Ballard, David; Abraham, Clara; Cho, Judy; Zhao, Hongyu
The use of biological annotation such as genes and pathways in the analysis of gene expression data has aided the identification of genes for follow-up studies and suggested functional information to uncharacterized genes. Several studies have applied similar methods to genome wide association studies and identified a number of disease related pathways. However, many questions remain on how to best approach this problem, such as whether there is a need to obtain a score to summarize association evidence at the gene level, and whether a pathway, dominated by just a few highly significant genes, is of interest. We evaluated the performance of two pathway-based methods (Random Set, and Binomial approximation to the hypergeometric test) based on their applications to three data sets of Crohn's disease. We consider both the disease status as a phenotype as well as the residuals after conditioning on IL23R, a known Crohn's related gene, as a phenotype. Our results show that Random Set method has the most power to identify disease related pathways. We confirm previously reported disease related pathways and provide evidence for IL-2 Receptor Beta Chain in T cell Activation and IL-9 signaling as Crohn's disease associated pathways. Our results highlight the need to apply powerful gene score methods prior to pathway enrichment tests, and that controlling for genes that attain genome wide significance enable further biological insight.
Full Text Available Abstract Background The use of biological annotation such as genes and pathways in the analysis of gene expression data has aided the identification of genes for follow-up studies and suggested functional information to uncharacterized genes. Several studies have applied similar methods to genome wide association studies and identified a number of disease related pathways. However, many questions remain on how to best approach this problem, such as whether there is a need to obtain a score to summarize association evidence at the gene level, and whether a pathway, dominated by just a few highly significant genes, is of interest. Methods We evaluated the performance of two pathway-based methods (Random Set, and Binomial approximation to the hypergeometric test based on their applications to three data sets of Crohn's disease. We consider both the disease status as a phenotype as well as the residuals after conditioning on IL23R, a known Crohn's related gene, as a phenotype. Results Our results show that Random Set method has the most power to identify disease related pathways. We confirm previously reported disease related pathways and provide evidence for IL-2 Receptor Beta Chain in T cell Activation and IL-9 signaling as Crohn's disease associated pathways. Conclusions Our results highlight the need to apply powerful gene score methods prior to pathway enrichment tests, and that controlling for genes that attain genome wide significance enable further biological insight.
del Giacco Stefano
Full Text Available Abstract Background Association studies consist in identifying the genetic variants which are related to a specific disease through the use of statistical multiple hypothesis testing or segregation analysis in pedigrees. This type of studies has been very successful in the case of Mendelian monogenic disorders while it has been less successful in identifying genetic variants related to complex diseases where the insurgence depends on the interactions between different genes and the environment. The current technology allows to genotype more than a million of markers and this number has been rapidly increasing in the last years with the imputation based on templates sets and whole genome sequencing. This type of data introduces a great amount of noise in the statistical analysis and usually requires a great number of samples. Current methods seldom take into account gene-gene and gene-environment interactions which are fundamental especially in complex diseases. In this paper we propose to use a non-parametric additive model to detect the genetic variants related to diseases which accounts for interactions of unknown order. Although this is not new to the current literature, we show that in an isolated population, where the most related subjects share also most of their genetic code, the use of additive models may be improved if the available genealogical tree is taken into account. Specifically, we form a sample of cases and controls with the highest inbreeding by means of the Hungarian method, and estimate the set of genes/environmental variables, associated with the disease, by means of Random Forest. Results We have evidence, from statistical theory, simulations and two applications, that we build a suitable procedure to eliminate stratification between cases and controls and that it also has enough precision in identifying genetic variants responsible for a disease. This procedure has been successfully used for the beta-thalassemia, which is
Full Text Available Abstract Background Most software packages for whole genome association studies are non-graphical, purely text based programs originally designed to run with UNIX-like operating systems. Graphical output is often not intended or supposed to be performed with other command line tools, e.g. gnuplot. Results Using the Microsoft .NET 2.0 platform and Visual Studio 2005, we have created a graphical software package to analyze data from microarray whole genome association studies, both for a DNA-pooling based approach as well as regular single sample data. Part of this package was made to integrate with GenePool 0.8.2, a previously existing software suite for GNU/Linux systems, which we have modified to run in a Microsoft Windows environment. Further modifications cause it to generate some additional data. This enables GenePool to interact with the .NET parts created by us. The programs we developed are GPFrontend, a graphical user interface and frontend to use GenePool and create metadata files for it, and GPGraphics, a program to further analyze and graphically evaluate output of different WGA analysis programs, among them also GenePool. Conclusions Our programs enable regular MS Windows users without much experience in bioinformatics to easily visualize whole genome data from a variety of sources.
However, in Australia, Finland, Spain, Sweden and U.S., there is no significant association between CASP8 D302H and breast cancer risk (Figure 3). No heterogeneity was found between groups or between studies. Hence, the association between CASP8 D302H and breast cancer risk may be country variable. Previously ...
Derkach, Andriy; Zhang, Haoyu; Chatterjee, Nilanjan
Genome-wide association studies are now shifting focus from analysis of common to rare variants. As power for association testing for individual rare variants may often be low, various aggregate level association tests have been proposed to detect genetic loci. Typically, power calculations for such tests require specification of large number of parameters, including effect sizes and allele frequencies of individual variants, making them difficult to use in practice. We propose to approximate power to varying degree of accuracy using a smaller number of key parameters, including the total genetic variance explained by multiple variants within a locus. We perform extensive simulation studies to assess the accuracy of the proposed approximations in realistic settings. Using these simplified power calculations, we develop an analytic framework to obtain bounds on genetic architecture of an underlying trait given results from a genome-wide association studies with rare variants. Finally, we provide insights into the required quality of annotation/functional information for identification of likely causal variants to make meaningful improvement in power. A shiny application that allows a variety of Power Analysis of GEnetic AssociatioN Tests (PAGEANT), in R is made publicly available at https://andrewhaoyu.shinyapps.io/PAGEANT/. email@example.com. Supplementary data are available at Bioinformatics online.
