting catalytic...... is often scattered across different sources, which makes the integrative analysis complex and laborious. wKinMut-2 constitutes a solution to facilitate the interpretation of the consequences of human protein kinase variation. Nine methods predict their pathogenicity, including a kinase-specific random...

  12. Novel RNA variants in colorectal cancers.

    Science.gov (United States)

    Hoff, Andreas M; Johannessen, Bjarne; Alagaratnam, Sharmini; Zhao, Sen; Nome, Torfinn; Løvf, Marthe; Bakken, Anne C; Hektoen, Merete; Sveen, Anita; Lothe, Ragnhild A; Skotheim, Rolf I

    2015-11-03

    With an annual estimated incidence of 1.4 million, and a five-year survival rate of 60%, colorectal cancer (CRC) is a major clinical burden. To identify novel RNA variants in CRC, we analyzed exon-level microarray expression data from a cohort of 202 CRCs. We nominated 25 genes with increased expression of their 3' parts in at least one cancer sample each. To efficiently investigate underlying transcript structures, we developed an approach using rapid amplification of cDNA ends followed by high throughput sequencing (RACE-seq). RACE products from the targeted genes in 23 CRC samples were pooled together and sequenced. We identified VWA2-TCF7L2, DHX35-BPIFA2 and CASZ1-MASP2 as private fusion events, and novel transcript structures for 17 of the 23 other candidate genes. The high-throughput approach facilitated identification of CRC specific RNA variants. These include a recurrent read-through fusion transcript between KLK8 and KLK7, and a splice variant of S100A2. Both of these were overrepresented in CRC tissue and cell lines from external RNA-seq datasets.

  13. [Dandy-Walker variant: Case report].

    Science.gov (United States)

    Cueva-Núñez, José E; Lozano-Bustillo, Alejandra; Irias-Álvarez, Merlyn S; Vásquez-Montes, Raúl F; Varela-González, Douglas M

    Dandy Walker variant is defined by a variable hypoplasia of the cerebellar vermix with or without posterior fossa increase and without tentorium elevation. describe the case of a rare disease and emphasise the need to clarify the aetiology of prenatal malformations, as well as its multidisciplinary management. A male patient, 8 years of age, with a history of Infantile Cerebral Palsy and epilepsy, who was admitted with a history of tonic-clonic seizures. He was admitted due to psycho-motor developmental delay. During his hospitalisation, he had multiple seizure episodes, controlled with anticonvulsants. A computerized tomography was performed, in which communication was observed between the cisterna magna and fourth ventricle (the latter increased in size). In addition, the cerebellar vermix showed a partial hypoplasia. All these findings were compatible with a variant of the Dandy Walker syndrome. Dandy Walker variant may be asymptomatic and the images found may not indicate them as the cause of developmental disorders, due to its association with multiple syndromes and chromosomal abnormalities. Clinical presentation and prognosis depends on the related disorders, and a multidisciplinary approach is important, because the treatment depends on the symptoms presented. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  14. The benefit of non contrast-enhanced magnetic resonance angiography for predicting vascular access surgery outcome: a computer model perspective.

    Science.gov (United States)

    Merkx, Maarten A G; Huberts, Wouter; Bosboom, E Mariëlle H; Bode, Aron S; Bescós, Javier Oliván; Tordoir, Jan H M; Breeuwer, Marcel; van de Vosse, Frans N

    2013-01-01

    Vascular access (VA) surgery, a prerequisite for hemodialysis treatment of end-stage renal-disease (ESRD) patients, is hampered by complication rates, which are frequently related to flow enhancement. To assist in VA surgery planning, a patient-specific computer model for postoperative flow enhancement was developed. The purpose of this study is to assess the benefit of non contrast-enhanced magnetic resonance angiography (NCE-MRA) data as patient-specific geometrical input for the model-based prediction of surgery outcome. 25 ESRD patients were included in this study. All patients received a NCE-MRA examination of the upper extremity blood vessels in addition to routine ultrasound (US). Local arterial radii were assessed from NCE-MRA and converted to model input using a linear fit per artery. Venous radii were determined with US. The effect of radius measurement uncertainty on model predictions was accounted for by performing Monte-Carlo simulations. The resulting flow prediction interval of the computer model was compared with the postoperative flow obtained from US. Patients with no overlap between model-based prediction and postoperative measurement were further analyzed to determine whether an increase in geometrical detail improved computer model prediction. Overlap between postoperative flows and model-based predictions was obtained for 71% of patients. Detailed inspection of non-overlapping cases revealed that the geometrical details that could be assessed from NCE-MRA explained most of the differences, and moreover, upon addition of these details in the computer model the flow predictions improved. The results demonstrate clearly that NCE-MRA does provide valuable geometrical information for VA surgery planning. Therefore, it is recommended to use this modality, at least for patients at risk for local or global narrowing of the blood vessels as well as for patients for whom an US-based model prediction would not overlap with surgical choice, as the

  15. Alternative splicing modulated by genetic variants demonstrates accelerated evolution regulated by highly conserved proteins.

    Science.gov (United States)

    Hsiao, Yun-Hua Esther; Bahn, Jae Hoon; Lin, Xianzhi; Chan, Tak-Ming; Wang, Rena; Xiao, Xinshu

    2016-04-01

    Identification of functional genetic variants and elucidation of their regulatory mechanisms represent significant challenges of the post-genomic era. A poorly understood topic is the involvement of genetic variants in mediating post-transcriptional RNA processing, including alternative splicing. Thus far, little is known about the genomic, evolutionary, and regulatory features of genetically modulated alternative splicing (GMAS). Here, we systematically identified intronic tag variants for genetic modulation of alternative splicing using RNA-seq data specific to cellular compartments. Combined with our previous method that identifies exonic tags for GMAS, this study yielded 622 GMAS exons. We observed that GMAS events are highly cell type independent, indicating that splicing-altering genetic variants could have widespread function across cell types. Interestingly, GMAS genes, exons, and single-nucleotide variants (SNVs) all demonstrated positive selection or accelerated evolution in primates. We predicted that GMAS SNVs often alter binding of splicing factors, with SRSF1 affecting the most GMAS events and demonstrating global allelic binding bias. However, in contrast to their GMAS targets, the predicted splicing factors are more conserved than expected, suggesting that cis-regulatory variation is the major driving force of splicing evolution. Moreover, GMAS-related splicing factors had stronger consensus motifs than expected, consistent with their susceptibility to SNV disruption. Intriguingly, GMAS SNVs in general do not alter the strongest consensus position of the splicing factor motif, except the more than 100 GMAS SNVs in linkage disequilibrium with polymorphisms reported by genome-wide association studies. Our study reports many GMAS events and enables a better understanding of the evolutionary and regulatory features of this phenomenon. © 2016 Hsiao et al.; Published by Cold Spring Harbor Laboratory Press.

  16. Microsatellite Instability Use in Mismatch Repair Gene Sequence Variant Classification

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    Bryony A. Thompson

    2015-03-01

    Full Text Available Inherited mutations in the DNA mismatch repair genes (MMR can cause MMR deficiency and increased susceptibility to colorectal and endometrial cancer. Microsatellite instability (MSI is the defining molecular signature of MMR deficiency. The clinical classification of identified MMR gene sequence variants has a direct impact on the management of patients and their families. For a significant proportion of cases sequence variants of uncertain clinical significance (also known as unclassified variants are identified, constituting a challenge for genetic counselling and clinical management of families. The effect on protein function of these variants is difficult to interpret. The presence or absence of MSI in tumours can aid in determining the pathogenicity of associated unclassified MMR gene variants. However, there are some considerations that need to be taken into account when using MSI for variant interpretation. The use of MSI and other tumour characteristics in MMR gene sequence variant classification will be explored in this review.

  17. Characterization of coding synonymous and non-synonymous variants in ADAMTS13 using ex vivo and in silico approaches.

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    Nathan C Edwards

    Full Text Available Synonymous variations, which are defined as codon substitutions that do not change the encoded amino acid, were previously thought to have no effect on the properties of the synthesized protein(s. However, mounting evidence shows that these "silent" variations can have a significant impact on protein expression and function and should no longer be considered "silent". Here, the effects of six synonymous and six non-synonymous variations, previously found in the gene of ADAMTS13, the von Willebrand Factor (VWF cleaving hemostatic protease, have been investigated using a variety of approaches. The ADAMTS13 mRNA and protein expression levels, as well as the conformation and activity of the variants have been compared to that of wild-type ADAMTS13. Interestingly, not only the non-synonymous variants but also the synonymous variants have been found to change the protein expression levels, conformation and function. Bioinformatic analysis of ADAMTS13 mRNA structure, amino acid conservation and codon usage allowed us to establish correlations between mRNA stability, RSCU, and intracellular protein expression. This study demonstrates that variants and more specifically, synonymous variants can have a substantial and definite effect on ADAMTS13 function and that bioinformatic analysis may allow development of predictive tools to identify variants that will have significant effects on the encoded protein.

  18. Functional Analysis of BARD1 Missense Variants in Homology-Directed Repair of DNA Double Strand Breaks.

    Science.gov (United States)

    Lee, Cindy; Banerjee, Tapahsama; Gillespie, Jessica; Ceravolo, Amanda; Parvinsmith, Matthew R; Starita, Lea M; Fields, Stanley; Toland, Amanda E; Parvin, Jeffrey D

    2015-12-01

    Genes associated with hereditary breast and ovarian cancer (HBOC) are often sequenced in search of mutations that are predictive of susceptibility to these cancer types, but the sequence results are frequently ambiguous because of the detection of missense substitutions for which the clinical impact is unknown. The BARD1 protein is the heterodimeric partner of BRCA1 and is included on clinical gene panels for testing for susceptibility to HBOC. Like BRCA1, it is required for homology-directed DNA repair (HDR). We measured the HDR function of 29 BARD1 missense variants, 27 culled from clinical test results and two synthetic variants. Twenty-three of the assayed variants were functional for HDR; of these, four are known neutral variants. Three variants showed intermediate function, and three others were defective in HDR. When mapped to BARD1 domains, residues crucial for HDR were located in the N- and C- termini of BARD1. In the BARD1 RING domain, critical residues mapped to the zinc-coordinating amino acids and to the BRCA1-BARD1 binding interface, highlighting the importance of interaction between BRCA1 and BARD1 for HDR activity. Based on these results, we propose that the HDR assay is a useful complement to genetic analyses to classify BARD1 variants of unknown clinical significance. © 2015 WILEY PERIODICALS, INC.

  19. Analysis of non-synonymous-coding variants of Parkinson's disease-related pathogenic and susceptibility genes in East Asian populations.

    Science.gov (United States)

    Foo, Jia Nee; Tan, Louis C; Liany, Herty; Koh, Tat Hung; Irwan, Ishak D; Ng, Yen Yek; Ahmad-Annuar, Azlina; Au, Wing-Lok; Aung, Tin; Chan, Anne Y Y; Chong, Siow-Ann; Chung, Sun Ju; Jung, Yusun; Khor, Chiea Chuen; Kim, Juyeon; Lee, Jimmy; Lim, Shen-Yang; Mok, Vincent; Prakash, Kumar-M; Song, Kyuyoung; Tai, E-Shyong; Vithana, Eranga N; Wong, Tien-Yin; Tan, Eng-King; Liu, Jianjun

    2014-07-15

    To evaluate the contribution of non-synonymous-coding variants of known familial and genome-wide association studies (GWAS)-linked genes for Parkinson's disease (PD) to PD risk in the East Asian population, we sequenced all the coding exons of 39 PD-related disease genes and evaluated the accumulation of rare non-synonymous-coding variants in 375 early-onset PD cases and 399 controls. We also genotyped 782 non-synonymous-coding variants of these genes in 710 late-onset PD cases and 9046 population controls. Significant enrichment of LRRK2 variants was observed in both early- and late-onset PD (odds ratio = 1.58; 95% confidence interval = 1.29-1.93; P = 8.05 × 10(-6)). Moderate enrichment was also observed in FGF20, MCCC1, GBA and ITGA8. Half of the rare variants anticipated to cause loss of function of these genes were present in healthy controls. Overall, non-synonymous-coding variants of known familial and GWAS-linked genes appear to make a limited contribution to PD risk, suggesting that clinical sequencing of these genes will provide limited information for risk prediction and molecular diagnosis. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database.

    Science.gov (United States)

    Betsalel, Ofir T; Rosenberg, Efraim H; Almeida, Ligia S; Kleefstra, Tjitske; Schwartz, Charles E; Valayannopoulos, Vassili; Abdul-Rahman, Omar; Poplawski, Nicola; Vilarinho, Laura; Wolf, Philipp; den Dunnen, Johan T; Jakobs, Cornelis; Salomons, Gajja S

    2011-01-01

    The X-linked creatine transporter defect is caused by mutations in the SLC6A8 gene. Until now, 66 synonymous and intronic variants in SLC6A8 were detected in our laboratory. To gain more insight in the effect of the detected variants, we applied five free web-based splice-site analysis tools to 25 published variants that were stratified as (non-)disease causing. All were correctly predicted to have no effect (n=18) or to cause erroneous splicing (n=7), with the exception of a pathogenic de novo 24 bp intronic deletion. Second, 41 unclassified variants, including 28 novel, were subjected to analysis by these tools. At least four splice-site analysis tools predicted that three of the variants would affect splicing as the mutations disrupted the canonical splice site. Urinary creatine/creatinine and brain MRS confirmed creatine transporter deficiency in five patients (four families), including one female. Another variant was predicted to moderately affect splicing by all five tools. However, transient transfection of a minigene containing the variant in a partial SLC6A8 segment showed no splicing errors, and thus was finally classified as non-disease causing. This study shows that splice tools are useful for the characterization of the majority of variants, but also illustrates that the actual effect can be misclassified in rare occasions. Therefore, further laboratory studies should be considered before final conclusions on the disease-causing nature are drawn. To provide an accessible database, the 109 currently known SLC6A8 variants, including 35 novel ones, are included in a newly developed LOVD DNA variation database.

  1. Interdisciplinary Analysis of HIV-Specific CD8(+) T Cell Responses against Variant Epitopes Reveals Restricted TCR Promiscuity

    DEFF Research Database (Denmark)

    Hoof, Ilka; Perez, C.L.; Buggert, M.

    2010-01-01

    positions in the epitope were particularly likely to result in abrogation of recognition. In summary, the presented data demonstrate a highly restricted promiscuity of HIV-1 specific CTL in the recognition of variant epitopes. In addition, our results illustrate that bioinformatic prediction methods...

  2. COMT Val[superscript 108/158] Met Gene Variant, Birth Weight, and Conduct Disorder in Children with ADHD

    Science.gov (United States)

    Sengupta, Sarojini M.; Grizenko, Natalie; Schmitz, Norbert; Schwartz, George; Amor, Leila Ben; Bellingham, Johanne; de Guzman, Rosherrie; Polotskaia, Anna; Stepanian, Marina Ter; Thakur, Geeta; Joober, Ridha

    2006-01-01

    Objective: In a recent study, Thapar and colleagues reported that COMT "gene variant and birth weight predict early-onset antisocial behavior in children" with attention-deficit/hyperactivity disorder. We have attempted to replicate these findings in a group of ADHD children using a similar research design. Method: Children (n = 191)…

  3. The relationship between the GJB3 c.538C>T variant and hearing phenotype in the Chinese population.

    Science.gov (United States)

    Huang, Shasha; Huang, Bangqing; Wang, Guojian; Kang, Dong Yang; Zhang, Xin; Meng, Xiaoxiao; Dai, Pu

    2017-11-01

    Mutations in GJB3 were originally shown to underlie an autosomal dominant form of non-syndromic deafness in Chinese patients and the c.538C>T (p.R180*) variants caused high-frequency hearing loss. But after that, few reports have reported this mutation. This study investigated the relationship between the GJB3 c.538C>T variant and hearing phenotype in Chinese to assist with risk assessment and genetic counseling for hearing loss patients and their families. The study enrolled 5700 patients with hearing loss and 4600 normal subjects. Deafness gene mutations were distinguished using a gene chip. The GJB3 c.538C>T variant rate was calculated from the results. Of the 5700 patients, 23 (0.40%) carried a GJB3 c.538C>T heterozygous variant; of these, 11 patients had other gene (GJB2/SLC26A4) mutations simultaneously. Most patients had moderate to profound hearing loss. All 23 patients were sporadic cases and had no family history of deafness. Of the 4600 normal individuals, 11 (0.24%) had GJB3 c.538C>T heterozygous variant. There was no statistical difference in incidence between the two groups. Our results showed that the GJB3 c.538C>T variant has a very low incidence in the Chinese population, and there was no clear evidence to support a role of the GJB3 c.538C>T variant in the autosomal dominant form of non-syndromic deafness. Our findings suggested that GJB3 c.538C>T does not contribute to hearing loss, and this conclusion will assist with genetic counseling and risk prediction for deafness related to the GJB3 c.538C>T variant. Copyright © 2017. Published by Elsevier B.V.

  4. Rare, Potentially Pathogenic Variants in ZNF469 Are Not Enriched in Keratoconus in a Large Australian Cohort of European Descent.

    Science.gov (United States)

    Lucas, Sionne E M; Zhou, Tiger; Blackburn, Nicholas B; Mills, Richard A; Ellis, Jonathan; Leo, Paul; Souzeau, Emmanuelle; Ridge, Bronwyn; Charlesworth, Jac C; Brown, Matthew A; Lindsay, Richard; Craig, Jamie E; Burdon, Kathryn P

    2017-12-01

    The Zinc Finger Protein 469 (ZNF469) gene has been proposed as a candidate gene for keratoconus due to the association of an upstream polymorphism (rs9938149) with the disease in two independent studies, and the role of the gene in the autosomal recessive disease Brittle Cornea Syndrome. Coding variants in ZNF469 have been assessed for association with keratoconus in several small studies, with conflicting results. We assessed rare, potentially pathogenic variants in ZNF469 for enrichment in keratoconus patients in a cohort larger than all previous studies combined. ZNF469 was sequenced in 385 Australian keratoconus patients of European descent, 346 population controls, and 230 ethnically matched screened controls by either whole exome sequencing or targeted gene sequencing. The frequency of rare and very rare potentially pathogenic variants was compared between cases and controls using χ2 or Fisher's exact tests and further explored using a gene based test (Sequence Kernel Association Test [SKAT]), weighting on the rarity of variants. A total of 49 rare, including 33 very rare, potentially pathogenic variants were identified across all groups. No enrichment of rare or very rare potentially pathogenic variants in ZNF469 was observed in our cases compared to the control groups following analysis using χ2 or Fisher's exact tests. This finding was further supported by the SKAT results, which found no significant difference in the frequency of variants predicted to be damaging between cases and either control group (P = 0.06). Rare variants in ZNF469 do not contribute to keratoconus susceptibility and do not account for the association at rs9938149.

  5. Screening for coding variants in FTO and SH2B1 genes in Chinese patients with obesity.

    Directory of Open Access Journals (Sweden)

    Zhaojing Zheng

    Full Text Available To investigate potential functional variants in FTO and SH2B1 genes among Chinese children with obesity.Sanger sequencing of PCR products of all FTO and SH2B1 exons and their flanking regions were performed in 338 Chinese Han children with obesity and 221 age- and sex-matched lean controls.A total of seven and five rare non-synonymous variants were identified in FTO and SH2B1, respectively. The overall frequencies of FTO and SH2B1 rare non-synonymous variants were similar in obese and lean children (2.37% and 0.90% vs. 1.81% and 1.36%, P>0.05. However, four out of the seven variants in FTO were novel and all were unique to obese children (p>0.05. None of the novel variants was consistently being predicted to be deleterious. Four out of five variants in SH2B1 were novel and one was unique to obese children (p>0.05. One variant (L293R that was consistently being predicted as deleterious in SH2B1 gene was unique to lean control. While rare missense mutations were more frequently detected in girls from obesity as well as lean control than boys, the difference was not statistically significant. In addition, it's shown that the prevalence of rare missense mutations of FTO as well as SH2B1 was similar across different ethnic groups.The rare missense mutations of FTO and SH2B1 did not confer risks of obesity in Chinese Han children in our cohort.

  6. Production and characterization of genetically modified human IL-11 variants.

    Science.gov (United States)

    Sano, Emiko; Takei, Toshiaki; Ueda, Takuya; Tsumoto, Kouhei

    2017-02-01

    Interleukin-11 (IL-11) has been expected as a drug on severe thrombocytopenia caused by myelo-suppressive chemotherapy. Whereas, development of IL-11 inhibitor is also expected for a treatment against IL-11 related cancer progression. Here, we will demonstrate the creation of various kinds of genetically modified hIL-11s. Modified vectors were constructed by introducing N- or O-glycosylation site on the region of hIL-11 that does not belong to the core α-helical motif based on the predicted secondary structure. N-terminal (N: between 22 to 23 aa), the first loop (M1:70 to 71 aa), the second loop (M2:114-115 aa), the third loop (M3:160-161 aa) and C-terminal (C: 200- aa) were selected for modification. A large scale production system was established and the characteristics of modified hIL-11s were evaluated. The structure was analyzed by amino acid sequence and composition analysis and CD-spectra. Glycan was assessed by monosaccharide composition analysis. Growth promoting activity and biological stability were analyzed by proliferation of T1165 cells. N-terminal modified proteins were well glycosylated and produced. Growth activity of 3NN with NASNASNAS sequence on N-terminal was about tenfold higher than wild type (WT). Structural and biological stabilities of 3NN were also better than WT and residence time in mouse blood was longer than WT. M1 variants lacked growth activity though they are well glycosylated and secondary structure is very stable. Both of 3NN and OM1 with AAATPAPG on M1 associated with hIL-11R strongly. These results indicate N-terminal and M1 variants will be expected for practical use as potent agonists or antagonists of hIL-11. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors

    Science.gov (United States)

    Bahl, Ethan; Hannah, Claire; Hofammann, Dabney; Acevedo, Summer; Cui, Huxing; McAdams, Carrie J.

    2017-01-01

    Objective Eating disorders develop through a combination of genetic vulnerability and environmental stress, however the genetic basis of this risk is unknown. Methods To understand the genetic basis of this risk, we performed whole exome sequencing on 93 unrelated individuals with eating disorders (38 restricted-eating and 55 binge-eating) to identify novel damaging variants. Candidate genes with an excessive burden of predicted damaging variants were then prioritized based upon an unbiased, data-driven bioinformatic analysis. One top candidate pathway was empirically tested for therapeutic potential in a mouse model of binge-like eating. Results An excessive burden of novel damaging variants was identified in 186 genes in the restricted-eating group and 245 genes in the binge-eating group. This list is significantly enriched (OR = 4.6, peating. Conclusions These findings implicate ultra-rare and novel damaging variants in neuropeptide/neurotropic factor signaling pathways in the development of eating disorder behaviors and identify glucagon-like peptide 1-receptor agonists as a potential treatment for binge eating. PMID:28846695

  8. Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder.

    Directory of Open Access Journals (Sweden)

    René A W Frank

    2011-04-01

    Full Text Available Current models of schizophrenia and bipolar disorder implicate multiple genes, however their biological relationships remain elusive. To test the genetic role of glutamate receptors and their interacting scaffold proteins, the exons of ten glutamatergic 'hub' genes in 1304 individuals were re-sequenced in case and control samples. No significant difference in the overall number of non-synonymous single nucleotide polymorphisms (nsSNPs was observed between cases and controls. However, cluster analysis of nsSNPs identified two exons encoding the cysteine-rich domain and first transmembrane helix of GRM1 as a risk locus with five mutations highly enriched within these domains. A new splice variant lacking the transmembrane GPCR domain of GRM1 was discovered in the human brain and the GRM1 mutation cluster could perturb the regulation of this variant. The predicted effect on individuals harbouring multiple mutations distributed in their ten hub genes was also examined. Diseased individuals possessed an increased load of deleteriousness from multiple concurrent rare and common coding variants. Together, these data suggest a disease model in which the interplay of compound genetic coding variants, distributed among glutamate receptors and their interacting proteins, contribute to the pathogenesis of schizophrenia and bipolar disorders.

  9. A Comparison of Variant Calling Pipelines Using Genome in a Bottle as a Reference

    Directory of Open Access Journals (Sweden)

    Adam Cornish

    2015-01-01

    Full Text Available High-throughput sequencing, especially of exomes, is a popular diagnostic tool, but it is difficult to determine which tools are the best at analyzing this data. In this study, we use the NIST Genome in a Bottle results as a novel resource for validation of our exome analysis pipeline. We use six different aligners and five different variant callers to determine which pipeline, of the 30 total, performs the best on a human exome that was used to help generate the list of variants detected by the Genome in a Bottle Consortium. Of these 30 pipelines, we found that Novoalign in conjunction with GATK UnifiedGenotyper exhibited the highest sensitivity while maintaining a low number of false positives for SNVs. However, it is apparent that indels are still difficult for any pipeline to handle with none of the tools achieving an average sensitivity higher than 33% or a Positive Predictive Value (PPV higher than 53%. Lastly, as expected, it was found that aligners can play as vital a role in variant detection as variant callers themselves.

  10. Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors.

    Directory of Open Access Journals (Sweden)

    Michael Lutter

    Full Text Available Eating disorders develop through a combination of genetic vulnerability and environmental stress, however the genetic basis of this risk is unknown.To understand the genetic basis of this risk, we performed whole exome sequencing on 93 unrelated individuals with eating disorders (38 restricted-eating and 55 binge-eating to identify novel damaging variants. Candidate genes with an excessive burden of predicted damaging variants were then prioritized based upon an unbiased, data-driven bioinformatic analysis. One top candidate pathway was empirically tested for therapeutic potential in a mouse model of binge-like eating.An excessive burden of novel damaging variants was identified in 186 genes in the restricted-eating group and 245 genes in the binge-eating group. This list is significantly enriched (OR = 4.6, p<0.0001 for genes involved in neuropeptide/neurotrophic pathways implicated in appetite regulation, including neurotensin-, glucagon-like peptide 1- and BDNF-signaling. Administration of the glucagon-like peptide 1 receptor agonist exendin-4 significantly reduced food intake in a mouse model of 'binge-like' eating.These findings implicate ultra-rare and novel damaging variants in neuropeptide/neurotropic factor signaling pathways in the development of eating disorder behaviors and identify glucagon-like peptide 1-receptor agonists as a potential treatment for binge eating.

  11. The burden of multiple sclerosis variants in continental Italians and Sardinians.

    Science.gov (United States)

    Barizzone, Nadia; Zara, Ilenia; Sorosina, Melissa; Lupoli, Sara; Porcu, Eleonora; Pitzalis, Maristella; Zoledziewska, Magdalena; Esposito, Federica; Leone, Maurizio; Mulas, Antonella; Cocco, Eleonora; Ferrigno, Paola; Guerini, Franca R; Brambilla, Paola; Farina, Gabriele; Murru, Raffaele; Deidda, Francesca; Sanna, Sonia; Loi, Alessia; Barlassina, Cristina; Vecchio, Domizia; Zauli, Andrea; Clarelli, Ferdinando; Braga, Daniele; Poddie, Fausto; Cantello, Roberto; Martinelli, Vittorio; Comi, Giancarlo; Frau, Jessica; Lorefice, Lorena; Pugliatti, Maura; Rosati, Giulio; Melis, Maurizio; Marrosu, Maria G; Cusi, Daniele; Cucca, Francesco; Martinelli Boneschi, Filippo; Sanna, Serena; D'Alfonso, Sandra

    2015-10-01

    Recent studies identified > 100 non-HLA (human leukocyte antigen) multiple sclerosis (MS) susceptibility variants in Northern European populations, but their role in Southern Europeans is largely unexplored. We aimed to investigate the cumulative impact of those variants in two Mediterranean populations: Continental Italians and Sardinians. We calculated four weighted Genetic Risk Scores (wGRS), using up to 102 non-HLA MS risk variants and 5 HLA MS susceptibility markers in 1691 patients and 2194 controls from continental Italy; and 2861 patients and 3034 controls from Sardinia. We then assessed the differences between populations using Nagelkerke's R(2) and the area under the Receiver Operating Characteristic (ROC) curves. As expected, the genetic burden (mean wGRS value) was significantly higher in MS patients than in controls, in both populations. Of note, the burden was significantly higher in Sardinians. Conversely, the proportion of variability explained and the predictive power were significantly higher in continental Italians. Notably, within the Sardinian patients, we also observed a significantly higher burden of non-HLA variants in individuals who do not carry HLA risk alleles. The observed differences in MS genetic burden between the two Mediterranean populations highlight the need for more genetic studies in South Europeans, to further expand the knowledge of MS genetics. © The Author(s), 2015.

  12. Identification of novel variants in LRRK2 gene in patients with Parkinson's disease in Serbian population.

    Science.gov (United States)

    Janković, Milena Z; Kresojević, Nikola D; Dobričić, Valerija S; Marković, Vladana V; Petrović, Igor N; Novaković, Ivana V; Kostić, Vladimir S

    2015-01-01

    Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most common cause of autosomal dominant Parkinson's disease (PD). Large international studies have revealed that pathogenic mutations are clustered in several exons coding for functional domains of LRRK2 protein, but the mutation frequency differs among populations. Systematic study of LRRK2 mutation prevalence and phenotype in Serbian population has not been performed. Comprehensive mutation screening of selected exons of LRRK2 was performed in 486 Serbian PD patients. Previously reported mutations I1371V and G2019S were identified in a single patient each, and c.4536+3A>G substitution in two patients. G2019S is the most common, pathogenic mutation, while pathogenic roles for recurrent variants I1371V and c.4536+3A>G are not confirmed yet. Two novel variants S1508G and I1991V were discovered in 2 unrelated patients. These variants are considered as disease causing according to several software predictions, but additional segregation and functional analyses are required. Mutation frequency in our study (1.23%) was similar to other European populations, although the most common mutations were underestimated and novel variants were detected. In most cases, symptoms of LRRK2-PD are similar to sporadic PD, so estimation of frequency and penetrance of mutations in different populations is important for efficient genetic testing strategy and counseling. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Melanoma risk associated with MC1R gene variants in Latvia and the functional analysis of rare variants.

    Science.gov (United States)

    Ozola, Aija; Azarjana, Kristīne; Doniņa, Simona; Proboka, Guna; Mandrika, Ilona; Petrovska, Ramona; Cēma, Ingrīda; Heisele, Olita; Eņģele, Ludmila; Streinerte, Baiba; Pjanova, Dace

    2013-03-01

    To evaluate the association of melanocortin 1 receptor gene (MC1R) variants with melanoma risk in a Latvian population, the MC1R gene was sequenced in 200 melanoma patients and 200 control persons. A functional study of previously uncharacterized, rare MC1R variants was also performed. In total, 26 different MC1R variants, including two novel variants Val165Ile and Val188Ile, were detected. The highest risk of melanoma was associated with the Arg151Cys variant (odds ratio (OR) 4.47, 95% confidence interval (CI) 2.19-9.14, PMC1R variants revealed that a subset of them is functionally relevant. Our results support the contribution of MC1R variants to a genetic predisposition to melanoma in Latvia. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. A genetic risk score of 45 coronary artery disease risk variants associates with increased risk of myocardial infarction in 6041 Danish individuals

    DEFF Research Database (Denmark)

    Krarup, N T; Borglykke, A; Allin, K H

    2015-01-01

    BACKGROUND: In Europeans, 45 genetic risk variants for coronary artery disease (CAD) have been identified in genome-wide association studies. We constructed a genetic risk score (GRS) of these variants to estimate the effect on incidence and clinical predictability of myocardial infarction (MI......) and CAD. METHODS: Genotype was available from 6041 Danes. An unweighted GRS was constructed by making a summated score of the 45 known genetic CAD risk variants. Registries provided information (mean follow-up = 11.6 years) on CAD (n = 374) and MI (n = 124) events. Cox proportional hazard estimates...

  15. Haplotype diversity in the equine myostatin gene with focus on variants associated with race distance propensity and muscle fiber type proportions

    OpenAIRE

    Petersen, Jessica L.; Valberg, Stephanie J; Mickelson, James R.; McCue, Molly E.

    2014-01-01

    Two variants in the equine myostatin gene (MSTN), including a T/C SNP substitution in the first intron and a 227-bp SINE insertion in the promoter, are associated with muscle fiber type proportions in the Quarter Horse (QH) and with the prediction of race distance propensity in the Thoroughbred (TB). Genotypes from these loci, along with 18 additional variants surrounding MSTN, were examined in 301 horses of 14 breeds to evaluate haplotype relationships and diversity. The C allele of intron 1...

  16. KinMutRF: a random forest classifier of sequence variants in the human protein kinase superfamily.

    Science.gov (United States)

    Pons, Tirso; Vazquez, Miguel; Matey-Hernandez, María Luisa; Brunak, Søren; Valencia, Alfonso; Izarzugaza, Jose Mg

    2016-06-23

    The association between aberrant signal processing by protein kinases and human diseases such as cancer was established long time ago. However, understanding the link between sequence variants in the protein kinase superfamily and the mechanistic complex traits at the molecular level remains challenging: cells tolerate most genomic alterations and only a minor fraction disrupt molecular function sufficiently and drive disease. KinMutRF is a novel random-forest method to automatically identify pathogenic variants in human kinases. Twenty six decision trees implemented as a random forest ponder a battery of features that characterize the variants: a) at the gene level, including membership to a Kinbase group and Gene Ontology terms; b) at the PFAM domain level; and c) at the residue level, the types of amino acids involved, changes in biochemical properties, functional annotations from UniProt, Phospho.ELM and FireDB. KinMutRF identifies disease-associated variants satisfactorily (Acc: 0.88, Prec:0.82, Rec:0.75, F-score:0.78, MCC:0.68) when trained and cross-validated with the 3689 human kinase variants from UniProt that have been annotated as neutral or pathogenic. All unclassified variants were excluded from the training set. Furthermore, KinMutRF is discussed with respect to two independent kinase-specific sets of mutations no included in the training and testing, Kin-Driver (643 variants) and Pon-BTK (1495 variants). Moreover, we provide predictions for the 848 protein kinase variants in UniProt that remained unclassified. A public implementation of KinMutRF, including documentation and examples, is available online ( http://kinmut2.bioinfo.cnio.es ). The source code for local installation is released under a GPL version 3 license, and can be downloaded from https://github.com/Rbbt-Workflows/KinMut2 . KinMutRF is capable of classifying kinase variation with good performance. Predictions by KinMutRF compare favorably in a benchmark with other state

  17. Homocysteine as a predictive biomarker in early diagnosis of renal failure susceptibility and prognostic diagnosis for end stages renal disease.

    Science.gov (United States)

    Amin, Hatem K; El-Sayed, Mohamed-I Kotb; Leheta, Ola F

    2016-09-01

    Glomerular filtration rate and/or creatinine are not accurate methods for renal failure prediction. This study tested homocysteine (Hcy) as a predictive and prognostic marker for end stage renal disease (ESRD). In total, 176 subjects were recruited and divided into: healthy normal group (108 subjects); mild-to-moderate impaired renal function group (21 patients); severe impaired renal function group (7 patients); and chronic renal failure group (40 patients) who were on regular hemodialysis. Blood samples were collected, and serum was separated for analysis of total Hcy, creatinine, high sensitive C-reactive protein (CRP), serum albumin, and calcium. Data showed that Hcy level was significantly increased from normal-to-mild impairment then significantly decreases from mild impairment until the patient reaches severe impairment while showing significant elevation in the last stage of chronic renal disease. Creatinine level was increased in all stages of kidney impairment in comparison with control. CRP level was showing significant elevation in the last stage. A significant decrease in both albumin and calcium was occurred in all stages of renal impairment. We conclude Hcy in combination with CRP, creatinine, albumin, and calcium can be used as a prognostic marker for ESRD and an early diagnostic marker for the risk of renal failure.

  18. Research progress of behavioral variant frontotemporal dementia

    Directory of Open Access Journals (Sweden)

    Xiao-hua GU

    2015-07-01

    Full Text Available There is no epidemiological data of frontotemporal dementia (FTD in China. The application of updated diagnostic criteria, publishing of frontotemporal lobar degeneration (FTLD consensus in China, development of multimodal imaging and biomarkers promote the clinical understanding on behavioral variant frontotemporal dementia (bvFTD. There is still no drugs treating FTD approved by U.S. Food and Drug Administration (FDA. Multidisciplinary intervention may delay the progression of bvFTD. DOI: 10.3969/j.issn.1672-6731.2015.07.006

  19. Space-variant polarized Airy beam

    CERN Document Server

    Chen, Hao

    2015-01-01

    We experimentally generate an Airy beam with polarization structure while keeping its original amplitude and phase profile intact. This class of Airy beam preserves the acceleration properties. By monitoring their initial polarization structure we have provided insight concerning the self-healing mechanism of Airy beams. We investigate both theoretically and experimentally the self-healing polarization properties of the space-variant polarized Airy beams. Amplitude as well as the polarization structure tends to reform during propagation in spite of the severe truncation of the beam by finite apertures.

  20. Sex steroids and variants of gender identity.

    Science.gov (United States)

    Meyer-Bahlburg, Heino F L

    2013-09-01

    This article summarizes for the practicing endocrinologist the current literature on the psychobiology of the development of gender identity and its variants in individuals with disorders of sex development (DSD) or with non-DSD transgenderism. Gender reassignment remains the treatment of choice for strong and persistent gender dysphoria in both categories, but more research is needed on the short-term and long-term effects of puberty-suppressing medications and cross-sex hormones on brain and behavior. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Genetic variants associated with lung function

    DEFF Research Database (Denmark)

    Thyagarajan, Bharat; Wojczynski, Mary; Minster, Ryan L

    2014-01-01

    BACKGROUND: Reduced forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) are strong predictors of mortality and lung function is higher among individuals with exceptional longevity. However, genetic factors associated with lung function in individuals...... with exceptional longevity have not been identified. METHOD: We conducted a genome wide association study (GWAS) to identify novel genetic variants associated with lung function in the Long Life Family Study (LLFS) (n = 3,899). Replication was performed using data from the CHARGE/SpiroMeta consortia...

  2. Performance comparison of various time variant filters

    Energy Technology Data Exchange (ETDEWEB)

    Kuwata, M. [JEOL Engineering Co. Ltd., Akishima, Tokyo (Japan); Husimi, K.

    1996-07-01

    This paper describes the advantage of the trapezoidal filter used in semiconductor detector system comparing with the other time variant filters. The trapezoidal filter is the compose of a rectangular pre-filter and a gated integrator. We indicate that the best performance is obtained by the differential-integral summing type rectangular pre-filter. This filter is not only superior in performance, but also has the useful feature that the rising edge of the output waveform is linear. We introduce an example of this feature used in a high-energy experiment. (author)

  3. Oral fibrolipoma: A rare histological variant

    Directory of Open Access Journals (Sweden)

    Treville Pereira

    2014-01-01

    Full Text Available Lipomas are benign soft tissue mesenchymal neoplasms. Fibrolipoma is a histological variant of lipoma that mostly affects the buccal mucosa and causes functional and cosmetic disabilities. The diagnosis and differentiation of fibrolipoma with clinically similar lesions such as fibroma and pleomorphic adenoma is very essential for a correct treatment plan and complete follow-up. This article presents a case of a 35-year-old female with a fibrolipoma on the lingual marginal gingiva of the mandibular left third molar.

  4. Predicting mortality in patients with diabetes starting dialysis.

    Directory of Open Access Journals (Sweden)

    Merel van Diepen

    Full Text Available BACKGROUND: While some prediction models have been developed for diabetic populations, prediction rules for mortality in diabetic dialysis patients are still lacking. Therefore, the objective of this study was to identify predictors for 1-year mortality in diabetic dialysis patients and use these results to develop a prediction model. METHODS: Data were used from the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD, a multicenter, prospective cohort study in which incident patients with end stage renal disease (ESRD were monitored until transplantation or death. For the present analysis, patients with DM at baseline were included. A prediction algorithm for 1-year all-cause mortality was developed through multivariate logistic regression. Candidate predictors were selected based on literature and clinical expertise. The final model was constructed through backward selection. The model's predictive performance, measured by calibration and discrimination, was assessed and internally validated through bootstrapping. RESULTS: A total of 394 patients were available for statistical analysis; 82 (21% patients died within one year after baseline (3 months after starting dialysis therapy. The final prediction model contained seven predictors; age, smoking, history of macrovascular complications, duration of diabetes mellitus, Karnofsky scale, serum albumin and hemoglobin level. Predictive performance was good, as shown by the c-statistic of 0.810. Internal validation showed a slightly lower, but still adequate performance. Sensitivity analyses showed stability of results. CONCLUSIONS: A prediction model containing seven predictors has been identified in order to predict 1-year mortality for diabetic incident dialysis patients. Predictive performance of the model was good. Before implementing the model in clinical practice, for example for counseling patients regarding their prognosis, external validation is necessary.

  5. ESRD Quality Incentive Program Public Reporting

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Medicare Improvements for Patients and Providers Act (MIPPA) of 2008 requires that CMS and facilities inform beneficiaries about facility performance under the...

  6. ESRD - Clinical Performance Measures (CPM) Project

    Data.gov (United States)

    U.S. Department of Health & Human Services — Section 4558 (b) of the Balanced Budget Act (BBA) requires CMS to develop and implement by January 1, 2000, a method to measure and report the quality of renal...

  7. Bicarbonate Balance and Prescription in ESRD.

    Science.gov (United States)

    Abramowitz, Matthew K

    2017-03-01

    The optimal approach to managing acid-base balance is less well defined for patients receiving hemodialysis than for those receiving peritoneal dialysis. Interventional studies in hemodialysis have been limited and inconsistent in their findings, whereas more compelling data are available from interventional studies in peritoneal dialysis. Both high and low serum bicarbonate levels associate with an increased risk of mortality in patients receiving hemodialysis, but high values are a marker for poor nutrition and comorbidity and are often highly variable from month to month. Measurement of pH would likely provide useful additional data. Concern has arisen regarding high-bicarbonate dialysate and dialysis-induced alkalemia, but whether these truly cause harm remains to be determined. The available evidence is insufficient for determining the optimal target for therapy at this time. Copyright © 2017 by the American Society of Nephrology.

  8. ESRD QIP - Vascular Access - Payment Year 2018

    Data.gov (United States)

    U.S. Department of Health & Human Services — This dataset includes facility details, performance rates, vascular access topic measure score, and the state and national average measure scores for the vascular...

  9. ESRD QIP - Dialysis Adequacy - Payment Year 2018

    Data.gov (United States)

    U.S. Department of Health & Human Services — This dataset includes facility details, performance rate, dialysis adequacy topic measure score, and the state and national average measure scores for the dialysis...

  10. Update of the pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants.

    Science.gov (United States)

    Kroos, Marian; Hoogeveen-Westerveld, Marianne; Michelakakis, Helen; Pomponio, Robert; Van der Ploeg, Ans; Halley, Dicky; Reuser, Arnold

    2012-08-01

    Pompe disease is an autosomal recessive lysosomal glycogen storage disorder, characterized by progressive muscle weakness. Deficiency of acid α-glucosidase (EC; 3.2.1.20/3) can be caused by numerous pathogenic variants in the GAA gene. The Pompe Disease Mutation Database at http://www.pompecenter.nl aims to list all variants and their effect. This update reports on 94 variants. We examined 35 novel and 34 known mutations by site-directed mutagenesis and transient expression in COS-7 cells or HEK293T cells. Each of these mutations was given a severity rating using a previously published system, based on the level of acid α-glucosidase activity in medium and transfected cells and on the quantity and quality of the different molecular mass species in the posttranslational modification and transport of acid α-glucosidase. This approach enabled to classify 55 missense mutations as pathogenic and 13 as likely nonpathogenic. Based on their nature and the use of in silico analysis (Alamut® software), 12 of the additional 25 novel mutations were predicted to be pathogenic including 4 splicing mutations, 6 mutations leading to frameshift, and 2 point mutations causing stop codons. Seven of the additional mutations were considered nonpathogenic (4 silent and 3 occurring in intron regions), and 6 are still under investigation. © 2012 Wiley Periodicals, Inc.

  11. Association between MTHFR variant and diabetic neuropathy.

    Science.gov (United States)

    Kakavand Hamidi, Armita; Radfar, Mania; Amoli, Mahsa M

    2017-04-26

    Methylene-tetrahydrofolate reductase (MTHFR) gene variant may play an important role in the pathophysiology of diabetes and its complications due to its influence on plasma homocysteine levels and also its effect on scavenging peroxynitrite radicals. Diabetic peripheral neuropathy (DPN) is one of the most common diabetic chronic complications. The aim of this study was to investigate the relationship between diabetic neuropathy and MTHFR gene C677T and 1298A ⁄C polymorphisms. Patients with type 2 diabetes N=248 were enrolled in the study, consisting of patients with neuropathy (N=141) and patients without neuropathy (N=107). MTHFR C677T polymorphism was analyzed using polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) of genomic DNA for genotyping of samples. 1298A/C polymorphism was evaluated using ARMS-PCR. There was a significant difference in MTHFR polymorphism between the groups with and without neuropathy. Our results suggest that MTHFR 677 variant confer risk for diabetic neuropathy among Iranian patients with type 2 diabetes. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  12. A TIMP-1 splice variant transcript

    DEFF Research Database (Denmark)

    Øbro, Nina Friesgård; Lademann, Ulrik Axel; Birkenkamp-Demtroder, Karin

    2008-01-01

    A splice variant of tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA lacking exon 2 (TIMP-1-v2) has been identified in human cancer cells and in colorectal and breast cancer tumors. The purpose of this study was (1) to study the level of full length TIMP-1 and TIMP-1-v2 transcripts in color...... of TIMP-1 pre-mRNA to TIMP-1-v2 mRNA might be involved in regulating TIMP-1 expression.......A splice variant of tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA lacking exon 2 (TIMP-1-v2) has been identified in human cancer cells and in colorectal and breast cancer tumors. The purpose of this study was (1) to study the level of full length TIMP-1 and TIMP-1-v2 transcripts...... in colorectal tumors; (2) to investigate if TIMP-1-v2 is translated to protein. Full length TIMP-1 and TIMP-1-v2 mRNA levels were compared between colorectal tumors and normal mucosa by Q-PCR. Both full length TIMP-1 and TIMP-1-v2 transcripts were upregulated in tumor tissue. However, the level of TIMP-1-v2...

  13. COMT gene locus: new functional variants

    Science.gov (United States)

    Meloto, Carolina B.; Segall, Samantha K.; Smith, Shad; Parisien, Marc; Shabalina, Svetlana A.; Rizzatti-Barbosa, Célia M.; Gauthier, Josée; Tsao, Douglas; Convertino, Marino; Piltonen, Marjo H.; Slade, Gary Dmitri; Fillingim, Roger B.; Greenspan, Joel D.; Ohrbach, Richard; Knott, Charles; Maixner, William; Zaykin, Dmitri; Dokholyan, Nikolay V.; Reenilä, Ilkka; Männistö, Pekka T.; Diatchenko, Luda

    2015-01-01

    Abstract Catechol-O-methyltransferase (COMT) metabolizes catecholaminergic neurotransmitters. Numerous studies have linked COMT to pivotal brain functions such as mood, cognition, response to stress, and pain. Both nociception and risk of clinical pain have been associated with COMT genetic variants, and this association was shown to be mediated through adrenergic pathways. Here, we show that association studies between COMT polymorphic markers and pain phenotypes in 2 independent cohorts identified a functional marker, rs165774, situated in the 3′ untranslated region of a newfound splice variant, (a)-COMT. Sequence comparisons showed that the (a)-COMT transcript is highly conserved in primates, and deep sequencing data demonstrated that (a)-COMT is expressed across several human tissues, including the brain. In silico analyses showed that the (a)-COMT enzyme features a distinct C-terminus structure, capable of stabilizing substrates in its active site. In vitro experiments demonstrated not only that (a)-COMT is catalytically active but also that it displays unique substrate specificity, exhibiting enzymatic activity with dopamine but not epinephrine. They also established that the pain-protective A allele of rs165774 coincides with lower COMT activity, suggesting contribution to decreased pain sensitivity through increased dopaminergic rather than decreased adrenergic tone, characteristic of reference isoforms. Our results provide evidence for an essential role of the (a)-COMT isoform in nociceptive signaling and suggest that genetic variations in (a)-COMT isoforms may contribute to individual variability in pain phenotypes. PMID:26207649

  14. Anatomic variants in Dandy-Walker complex.

    Science.gov (United States)

    Jurcă, Maria Claudia; Kozma, Kinga; Petcheşi, CodruŢa Diana; Bembea, Marius; Pop, Ovidiu Laurean; MuŢiu, Gabriela; Coroi, Mihaela Cristiana; Jurcă, Alexandru Daniel; Dobjanschi, Luciana

    2017-01-01

    Dandy-Walker complex (DWC) is a malformative association of the central nervous system. DWC includes four different types: Dandy-Walker malformation (vermis agenesis or hypoplasia, cystic dilatation of the fourth ventricle and a large posterior fossa); Dandy-Walker variant (vermis hypoplasia, cystic dilatation of the fourth ventricle, normal posterior fossa); mega cysterna magna (large posterior fossa, normal vermis and fourth ventricle) and posterior fossa arachnoid cyst. We present and discuss four cases with different morphological and clinical forms of the Dandy-Walker complex. In all four cases, diagnosis was reached by incorporation of clinical (macrocephaly, seizures) and imaging [X-ray, computed tomography (CT), magnetic resonance imaging (MRI)] data. Two patients were diagnosed with Dandy-Walker complex, one patient was diagnosed with Dandy-Walker variant in a rare association with neurofibromatosis and one patient was diagnosed with a posterior fossa arachnoid cyst associated with left-sided Claude Bernard-Horner syndrome, congenital heart disease (coarctation of the aorta, mitral stenosis) and gastroesophageal reflux. In all forms of DWC, the clinical, radiological and functional manifestations are variable and require adequate diagnostic and therapeutic measures.

  15. Flavonoids as Inhibitors of Human Butyrylcholinesterase Variants

    Directory of Open Access Journals (Sweden)

    Maja Katalinić

    2014-01-01

    Full Text Available The inhibition of butyrylcholinesterase (BChE, EC 3.1.1.8 appears to be of interest in treating diseases with symptoms of reduced neurotransmitter levels, such as Alzheimer’s disease. However, BCHE gene polymorphism should not be neglected in research since it could have an effect on the expected outcome. Several well-known cholinergic drugs (e.g. galantamine, huperzine and rivastigmine originating from plants, or synthesised as derivatives of plant compounds, have shown that herbs could serve as a source of novel target-directed compounds. We focused our research on flavonoids, biologically active polyphenolic compounds found in many plants and plant-derived products, as BChE inhibitors. All of the tested flavonoids: galangin, quercetin, fisetin and luteolin reversibly inhibited usual, atypical, and fluoride-resistant variants of human BChE. The inhibition potency increased in the following order, identically for all three BChE variants: luteolin

  16. GenProBiS: web server for mapping of sequence variants to protein binding sites.

    Science.gov (United States)

    Konc, Janez; Skrlj, Blaz; Erzen, Nika; Kunej, Tanja; Janezic, Dusanka

    2017-05-11

    Discovery of potentially deleterious sequence variants is important and has wide implications for research and generation of new hypotheses in human and veterinary medicine, and drug discovery. The GenProBiS web server maps sequence variants to protein structures from the Protein Data Bank (PDB), and further to protein-protein, protein-nucleic acid, protein-compound, and protein-metal ion binding sites. The concept of a protein-compound binding site is understood in the broadest sense, which includes glycosylation and other post-translational modification sites. Binding sites were defined by local structural comparisons of whole protein structures using the Protein Binding Sites (ProBiS) algorithm and transposition of ligands from the similar binding sites found to the query protein using the ProBiS-ligands approach with new improvements introduced in GenProBiS. Binding site surfaces were generated as three-dimensional grids encompassing the space occupied by predicted ligands. The server allows intuitive visual exploration of comprehensively mapped variants, such as human somatic mis-sense mutations related to cancer and non-synonymous single nucleotide polymorphisms from 21 species, within the predicted binding sites regions for about 80 000 PDB protein structures using fast WebGL graphics. The GenProBiS web server is open and free to all users at http://genprobis.insilab.org. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  17. BRCA1 and BRCA2 missense variants of high and low clinical significance influence lymphoblastoid cell line post-irradiation gene expression.

    Directory of Open Access Journals (Sweden)

    Nic Waddell

    2008-05-01

    Full Text Available The functional consequences of missense variants in disease genes are difficult to predict. We assessed if gene expression profiles could distinguish between BRCA1 or BRCA2 pathogenic truncating and missense mutation carriers and familial breast cancer cases whose disease was not attributable to BRCA1 or BRCA2 mutations (BRCAX cases. 72 cell lines from affected women in high-risk breast ovarian families were assayed after exposure to ionising irradiation, including 23 BRCA1 carriers, 22 BRCA2 carriers, and 27 BRCAX individuals. A subset of 10 BRCAX individuals carried rare BRCA1/2 sequence variants considered to be of low clinical significance (LCS. BRCA1 and BRCA2 mutation carriers had similar expression profiles, with some subclustering of missense mutation carriers. The majority of BRCAX individuals formed a distinct cluster, but BRCAX individuals with LCS variants had expression profiles similar to BRCA1/2 mutation carriers. Gaussian Process Classifier predicted BRCA1, BRCA2 and BRCAX status, with a maximum of 62% accuracy, and prediction accuracy decreased with inclusion of BRCAX samples carrying an LCS variant, and inclusion of pathogenic missense carriers. Similarly, prediction of mutation status with gene lists derived using Support Vector Machines was good for BRCAX samples without an LCS variant (82-94%, poor for BRCAX with an LCS (40-50%, and improved for pathogenic BRCA1/2 mutation carriers when the gene list used for prediction was appropriate to mutation effect being tested (71-100%. This study indicates that mutation effect, and presence of rare variants possibly associated with a low risk of cancer, must be considered in the development of array-based assays of variant pathogenicity.

  18. Critical Roles of Xirp Proteins in Cardiac Conduction and Their Rare Variants Identified in Sudden Unexplained Nocturnal Death Syndrome and Brugada Syndrome in Chinese Han Population.

    Science.gov (United States)

    Huang, Lei; Wu, Kuo-Ho; Zhang, Liyong; Wang, Qinchuan; Tang, Shuangbo; Wu, Qiuping; Jiang, Pei-Hsiu; Lin, Jim Jung-Ching; Guo, Jian; Wang, Lin; Loh, Shih-Hurng; Cheng, Jianding

    2018-01-06

    Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative entity with unclear etiology. Arrhythmia has been implicated in SUNDS. Mutations/deficiencies in intercalated disc components have been shown to cause arrhythmias. Human cardiomyopathy-associated 1 (XIRP1) and 3 (XIRP2) are intercalated disc-associated, Xin repeats-containing proteins. Mouse Xirp1 is necessary for the integrity of intercalated disc and for the surface expression of transient outward and delayed rectifier K+ channels, whereas mouse Xirp2 is required for Xirp1 intercalated disc localization. Thus, XIRP1 and XIRP2 may be potentially causal genes for SUNDS. We genetically screened XIRP genes in 134 sporadic SUNDS victims and 22 Brugada syndrome (BrS) cases in a Chinese Han population. We identified 16 rare variants (6 were in silico predicted as deleterious) in SUNDS victims, including a novel variant, XIRP2-E215K. There were also four rare variants (2 were in silico predicted as deleterious) detected in BrS cases, including a novel variant, XIRP2-L2718P. Interestingly, among these 20 variants, we detected 2 likely pathogenic variants: a nonsense variant (XIRP2-Q2875*) and a frameshift variant (XIRP2-T2238QfsX7). Analyzing available Xirp2 knockout mice, we further found that mouse hearts without Xirp2 exhibited prolonged PR and QT intervals, slow conduction velocity, atrioventricular conduction block, and an abnormal infranodal ventricular conduction system. Whole-cell patch-clamp detected altered ionic currents in Xirp2-/- cardiomyocytes, consistent with the observed association between Xirp2 and Nav1.5/Kv1.5 in co-immunoprecipitation. This is the first report identifying likely pathogenic XIRP rare variants in arrhythmogenic disorders such as SUNDS and Brugada syndrome, and showing critical roles of Xirp2 in cardiac conduction. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  19. OCA2 splice site variant in German Spitz dogs with oculocutaneous albinism

    Science.gov (United States)

    Caduff, Madleina; Bauer, Anina; Jagannathan, Vidhya

    2017-01-01

    We investigated a German Spitz family where the mating of a black male to a white female had yielded three puppies with an unexpected light brown coat color, lightly pigmented lips and noses, and blue eyes. Combined linkage and homozygosity analysis based on a fully penetrant monogenic autosomal recessive mode of inheritance identified a critical interval of 15 Mb on chromosome 3. We obtained whole genome sequence data from one affected dog, three wolves, and 188 control dogs. Filtering for private variants revealed a single variant with predicted high impact in the critical interval in LOC100855460 (XM_005618224.1:c.377+2T>G LT844587.1:c.-45+2T>G). The variant perfectly co-segregated with the phenotype in the family. We genotyped 181 control dogs with normal pigmentation from diverse breeds including 22 unrelated German Spitz dogs, which were all homozygous wildtype. Comparative sequence analyses revealed that LOC100855460 actually represents the 5’-end of the canine OCA2 gene. The CanFam 3.1 reference genome assembly is incorrect and separates the first two exons from the remaining exons of the OCA2 gene. We amplified a canine OCA2 cDNA fragment by RT-PCR and determined the correct full-length mRNA sequence (LT844587.1). Variants in the OCA2 gene cause oculocutaneous albinism type 2 (OCA2) in humans, pink-eyed dilution in mice, and similar phenotypes in corn snakes, medaka and Mexican cave tetra fish. We therefore conclude that the observed oculocutaneous albinism in German Spitz is most likely caused by the identified variant in the 5’-splice site of the first intron of the canine OCA2 gene. PMID:28973042

  20. A Non-Synonymous HMGA2 Variant Decreases Height in Shetland Ponies and Other Small Horses.

    Directory of Open Access Journals (Sweden)

    Mirjam Frischknecht

    Full Text Available The identification of quantitative trait loci (QTL such as height and their underlying causative variants is still challenging and often requires large sample sizes. In humans hundreds of loci with small effects control the heritable portion of height variability. In domestic animals, typically only a few loci with comparatively large effects explain a major fraction of the heritability. We investigated height at withers in Shetland ponies and mapped a QTL to ECA 6 by genome-wide association (GWAS using a small cohort of only 48 animals and the Illumina equine SNP70 BeadChip. Fine-mapping revealed a shared haplotype block of 793 kb in small Shetland ponies. The HMGA2 gene, known to be associated with height in horses and many other species, was located in the associated haplotype. After closing a gap in the equine reference genome we identified a non-synonymous variant in the first exon of HMGA2 in small Shetland ponies. The variant was predicted to affect the functionally important first AT-hook DNA binding domain of the HMGA2 protein (c.83G>A; p.G28E. We assessed the functional impact and found impaired DNA binding of a peptide with the mutant sequence in an electrophoretic mobility shift assay. This suggests that the HMGA2 variant also affects DNA binding in vivo and thus leads to reduced growth and a smaller stature in Shetland ponies. The identified HMGA2 variant also segregates in several other pony breeds but was not found in regular-sized horse breeds. We therefore conclude that we identified a quantitative trait nucleotide for height in horses.

  1. OCA2 splice site variant in German Spitz dogs with oculocutaneous albinism.

    Directory of Open Access Journals (Sweden)

    Madleina Caduff

    Full Text Available We investigated a German Spitz family where the mating of a black male to a white female had yielded three puppies with an unexpected light brown coat color, lightly pigmented lips and noses, and blue eyes. Combined linkage and homozygosity analysis based on a fully penetrant monogenic autosomal recessive mode of inheritance identified a critical interval of 15 Mb on chromosome 3. We obtained whole genome sequence data from one affected dog, three wolves, and 188 control dogs. Filtering for private variants revealed a single variant with predicted high impact in the critical interval in LOC100855460 (XM_005618224.1:c.377+2T>G LT844587.1:c.-45+2T>G. The variant perfectly co-segregated with the phenotype in the family. We genotyped 181 control dogs with normal pigmentation from diverse breeds including 22 unrelated German Spitz dogs, which were all homozygous wildtype. Comparative sequence analyses revealed that LOC100855460 actually represents the 5'-end of the canine OCA2 gene. The CanFam 3.1 reference genome assembly is incorrect and separates the first two exons from the remaining exons of the OCA2 gene. We amplified a canine OCA2 cDNA fragment by RT-PCR and determined the correct full-length mRNA sequence (LT844587.1. Variants in the OCA2 gene cause oculocutaneous albinism type 2 (OCA2 in humans, pink-eyed dilution in mice, and similar phenotypes in corn snakes, medaka and Mexican cave tetra fish. We therefore conclude that the observed oculocutaneous albinism in German Spitz is most likely caused by the identified variant in the 5'-splice site of the first intron of the canine OCA2 gene.

  2. A Non-Synonymous HMGA2 Variant Decreases Height in Shetland Ponies and Other Small Horses.

    Science.gov (United States)

    Frischknecht, Mirjam; Jagannathan, Vidhya; Plattet, Philippe; Neuditschko, Markus; Signer-Hasler, Heidi; Bachmann, Iris; Pacholewska, Alicja; Drögemüller, Cord; Dietschi, Elisabeth; Flury, Christine; Rieder, Stefan; Leeb, Tosso

    2015-01-01

    The identification of quantitative trait loci (QTL) such as height and their underlying causative variants is still challenging and often requires large sample sizes. In humans hundreds of loci with small effects control the heritable portion of height variability. In domestic animals, typically only a few loci with comparatively large effects explain a major fraction of the heritability. We investigated height at withers in Shetland ponies and mapped a QTL to ECA 6 by genome-wide association (GWAS) using a small cohort of only 48 animals and the Illumina equine SNP70 BeadChip. Fine-mapping revealed a shared haplotype block of 793 kb in small Shetland ponies. The HMGA2 gene, known to be associated with height in horses and many other species, was located in the associated haplotype. After closing a gap in the equine reference genome we identified a non-synonymous variant in the first exon of HMGA2 in small Shetland ponies. The variant was predicted to affect the functionally important first AT-hook DNA binding domain of the HMGA2 protein (c.83G>A; p.G28E). We assessed the functional impact and found impaired DNA binding of a peptide with the mutant sequence in an electrophoretic mobility shift assay. This suggests that the HMGA2 variant also affects DNA binding in vivo and thus leads to reduced growth and a smaller stature in Shetland ponies. The identified HMGA2 variant also segregates in several other pony breeds but was not found in regular-sized horse breeds. We therefore conclude that we identified a quantitative trait nucleotide for height in horses.

  3. OCA2 splice site variant in German Spitz dogs with oculocutaneous albinism.

    Science.gov (United States)

    Caduff, Madleina; Bauer, Anina; Jagannathan, Vidhya; Leeb, Tosso

    2017-01-01

    We investigated a German Spitz family where the mating of a black male to a white female had yielded three puppies with an unexpected light brown coat color, lightly pigmented lips and noses, and blue eyes. Combined linkage and homozygosity analysis based on a fully penetrant monogenic autosomal recessive mode of inheritance identified a critical interval of 15 Mb on chromosome 3. We obtained whole genome sequence data from one affected dog, three wolves, and 188 control dogs. Filtering for private variants revealed a single variant with predicted high impact in the critical interval in LOC100855460 (XM_005618224.1:c.377+2T>G LT844587.1:c.-45+2T>G). The variant perfectly co-segregated with the phenotype in the family. We genotyped 181 control dogs with normal pigmentation from diverse breeds including 22 unrelated German Spitz dogs, which were all homozygous wildtype. Comparative sequence analyses revealed that LOC100855460 actually represents the 5'-end of the canine OCA2 gene. The CanFam 3.1 reference genome assembly is incorrect and separates the first two exons from the remaining exons of the OCA2 gene. We amplified a canine OCA2 cDNA fragment by RT-PCR and determined the correct full-length mRNA sequence (LT844587.1). Variants in the OCA2 gene cause oculocutaneous albinism type 2 (OCA2) in humans, pink-eyed dilution in mice, and similar phenotypes in corn snakes, medaka and Mexican cave tetra fish. We therefore conclude that the observed oculocutaneous albinism in German Spitz is most likely caused by the identified variant in the 5'-splice site of the first intron of the canine OCA2 gene.

  4. A community-based resource for automatic exome variant-calling and annotation in Mendelian disorders.

    Science.gov (United States)

    Mutarelli, Margherita; Marwah, Veer; Rispoli, Rossella; Carrella, Diego; Dharmalingam, Gopuraja; Oliva, Gennaro; di Bernardo, Diego

    2014-01-01

    Mendelian disorders are mostly caused by single mutations in the DNA sequence of a gene, leading to a phenotype with pathologic consequences. Whole Exome Sequencing of patients can be a cost-effective alternative to standard genetic screenings to find causative mutations of genetic diseases, especially when the number of cases is limited. Analyzing exome sequencing data requires specific expertise, high computational resources and a reference variant database to identify pathogenic variants. We developed a database of variations collected from patients with Mendelian disorders, which is automatically populated thanks to an associated exome-sequencing pipeline. The pipeline is able to automatically identify, annotate and store insertions, deletions and mutations in the database. The resource is freely available online http://exome.tigem.it. The exome sequencing pipeline automates the analysis workflow (quality control and read trimming, mapping on reference genome, post-alignment processing, variation calling and annotation) using state-of-the-art software tools. The exome-sequencing pipeline has been designed to run on a computing cluster in order to analyse several samples simultaneously. The detected variants are annotated by the pipeline not only with the standard variant annotations (e.g. allele frequency in the general population, the predicted effect on gene product activity, etc.) but, more importantly, with allele frequencies across samples progressively collected in the database itself, stratified by Mendelian disorder. We aim at providing a resource for the genetic disease community to automatically analyse whole exome-sequencing samples with a standard and uniform analysis pipeline, thus collecting variant allele frequencies by disorder. This resource may become a valuable tool to help dissecting the genotype underlying the disease phenotype through an improved selection of putative patient-specific causative or phenotype-associated variations.

  5. TRPM4 non-selective cation channel variants in long QT syndrome.

    Science.gov (United States)

    Hof, Thomas; Liu, Hui; Sallé, Laurent; Schott, Jean-Jacques; Ducreux, Corinne; Millat, Gilles; Chevalier, Philippe; Probst, Vincent; Guinamard, Romain; Bouvagnet, Patrice

    2017-03-18

    Long QT syndrome (LQTS) is an inherited arrhythmic disorder characterized by prolongation of the QT interval, a risk of syncope, and sudden death. There are already a number of causal genes in LQTS, but not all LQTS patients have an identified mutation, which suggests LQTS unknown genes. A cohort of 178 LQTS patients, with no mutations in the 3 major LQTS genes (KCNQ1, KCNH2, and SCN5A), was screened for mutations in the transient potential melastatin 4 gene (TRPM4). Four TRPM4 variants (2.2% of the cohort) were found to change highly conserved amino-acids and were either very rare or absent from control populations. Therefore, these four TRPM4 variants were predicted to be disease causing. Furthermore, no mutations were found in the DNA of these TRPM4 variant carriers in any of the 13 major long QT syndrome genes. Two of these variants were further studied by electrophysiology (p.Val441Met and p.Arg499Pro). Both variants showed a classical TRPM4 outward rectifying current, but the current was reduced by 61 and 90% respectively, compared to wild type TRPM4 current. This study supports the view that TRPM4 could account for a small percentage of LQTS patients. TRPM4 contribution to the QT interval might be multifactorial by modulating whole cell current but also, as shown in Trpm4-/- mice, by modulating cardiomyocyte proliferation. TRPM4 enlarges the subgroup of LQT genes (KCNJ2 in Andersen syndrome and CACNA1C in Timothy syndrome) known to increase the QT interval through a more complex pleiotropic effect than merely action potential alteration.

  6. Formin homology 2 domain containing 3 variants associated with hypertrophic cardiomyopathy.

    Science.gov (United States)

    Wooten, Eric C; Hebl, Virginia B; Wolf, Matthew J; Greytak, Sarah R; Orr, Nicole M; Draper, Isabelle; Calvino, Jenna E; Kapur, Navin K; Maron, Martin S; Kullo, Iftikhar J; Ommen, Steve R; Bos, J Martijn; Ackerman, Michael J; Huggins, Gordon S

    2013-02-01

    Incomplete penetrance and variable expression of hypertrophic cardiomyopathy (HCM) is well appreciated. Common genetic polymorphisms variants that may affect HCM penetrance and expression have been predicted but are not well established. We performed a case-control genomewide association study to identify common HCM-associated genetic polymorphisms and then asked whether such common variants were more represented in HCM or could explain the heterogeneity of HCM phenotypes. We identified an intronic FHOD3 variant (rs516514) associated with HCM (odds ratio, 2.45; 95% confidence interval, 1.76-3.41; P=1.25×10(-7)) and validated this finding in an independent cohort. Next, we tested FHOD3-V1151I (rs2303510), a nonsynonymous variant in partial linkage disequilibrium with rs516514, and we detected an even stronger association with HCM (P=1.76×10(-9)). Although HCM patients were more likely to carry these, FHOD3 allele subjects homozygous for FHOD3-1151I had similar HCM phenotypes as carriers of the V1151 allele. FHOD3 expression is increased in the setting of HCM, and both alleles of FHOD3-V1151I were detected in HCM myectomy tissue. Previously, FHOD3 was found to be required for formation of the sarcomere, and here we demonstrate that its fly homolog fhos is required for normal adult heart systolic contraction. Here we demonstrate the association of a common nonsynonymous FHOD3 genetic variant with HCM. This discovery further strengthens the potential role of gene mutations and polymorphisms that alter the amino acid sequence of sarcomere proteins and HCM.

  7. Formin Homology 2 Domain Containing 3 (FHOD3) Variants Associated with Hypertrophic Cardiomyopathy

    Science.gov (United States)

    Wooten, Eric C.; Hebl, Virginia Bartleson; Wolf, Matthew J.; Greytak, Sarah R.; Orr, Nicole; Draper, Isabelle; Calvino, Jenna E.; Kapur, Navin K.; Maron, Martin S.; Kullo, Iftikhar J.; Ommen, Steve R.; Bos, J. Martijn; Ackerman, Michael J.; Huggins, Gordon S.

    2013-01-01

    Background Incomplete penetrance and variable expression of Hypertrophic Cardiomyopathy (HCM) is well appreciated. Common genetic polymorphisms variants that may affect HCM penetrance and expression have been predicted but are not well established. Methods and Results We performed a case-control genome wide association (GWA) study to identify common HCM-associated genetic polymorphisms and then asked whether such common variants were more represented in HCM or could explain the heterogeneity of HCM phenotypes. We identified an intronic FHOD3 variant (rs516514) associated with HCM (OR = 2.45 (95% CI 1.76–3.41), p=1.25 × 10−7) and validated this finding in an independent cohort. Next, we tested FHOD3-V1151I (rs2303510), a non-synonymous variant in partial linkage disequilibrium (LD) with rs516514, and we detected an even stronger association with HCM (p=1.76 × 10−9). While HCM patients were more likely to carry these FHOD3 alleles subjects homozygous for FHOD3-1151I had similar HCM phenotypes as carriers of the V1151 allele. FHOD3 expression is increased in the setting of HCM and both alleles of FHOD3-V1151I were detected in HCM myectomy tissue. Previously FHOD3 was found to be required for formation of the sarcomere and here we demonstrate that its fly homolog fhos is required for normal adult heart systolic contraction. Conclusions Here we demonstrate the association of a common non-synonymous FHOD3 genetic variant with HCM. This discovery further strengthens the potential role of gene mutations and polymorphisms that alter the amino acid sequence of sarcomere proteins and HCM. PMID:23255317

  8. BBCAnalyzer: a visual approach to facilitate variant calling

    OpenAIRE

    Sandmann, S.; Graaf, A.O. de; Dugas, M.

    2017-01-01

    Background Deriving valid variant calling results from raw next-generation sequencing data is a particularly challenging task, especially with respect to clinical diagnostics and personalized medicine. However, when using classic variant calling software, the user usually obtains nothing more than a list of variants that pass the corresponding caller?s internal filters. Any expected mutations (e.g. hotspot mutations), that have not been called by the software, need to be investigated manually...

  9. Copy number variants in patients with short stature

    OpenAIRE

    van Duyvenvoorde, Hermine A.; Lui, Julian C.; Kant, Sarina G; Oostdijk, Wilma; Gijsbers, Antoinet CJ; Hoffer, Mariëtte JV; Karperien, Marcel; Walenkamp, Marie JE; Noordam, Cees; Voorhoeve, Paul G; Mericq, Verónica; Alberto M. Pereira; Claahsen-van der Grinten, Hedi L.; van Gool, Sandy A; Breuning, Martijn H

    2013-01-01

    Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variant...

  10. Predictive Testing

    Science.gov (United States)

    ... you want to learn. Search form Search Predictive testing You are here Home Testing & Services Testing for ... you make the decision. What Is Predictive Genetic Testing Predictive genetic testing searches for genetic changes, or ...

  11. Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.

    Science.gov (United States)

    Decker, Brennan; Allen, Jamie; Luccarini, Craig; Pooley, Karen A; Shah, Mitul; Bolla, Manjeet K; Wang, Qin; Ahmed, Shahana; Baynes, Caroline; Conroy, Don M; Brown, Judith; Luben, Robert; Ostrander, Elaine A; Pharoah, Paul Dp; Dunning, Alison M; Easton, Douglas F

    2017-11-01

    Breast cancer (BC) is the most common malignancy in women and has a major heritable component. The risks associated with most rare susceptibility variants are not well estimated. To better characterise the contribution of variants in ATM, CHEK2, PALB2 and XRCC2, we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK. Gene coding regions were enriched via PCR, sequenced, variant called and filtered for quality. ORs for BC risk were estimated separately for carriers of truncating variants and of rare missense variants, which were further subdivided by functional domain and pathogenicity as predicted by four in silico algorithms. Truncating variants in PALB2 (OR=4.69, 95% CI 2.27 to 9.68), ATM (OR=3.26; 95% CI 1.82 to 6.46) and CHEK2 (OR=3.11; 95% CI 2.15 to 4.69), but not XRCC2 (OR=0.94; 95% CI 0.26 to 4.19) were associated with increased BC risk. Truncating variants in ATM and CHEK2 were more strongly associated with risk of oestrogen receptor (ER)-positive than ER-negative disease, while those in PALB2 were associated with similar risks for both subtypes. There was also some evidence that missense variants in ATM, CHEK2 and PALB2 may contribute to BC risk, but larger studies are necessary to quantify the magnitude of this effect. Truncating variants in PALB2 are associated with a higher risk of BC than those in ATM or CHEK2. A substantial risk of BC due to truncating XRCC2 variants can be excluded. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  12. A unified phylogeny-based nomenclature for histone variants.

    Science.gov (United States)

    Talbert, Paul B; Ahmad, Kami; Almouzni, Geneviève; Ausió, Juan; Berger, Frederic; Bhalla, Prem L; Bonner, William M; Cande, W Zacheus; Chadwick, Brian P; Chan, Simon W L; Cross, George A M; Cui, Liwang; Dimitrov, Stefan I; Doenecke, Detlef; Eirin-López, José M; Gorovsky, Martin A; Hake, Sandra B; Hamkalo, Barbara A; Holec, Sarah; Jacobsen, Steven E; Kamieniarz, Kinga; Khochbin, Saadi; Ladurner, Andreas G; Landsman, David; Latham, John A; Loppin, Benjamin; Malik, Harmit S; Marzluff, William F; Pehrson, John R; Postberg, Jan; Schneider, Robert; Singh, Mohan B; Smith, M Mitchell; Thompson, Eric; Torres-Padilla, Maria-Elena; Tremethick, David John; Turner, Bryan M; Waterborg, Jakob Harm; Wollmann, Heike; Yelagandula, Ramesh; Zhu, Bing; Henikoff, Steven

    2012-06-21

    Histone variants are non-allelic protein isoforms that play key roles in diversifying chromatin structure. The known number of such variants has greatly increased in recent years, but the lack of naming conventions for them has led to a variety of naming styles, multiple synonyms and misleading homographs that obscure variant relationships and complicate database searches. We propose here a unified nomenclature for variants of all five classes of histones that uses consistent but flexible naming conventions to produce names that are informative and readily searchable. The nomenclature builds on historical usage and incorporates phylogenetic relationships, which are strong predictors of structure and function. A key feature is the consistent use of punctuation to represent phylogenetic divergence, making explicit the relationships among variant subtypes that have previously been implicit or unclear. We recommend that by default new histone variants be named with organism-specific paralog-number suffixes that lack phylogenetic implication, while letter suffixes be reserved for structurally distinct clades of variants. For clarity and searchability, we encourage the use of descriptors that are separate from the phylogeny-based variant name to indicate developmental and other properties of variants that may be independent of structure.

  13. A unified phylogeny-based nomenclature for histone variants

    Directory of Open Access Journals (Sweden)

    Talbert Paul B

    2012-06-01

    Full Text Available Abstract Histone variants are non-allelic protein isoforms that play key roles in diversifying chromatin structure. The known number of such variants has greatly increased in recent years, but the lack of naming conventions for them has led to a variety of naming styles, multiple synonyms and misleading homographs that obscure variant relationships and complicate database searches. We propose here a unified nomenclature for variants of all five classes of histones that uses consistent but flexible naming conventions to produce names that are informative and readily searchable. The nomenclature builds on historical usage and incorporates phylogenetic relationships, which are strong predictors of structure and function. A key feature is the consistent use of punctuation to represent phylogenetic divergence, making explicit the relationships among variant subtypes that have previously been implicit or unclear. We recommend that by default new histone variants be named with organism-specific paralog-number suffixes that lack phylogenetic implication, while letter suffixes be reserved for structurally distinct clades of variants. For clarity and searchability, we encourage the use of descriptors that are separate from the phylogeny-based variant name to indicate developmental and other properties of variants that may be independent of structure.

  14. Population structure analysis using rare and common functional variants

    Directory of Open Access Journals (Sweden)

    Ding Lili

    2011-11-01

    Full Text Available Abstract Next-generation sequencing technologies now make it possible to genotype and measure hundreds of thousands of rare genetic variations in individuals across the genome. Characterization of high-density genetic variation facilitates control of population genetic structure on a finer scale before large-scale genotyping in disease genetics studies. Population structure is a well-known, prevalent, and important factor in common variant genetic studies, but its relevance in rare variants is unclear. We perform an extensive population structure analysis using common and rare functional variants from the Genetic Analysis Workshop 17 mini-exome sequence. The analysis based on common functional variants required 388 principal components to account for 90% of the variation in population structure. However, an analysis based on rare variants required 532 significant principal components to account for similar levels of variation. Using rare variants, we detected fine-scale substructure beyond the population structure identified using common functional variants. Our results show that the level of population structure embedded in rare variant data is different from the level embedded in common variant data and that correcting for population structure is only as good as the level one wishes to correct.

  15. XIAP Deficiency and MEFV Variants Resulting in Severe Manifestations – A Case Report

    DEFF Research Database (Denmark)

    Christiansen, Mette

    2016-01-01

    Background Heterozygous dominant or homozygous recessive MEFV mutations result in recurrent fever and abdominal pain, while XIAP deficiency is characterized by a high susceptibility to develop haemophagocytic lymphohistiocytosis triggered by EBV infection, recurrent splenomegaly and inflammatory...... abdominal pain and general malaise. Inflammation and sinus histiocytosis, but no malignancy or granuloma was found by histology of affected lymph nodes. Anti-Epstein-Barr virus (EBV) IgM and IgG were both negative prior to hospitalization, but positive IgG (VCA) was found during the hospitalization. Results...... the BIR3 domain and not predicted to affect the protein function per se but reduced protein level seems to affect signalling. We suggest that the heterozygous MEFV variant and the hemizygous XIAP variant in combination triggered the prolonged and serious response to EBV infection....

  16. Mechanistic modeling of ion-exchange process chromatography of charge variants of monoclonal antibody products.

    Science.gov (United States)

    Kumar, Vijesh; Leweke, Samuel; von Lieres, Eric; Rathore, Anurag S

    2015-12-24

    Ion-exchange chromatography (IEX) is universally accepted as the optimal method for achieving process scale separation of charge variants of a monoclonal antibody (mAb) therapeutic. These variants are closely related to the product and a baseline separation is rarely achieved. The general practice is to fractionate the eluate from the IEX column, analyze the fractions and then pool the desired fractions to obtain the targeted composition of variants. This is, however, a very cumbersome and time consuming exercise. A mechanistic model that is capable of simulating the peak profile will be a much more elegant and effective way to make a decision on the pooling strategy. This paper proposes a mechanistic model, based on the general rate model, to predict elution peak profile for separation of the main product from its variants. The proposed approach uses inverse fit of process scale chromatogram for estimation of model parameters using the initial values that are obtained from theoretical correlations. The packed bed column has been modeled along with the chromatographic system consisting of the mixer, tubing and detectors as a series of dispersed plug flow and continuous stirred tank reactors. The model uses loading ranges starting at 25% to a maximum of 70% of the loading capacity and hence is applicable to process scale separations. Langmuir model has been extended to include the effects of salt concentration and temperature on the model parameters. The extended Langmuir model that has been proposed uses one less parameter than the SMA model and this results in a significant ease of estimating the model parameters from inverse fitting. The proposed model has been validated with experimental data and has been shown to successfully predict peak profile for a range of load capacities (15-28mg/mL), gradient lengths (10-30CV), bed heights (6-20cm), and for three different resins with good accuracy (as measured by estimation of residuals). The model has been also

  17. Additive effects of genetic variants associated with intraocular pressure in primary open-angle glaucoma.

    Science.gov (United States)

    Mabuchi, Fumihiko; Mabuchi, Nakako; Sakurada, Yoichi; Yoneyama, Seigo; Kashiwagi, Kenji; Iijima, Hiroyuki; Yamagata, Zentaro; Takamoto, Mitsuko; Aihara, Makoto; Iwata, Takeshi; Kawase, Kazuhide; Shiga, Yukihiro; Nishiguchi, Koji M; Nakazawa, Toru; Ozaki, Mineo; Araie, Makoto

    2017-01-01

    To investigate the association between the additive effects of genetic variants associated with intraocular pressure (IOP) and IOP, vertical cup-to-disc ratio (VCDR), and high tension glaucoma (HTG) or normal tension glaucoma (NTG) as phenotypic features of primary open-angle glaucoma (POAG), and to evaluate the clinical usefulness of the additive effects of IOP-related genetic variants for predicting IOP elevation, Japanese patients with HTG (n = 255) and NTG (n = 261) and 246 control subjects were genotyped for nine IOP-related genetic variants near CAV2, GAS7, GLCCI1/ICA1, ABCA1, ARHGEF12, FAM125B, FNDC3B, ABO, and PTPRJ/AGBL2. The total number of risk alleles of these genetic variants was calculated for each participant as a genetic risk score (GRS), and the association between the GRS and the maximum IOP, mean VCDR, and phenotype (HTG or NTG) of POAG was evaluated. As the GRS increased, the maximum IOP (P = 0.012) and VCDR (P = 0.010) significantly increased. The GRS (9.1±1.9) in patients with HTG was significantly higher (P = 0.011) than that (8.7±1.8) in control subjects. The patients with GRS≥12 as a cut-off value had a 2.54 times higher (P = 0.0085) risk on HTG (maximum IOP≥22mmHg) compared with all patients. The IOP-related GRS approach substantiated that the IOP and VCDR were increased by the additive effects of IOP-related genetic variants in POAG. The high IOP-related GRS in patients with HTG but not NTG shows that there are differences in the genetic background between HTG and NTG and supports the notion that the phenotype (HTG or NTG) in patients with POAG depends on the additive effects of IOP-related genetic variants. The above-mentioned cut-off value of IOP-related GRS may be clinically useful for predicting the risk of IOP elevation.

  18. Additive effects of genetic variants associated with intraocular pressure in primary open-angle glaucoma.

    Directory of Open Access Journals (Sweden)

    Fumihiko Mabuchi

    Full Text Available To investigate the association between the additive effects of genetic variants associated with intraocular pressure (IOP and IOP, vertical cup-to-disc ratio (VCDR, and high tension glaucoma (HTG or normal tension glaucoma (NTG as phenotypic features of primary open-angle glaucoma (POAG, and to evaluate the clinical usefulness of the additive effects of IOP-related genetic variants for predicting IOP elevation, Japanese patients with HTG (n = 255 and NTG (n = 261 and 246 control subjects were genotyped for nine IOP-related genetic variants near CAV2, GAS7, GLCCI1/ICA1, ABCA1, ARHGEF12, FAM125B, FNDC3B, ABO, and PTPRJ/AGBL2. The total number of risk alleles of these genetic variants was calculated for each participant as a genetic risk score (GRS, and the association between the GRS and the maximum IOP, mean VCDR, and phenotype (HTG or NTG of POAG was evaluated. As the GRS increased, the maximum IOP (P = 0.012 and VCDR (P = 0.010 significantly increased. The GRS (9.1±1.9 in patients with HTG was significantly higher (P = 0.011 than that (8.7±1.8 in control subjects. The patients with GRS≥12 as a cut-off value had a 2.54 times higher (P = 0.0085 risk on HTG (maximum IOP≥22mmHg compared with all patients. The IOP-related GRS approach substantiated that the IOP and VCDR were increased by the additive effects of IOP-related genetic variants in POAG. The high IOP-related GRS in patients with HTG but not NTG shows that there are differences in the genetic background between HTG and NTG and supports the notion that the phenotype (HTG or NTG in patients with POAG depends on the additive effects of IOP-related genetic variants. The above-mentioned cut-off value of IOP-related GRS may be clinically useful for predicting the risk of IOP elevation.

  19. miRNA independent hepacivirus variants suggest a strong evolutionary pressure to maintain miR-122 dependence

    DEFF Research Database (Denmark)

    Yu, Yingpu; Scheel, Troels K.H.; Luna, Joseph M.

    2017-01-01

    relative is the equine non-primate hepacivirus (NPHV). Here, we used Argonaute cross-linking immunoprecipitation (AGO-CLIP) to confirm AGO binding to the single predicted miR-122 site in the NPHV 5’UTR in vivo. To study miR-122 requirements in the absence of NPHV-permissive cell culture systems, we...... partially dependent on miR-122 as well as robustly replicating NPHV/HCV variants completely independent of any miRNAs. These miRNA independent variants even replicate and produce infectious particles in non-hepatic cells after exogenous delivery of apolipoprotein E (ApoE). Our findings suggest that miR-122...... independent HCV and NPHV variants have arisen and been sampled during evolution, yet miR-122 dependence has prevailed. We propose that hepaciviruses may use this mechanism to guarantee liver tropism and exploit the tolerogenic liver environment to avoid clearance and promote chronicity....

  20. A rabies virus vampire bat variant shows increased neuroinvasiveness in mice when compared to a carnivore variant.

    Science.gov (United States)

    Mesquita, Leonardo Pereira; Gamon, Thais Helena Martins; Cuevas, Silvia Elena Campusano; Asano, Karen Miyuki; Fahl, Willian de Oliveira; Iamamoto, Keila; Scheffer, Karin Correa; Achkar, Samira Maria; Zanatto, Dennis Albert; Mori, Cláudia Madalena Cabrera; Maiorka, Paulo César; Mori, Enio

    2017-12-01

    Rabies is one of the most important zoonotic diseases and is caused by several rabies virus (RABV) variants. These variants can exhibit differences in neurovirulence, and few studies have attempted to evaluate the neuroinvasiveness of variants derived from vampire bats and wild carnivores. The aim of this study was to evaluate the neuropathogenesis of infection with two Brazilian RABV street variants (variant 3 and crab-eating fox) in mice. BALB/c mice were inoculated with RABV through the footpad, with the 50% mouse lethal dose (LD50) determined by intracranial inoculation. The morbidity of rabies in mice infected with variant 3 and the crab-eating fox strain was 100% and 50%, respectively, with an incubation period of 7 and 6 days post-inoculation (dpi), respectively. The clinical disease in mice was similar with both strains, and it was characterized initially by weight loss, ruffled fur, hunched posture, and hind limb paralysis progressing to quadriplegia and recumbency at 9 to 12 dpi. Histological lesions within the central nervous system (CNS) characterized by nonsuppurative encephalomyelitis with neuronal degeneration and necrosis were observed in mice infected with variant 3 and those infected with the crab-eating fox variant. However, lesions and the presence of RABV antigen, were more widespread within the CNS of variant-3-infected mice, whereas in crab-eating fox-variant-infected mice, RABV antigens were more restricted to caudal areas of the CNS, such as the spinal cord and brainstem. In conclusion, the results shown here demonstrate that the RABV vampire bat strain (variant 3) has a higher potential for neuroinvasiveness than the carnivore variant.

  1. Single Nucleotide Variants in Transcription Factors Associate More Tightly with Phenotype than with Gene Expression

    Science.gov (United States)

    Sudarsanam, Priya; Cohen, Barak A.

    2014-01-01

    Mapping the polymorphisms responsible for variation in gene expression, known as Expression Quantitative Trait Loci (eQTL), is a common strategy for investigating the molecular basis of disease. Despite numerous eQTL studies, the relationship between the explanatory power of variants on gene expression versus their power to explain ultimate phenotypes remains to be clarified. We addressed this question using four naturally occurring Quantitative Trait Nucleotides (QTN) in three transcription factors that affect sporulation efficiency in wild strains of the yeast, Saccharomyces cerevisiae. We compared the ability of these QTN to explain the variation in both gene expression and sporulation efficiency. We find that the amount of gene expression variation explained by the sporulation QTN is not predictive of the amount of phenotypic variation explained. The QTN are responsible for 98% of the phenotypic variation in our strains but the median gene expression variation explained is only 49%. The alleles that are responsible for most of the variation in sporulation efficiency do not explain most of the variation in gene expression. The balance between the main effects and gene-gene interactions on gene expression variation is not the same as on sporulation efficiency. Finally, we show that nucleotide variants in the same transcription factor explain the expression variation of different sets of target genes depending on whether the variant alters the level or activity of the transcription factor. Our results suggest that a subset of gene expression changes may be more predictive of ultimate phenotypes than the number of genes affected or the total fraction of variation in gene expression variation explained by causative variants, and that the downstream phenotype is buffered against variation in the gene expression network. PMID:24784239

  2. RAD51 and breast cancer susceptibility: no evidence for rare variant association in the Breast Cancer Family Registry study.

    Directory of Open Access Journals (Sweden)

    Florence Le Calvez-Kelm

    Full Text Available Although inherited breast cancer has been associated with germline mutations in genes that are functionally involved in the DNA homologous recombination repair (HRR pathway, including BRCA1, BRCA2, TP53, ATM, BRIP1, CHEK2 and PALB2, about 70% of breast cancer heritability remains unexplained. Because of their critical functions in maintaining genome integrity and already well-established associations with breast cancer susceptibility, it is likely that additional genes involved in the HRR pathway harbor sequence variants associated with increased risk of breast cancer. RAD51 plays a central biological function in DNA repair and despite the fact that rare, likely dysfunctional variants in three of its five paralogs, RAD51C, RAD51D, and XRCC2, have been associated with breast and/or ovarian cancer risk, no population-based case-control mutation screening data are available for the RAD51 gene. We thus postulated that RAD51 could harbor rare germline mutations that confer increased risk of breast cancer.We screened the coding exons and proximal splice junction regions of the gene for germline sequence variation in 1,330 early-onset breast cancer cases and 1,123 controls from the Breast Cancer Family Registry, using the same population-based sampling and analytical strategy that we developed for assessment of rare sequence variants in ATM and CHEK2. In total, 12 distinct very rare or private variants were characterized in RAD51, with 10 cases (0.75% and 9 controls (0.80% carrying such a variant. Variants were either likely neutral missense substitutions (3, silent substitutions (4 or non-coding substitutions (5 that were predicted to have little effect on efficiency of the splicing machinery.Altogether, our data suggest that RAD51 tolerates so little dysfunctional sequence variation that rare variants in the gene contribute little, if anything, to breast cancer susceptibility.

  3. Brittle cornea syndrome ZNF469 mutation carrier phenotype and segregation analysis of rare ZNF469 variants in familial keratoconus.

    Science.gov (United States)

    Davidson, Alice E; Borasio, Edmondo; Liskova, Petra; Khan, Arif O; Hassan, Hala; Cheetham, Michael E; Plagnol, Vincent; Alkuraya, Fowzan S; Tuft, Stephen J; Hardcastle, Alison J

    2015-01-06

    Brittle cornea syndrome 1 (BCS1) is a rare recessive condition characterized by extreme thinning of the cornea and sclera, caused by mutations in ZNF469. Keratoconus is a relatively common disease characterized by progressive thinning and ectasia of the cornea. The etiology of keratoconus is complex and not yet understood, but rare ZNF469 variants have recently been associated with disease. We investigated the phenotype of BCS1 carriers with known pathogenic ZNF469 mutations, and recruited families in which aggregation of keratoconus was observed to establish if rare variants in ZNF469 segregated with disease. Patients and family members were recruited and underwent comprehensive anterior segment examination, including corneal topography. Blood samples were donated and genomic DNA was extracted. The coding sequence and splice sites of ZNF469 were PCR amplified and Sanger sequenced. Four carriers of three BCS1-associated ZNF469 loss-of-function mutations (p.[Glu1392Ter], p.[Gln1930Argfs*6], p.[Gln1930fs*133]) were examined and none had keratoconus. One carrier had partially penetrant features of BCS1, including joint hypermobility. ZNF469 sequencing in 11 keratoconus families identified 9 rare (minor allele frequency [MAF] ≤ 0.025) variants predicted to be potentially damaging. However, in each instance the rare variant(s) identified, including two previously reported as potentially keratoconus-associated, did not segregate with the disease. The presence of heterozygous loss-of-function alleles in the ZNF469 gene did not cause keratoconus in the individuals examined. None of the rare nonsynonymous ZNF469 variants identified in the familial cohort conferred a high risk of keratoconus; therefore, genetic variants contributing to disease pathogenesis in these 11 families remain to be identified. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

  4. Mycoplasma genitalium non-adherent phase variants arise by multiple mechanisms and escape antibody-dependent growth inhibition.

    Science.gov (United States)

    Burgos, Raul; Wood, Gwendolyn E; Iverson-Cabral, Stefanie; Totten, Patricia A

    2018-01-22

    Antigenic variation of the immunodominant MgpB and MgpC proteins has been suggested as a mechanism of immune evasion of the human pathogen Mycoplasma genitalium, a cause of several reproductive tract disease syndromes. Phase variation resulting in the loss of adherence has also been documented, but the molecular mechanisms underlying this process and its role in pathogenesis are still poorly understood. In this study we isolated and characterized 40 spontaneous, non-adherent phase variants from in vitro-passaged M. genitalium cultures. In all cases, non-adherence was associated with loss of MgpBC protein expression, attributable to sequence changes in the mgpBC expression site. Phase variants were grouped into seven classes based on the nature of the mutation. Consistent with the established role of RecA in phase variation, thirty-one (79.5%) variants arose via recombination with MgPa repeat regions that contain mgpBC variable sequences. The remaining mutants arose via nonsense or frameshift mutations. As expected, revertants were obtained for phase variants predicted to be reversible but not from those that arose via an irreversible mechanism. Furthermore, phase variants were enriched in M. genitalium cultures exposed to antibodies reacting to the extracellular, conserved C-terminus of MgpB, but not by antibodies to an intracellular domain of MgpB or the cytoplasmic HU protein. Genetic characterization of the antibody-selected phase variants confirmed that they arose via reversible and irreversible recombination and point mutations within mgpBC These phase variants resisted antibody-mediated growth inhibition, suggesting that phase variation promotes immune evasion. Copyright © 2018 American Society for Microbiology.

  5. Genetic risk prediction for common diseases : methodology and applications

    NARCIS (Netherlands)

    R. Mihaescu (Raluca)

    2013-01-01

    textabstractThis thesis describes methodological and empirical studies of genetic risk prediction of common diseases. The methodological studies involved the evaluation of traditional and new methods of model performance, the evaluation of rare variants for risk prediction of common diseases, the

  6. Aequorin variants with improved bioluminescence properties.

    Science.gov (United States)

    Dikici, E; Qu, X; Rowe, L; Millner, L; Logue, C; Deo, S K; Ensor, M; Daunert, S

    2009-04-01

    The photoprotein aequorin has been widely used as a bioluminescent label in immunoassays, for the determination of calcium concentrations in vivo, and as a reporter in cellular imaging. It is composed of apoaequorin (189 amino acid residues), the imidazopyrazine chromophore coelenterazine and molecular oxygen. The emission characteristics of aequorin can be changed by rational design of the protein to introduce mutations in its structure, as well as by substituting different coelenterazine analogues to yield semi-synthetic aequorins. Variants of aequorin were created by mutating residues His16, Met19, Tyr82, Trp86, Trp108, Phe113 and Tyr132. Forty-two aequorin mutants were prepared and combined with 10 different coelenterazine analogues in a search for proteins with different emission wavelengths, altered decay kinetics and improved stability. This spectral tuning strategy resulted in semi-synthetic photoprotein mutants with significantly altered bioluminescent properties.

  7. A compendium of genetic variant data

    DEFF Research Database (Denmark)

    Cardoso, Joao; Schöning, Lars Yannik; Herrgard, Markus

    2014-01-01

    Laboratory strains are genetically unstable if exposed to selective pressure as encountered, for example, during molecular cloning, fermentation, or adaptive laboratory evolution experiments. This genetic variation is the consequence of an adaptation process of the microorganism to stress conditi...... obtained from distinct experiments. This compendium of genetic variant is a critical step to develop approaches to automatically and systematically characterize mutated strains in the future.......Laboratory strains are genetically unstable if exposed to selective pressure as encountered, for example, during molecular cloning, fermentation, or adaptive laboratory evolution experiments. This genetic variation is the consequence of an adaptation process of the microorganism to stress...... conditions, e.g., high pressure or temperature, nutrient limitation, or toxic byproduct concentrations. The evolved strains display then new phenotypes: tolerance to a toxic byproduct or higher temperature, improved production rate of a byproduct, or higher uptake rates of nutrients. To understand...

  8. A look-ahead variant of TFQMR

    Energy Technology Data Exchange (ETDEWEB)

    Freund, R.W. [AT& T Bell Labs., Murray Hill, NJ (United States); Nachtigal, N.M. [Oak Ridge National Lab., TN (United States)

    1994-12-31

    Recently, Freund proposed a Krylov subspace iteration, the transpose-free quasi-minimal residual method (TFQMR), for solving general nonsingular non-Hermitian linear systems. The algorithm relies on a version of the squared Lanczos process to generate the basis vectors for the underlying Krylov subspace. It then constructs iterates defined by a quasi-minimization property, which leads to a smooth and nearly monotone convergence behavior. The authors investigate a variant of TFQMR that uses look-ahead to avoid some of the problems associated with breakdowns in the underlying squared Lanczos procedure. They also present some numerical examples that illustrate the properties of the new method, as compared to the original TFQMR algorithm.

  9. Sturge -Weber Syndrome - Three Classic variants

    Directory of Open Access Journals (Sweden)

    R S Sathawane

    2006-01-01

    Full Text Available Sturge-Weber syndrome (SWS, also known as encephalotrigeminal angiomatosis, a sporadic, non-familial, congenital disorder consists of congenital hamartomatous malformations that may affect the eye, skin and central nervous system at different times. Sturge-Weber syndrome is classified as 1 Complete trisymptomatic: - when all three organ systems i.e. eye, skin and CNS are involved 2 Incomplete bisymptomatic:- when the involvement is either oculocutaneous or neurocutaneous, and 3 Incomplete monosymptomatic: when there is only neural or cutaneous involvement. Failure of proper vascular development is believed to be the most likely cause of this condition. The malformed blood vessels or hemangiomas may lead to port-wine stain, epilepsy and glaucoma depending on its location. Three classic variants with typical findings are discussed.

  10. LEWY BODY VARIANT OF ALZHEIMER DISEASE

    Directory of Open Access Journals (Sweden)

    Jera Jeruc

    2003-10-01

    Full Text Available Background. Clinicopathological studies indicate that Alzheimer’s disease (AD is the most common neurodegenerative cause of dementia, the other frequent causes are AD combined with diffuse Lewy bodies and dementia with Lewy bodies (DLB by itself. When histological features of AD and DLB are found together in one brain we speak about Lewy body variant of AD (LBVAD. Beside global cognitive impairment LBVAD patients show signs of subcortical dementia and mild extrapiramidal signs.Methods and results. We present two patients with post-mortem diagnosis of LBVAD. Clinical and pathomorphological characteristics of the disease are discussed.Conclusions. Post-mortem studies show that LBVAD is the second most common cause of dementia, following AB.

  11. Current conveyors variants, applications and hardware implementations

    CERN Document Server

    Senani, Raj; Singh, A K

    2015-01-01

    This book serves as a single-source reference to Current Conveyors and their use in modern Analog Circuit Design. The authors describe the various types of current conveyors discovered over the past 45 years, details of all currently available, off-the-shelf integrated circuit current conveyors, and implementations of current conveyors using other, off-the-shelf IC building blocks. Coverage includes prominent bipolar/CMOS/Bi-CMOS architectures of current conveyors, as well as all varieties of starting from third generation current conveyors to universal current conveyors, their implementations and applications. •Describes all commercially available off-the-shelf IC current conveyors, as well as hardware implementations of current conveyors using other off-the-shelf ICs; • Describes numerous variants of current conveyors evolved over the past forty five years; • Describes a number of Bipolar/CMOS/Bi-CMOS architectures of current conveyors, along with their characteristic features; • Includes a comprehe...

  12. Genetic variants in periodontal health and disease

    Energy Technology Data Exchange (ETDEWEB)

    Dumitrescu, Alexandrina L. [Tromsoe Univ. (Norway). Inst. of Clinical Dentistry; Kobayashi, Junya [Kyoto Univ. (Japan). Dept. of Genome Repair Dynamics

    2010-07-01

    Periodontitis is a complex, multifactorial disease and its susceptibility is genetically determined. The present book systematically reviews the evidence of the association between the genetic variants and periodontitis progression and/or treatment outcomes. Genetic syndromes known to be associated with periodontal disease, the candidate gene polymorphisms investigated in relation to periodontitis, the heritability of chronic and aggressive periodontitis, as well as common guidelines for association studies are described. This growing understanding of the role of genetic variation in inflammation and periodontal chronic disease presents opportunities to identify healthy persons who are at increased risk of disease and to potentially modify the trajectory of disease to prolong healthy aging. The book represents a new concept in periodontology with its pronounced focus on understanding through knowledge rather than presenting the presently valid answers. Connections between genetics and periodontology are systematically reviewed and covered in detail. (orig.)

  13. Multicentric variant of peripheral ossifying fibroma

    Directory of Open Access Journals (Sweden)

    Srikanth A Choudary

    2014-01-01

    Full Text Available Peripheral ossifying fibroma (POF is a solitary over growth of the gingiva known to arise from the cells of the periodontal ligament. The lesions usually start as a painless overgrowth of the interdental papilla unless associated with trauma and gradually involve the other counter parts of the gingiva. The lesion is more considered to be an inflammatory or reactive process rather than to be neoplastic. Here, the authors present a unique case of multiple POF in a young male adult aged 24 years where surgical excision was carried out quadrant wise. The biopsy specimen from multiple sites revealed similar histopathologic features consistent with POF, but also with the multicentric presentation of POF, which is a unique phenomenon. Multicentric variant of POF is indeed a rare case being only the second case so far which has been documented. Management of such case needs a multidisciplinary approach to prevent the recurrence along with regular long time follow-up.

  14. Exome sequencing in an admixed isolated population indicates NFXL1 variants confer a risk for specific language impairment.

    Directory of Open Access Journals (Sweden)

    Pía Villanueva

    2015-03-01

    Full Text Available Children affected by Specific Language Impairment (SLI fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile, who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations in the NFXL1 gene that confers a nonsynonymous change (N150K and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10-4, 8 variants tested. Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model.

  15. Exome sequencing in an admixed isolated population indicates NFXL1 variants confer a risk for specific language impairment.

    Science.gov (United States)

    Villanueva, Pía; Nudel, Ron; Hoischen, Alexander; Fernández, María Angélica; Simpson, Nuala H; Gilissen, Christian; Reader, Rose H; Jara, Lillian; Echeverry, María Magdalena; Echeverry, Maria Magdalena; Francks, Clyde; Baird, Gillian; Conti-Ramsden, Gina; O'Hare, Anne; Bolton, Patrick F; Hennessy, Elizabeth R; Palomino, Hernán; Carvajal-Carmona, Luis; Veltman, Joris A; Cazier, Jean-Baptiste; De Barbieri, Zulema; Fisher, Simon E; Newbury, Dianne F

    2015-03-01

    Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10-4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model.

  16. Decreased cyclooxygenase inhibition by aspirin in polymorphic variants of human prostaglandin H synthase-1.

    Science.gov (United States)

    Liu, Wen; Poole, Elizabeth M; Ulrich, Cornelia M; Kulmacz, Richard J

    2012-07-01

    Aspirin (ASA), a major antiplatelet and cancer-preventing drug, irreversibly blocks the cyclooxygenase (COX) activity of prostaglandin H synthase-1 (PGHS-1). Considerable differences in ASA effectiveness are observed between individuals, and some of this variability may be due to PGHS-1 protein variants. Our overall aim is to determine which, if any, of the known variants in the mature PGHS-1 protein lead to functional alterations in COX catalysis or inhibition by ASA. The present study targeted four PGHS-1 variants: R53H, R108Q, L237M, and V481I. Wild-type human PGHS-1 and the four polymorphic variants were expressed as histidine-tagged, homodimeric proteins in insect cells using baculovirus vectors, solubilized with a detergent, and purified by affinity chromatography. The purified proteins were characterized in vitro to evaluate COX and peroxidase (POX) catalytic parameters and the kinetics of COX inhibition by ASA and NS-398. Compared with the wild type, several variants showed a higher COX/POX ratio (up to 1.5-fold, for R108Q), an elevated arachidonate Km (up to 1.9-fold, for R108Q), and/or a lower ASA reactivity (up to 60% less, for R108Q). The decreased ASA reactivity in R108Q reflected both a 70% increase in the Ki for ASA and a 30% decrease in the rate constant for acetyl group transfer to the protein. Computational modeling of the brief ASA pulses experienced by PGHS-1 in circulating platelets during daily ASA dosing predicted that the 60% lower ASA reactivity in R108Q yields a 15-fold increase in surviving COX activity; smaller, approximately two-fold increases in surviving COX activity were predicted for L237M and V481I. NS-398 competitively inhibited COX catalysis of the wild type (Ki=6 µmol/l) and inhibited COX inactivation by 1.0 mmol/l ASA in both the wild type (IC50=0.8 µmol/l) and R108Q (IC50=2.1 µmol/l). Of the four PGHS-1 variants examined, R108Q exerts the largest functional effects, with evidence for impaired interactions with a COX

  17. Identifying novel sequence variants of RNA 3D motifs

    Science.gov (United States)

    Zirbel, Craig L.; Roll, James; Sweeney, Blake A.; Petrov, Anton I.; Pirrung, Meg; Leontis, Neocles B.

    2015-01-01

    Predicting RNA 3D structure from sequence is a major challenge in biophysics. An important sub-goal is accurately identifying recurrent 3D motifs from RNA internal and hairpin loop sequences extracted from secondary structure (2D) diagrams. We have developed and validated new probabilistic models for 3D motif sequences based on hybrid Stochastic Context-Free Grammars and Markov Random Fields (SCFG/MRF). The SCFG/MRF models are constructed using atomic-resolution RNA 3D structures. To parameterize each model, we use all instances of each motif found in the RNA 3D Motif Atlas and annotations of pairwise nucleotide interactions generated by the FR3D software. Isostericity relations between non-Watson–Crick basepairs are used in scoring sequence variants. SCFG techniques model nested pairs and insertions, while MRF ideas handle crossing interactions and base triples. We use test sets of randomly-generated sequences to set acceptance and rejection thresholds for each motif group and thus control the false positive rate. Validation was carried out by comparing results for four motif groups to RMDetect. The software developed for sequence scoring (JAR3D) is structured to automatically incorporate new motifs as they accumulate in the RNA 3D Motif Atlas when new structures are solved and is available free for download. PMID:26130723

  18. Contextual social cognition and the behavioral variant of frontotemporal dementia.

    Science.gov (United States)

    Ibañez, Agustin; Manes