Klein Robert J
Full Text Available Abstract Background Genome-wide association studies are a promising new tool for deciphering the genetics of complex diseases. To choose the proper sample size and genotyping platform for such studies, power calculations that take into account genetic model, tag SNP selection, and the population of interest are required. Results The power of genome-wide association studies can be computed using a set of tag SNPs and a large number of genotyped SNPs in a representative population, such as available through the HapMap project. As expected, power increases with increasing sample size and effect size. Power also depends on the tag SNPs selected. In some cases, more power is obtained by genotyping more individuals at fewer SNPs than fewer individuals at more SNPs. Conclusion Genome-wide association studies should be designed thoughtfully, with the choice of genotyping platform and sample size being determined from careful power calculations.
Ali, Fadhaa; Zhang, Jian
Multilocus haplotype analysis of candidate variants with genome wide association studies (GWAS) data may provide evidence of association with disease, even when the individual loci themselves do not. Unfortunately, when a large number of candidate variants are investigated, identifying risk haplotypes can be very difficult. To meet the challenge, a number of approaches have been put forward in recent years. However, most of them are not directly linked to the disease-penetrances of haplotypes and thus may not be efficient. To fill this gap, we propose a mixture model-based approach for detecting risk haplotypes. Under the mixture model, haplotypes are clustered directly according to their estimated disease penetrances. A theoretical justification of the above model is provided. Furthermore, we introduce a hypothesis test for haplotype inheritance patterns which underpin this model. The performance of the proposed approach is evaluated by simulations and real data analysis. The results show that the proposed approach outperforms an existing multiple testing method.
Morris, Andrew P.
The detection of loci contributing effects to complex human traits, and their subsequent fine-mapping for the location of causal variants, remains a considerable challenge for the genetics research community. Meta-analyses of genomewide association studies, primarily ascertained from European-descent populations, have made considerable advances in our understanding of complex trait genetics, although much of their heritability is still unexplained. With the increasing availability of genomewi...
Evangelou, Evangelos; Kerkhof, Hanneke J; Styrkarsdottir, Unnur
Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.......Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects....
Jun 17, 2017 ... Abstract. Caspase 8 (CASP8) is a regulator of apoptosis, whose genetic variation has been reported to be associated with the risk of various cancers. Especially, the single-nucleotide polymorphism (SNP) rs1045485, which generates the substitution. D302H in CASP8, is likely to be associated with breast ...
Caspase 8 (CASP8) is a regulator of apoptosis, whose genetic variation has been reported to be associated with the risk of various cancers. Especially, the single-nucleotide polymorphism (SNP) rs1045485, which generates the substitution D302H in CASP8, is likely to be associated with breast cancer. Several previous ...
E. Evangelou (Evangelos); J.M. Kerkhof (Hanneke); U. Styrkarsdottir (Unnur); E.E. Ntzani (Evangelia); S.D. Bos (Steffan); T. Esko (Tõnu); D.S. Evans (Daniel); S. Metrustry (Sarah); K. Panoutsopoulou (Kalliope); Y.F.M. Ramos (Yolande); G. Thorleifsson (Gudmar); K.K. Tsilidis (Konstantinos); N.K. Arden (Nigel); N. Aslam (Nadim); N. Bellamy (Nicholas); F. Birrell (Fraser); Blanco, F.J. (Francisco J.); A.J. Carr (Andrew Jonathan); K. Chapman (Kay); A.G. Day-Williams (Aaron); P. Deloukas (Panagiotis); M. Doherty (Michael); G. Engström; H.T. Helgadottir (Hafdis); A. Hofman (Albert); T. Ingvarsson (Torvaldur); H. Jonsson (Helgi); A. Keis (Aime); J.C. Keurentjes (J. Christiaan); M. Kloppenburg (Margreet); P.A. Lind (Penelope); A. McCaskie (Andrew); N.G. Martin (Nicholas); L. Milani (Lili); G.W. Montgomery (Grant); R.G.H.H. Nelissen (Rob); M.C. Nevitt (Michael); P. Nilsson (Peter); W.E.R. Ollier (William); N. Parimi (Neeta); A. Rai (Ashok); S.H. Ralston (Stuart); M.R. Reed (Mike); J.A. Riancho (José); F. Rivadeneira Ramirez (Fernando); C. Rodriguez-Fontenla (Cristina); L. Southam (Lorraine); U. Thorsteinsdottir (Unnur); A. Tsezou (Aspasia); G.A. Wallis (Gillian); J.M. Wilkinson (Mark); A. Gonzalez (Antonio); N.E. Lane; L.S. Lohmander (Stefan); J. Loughlin (John); A. Metspalu (Andres); A.G. Uitterlinden (André); I. Jonsdottir (Ingileif); J-A. Zwart (John-Anker); P.E. Slagboom (Eline); E. Zeggini (Eleftheria); I. Meulenbelt (Ingrid); J.P.A. Ioannidis (John); T.D. Spector (Timothy); J.B.J. van Meurs (Joyce); A.M. Valdes (Ana Maria)
textabstractOBJECTIVES: Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.METHODS: We performed a two-stage meta-analysis
E. Evangelou (Evangelos); J.M. Kerkhof (Hanneke); U. Styrkarsdottir (Unnur); E.E. Ntzani (Evangelia); S.D. Bos (Steffan); T. Esko (Tõnu); D.S. Evans (Daniel); S. Metrustry (Sarah); K. Panoutsopoulou (Kalliope); Y.F.M. Ramos (Yolande); G. Thorleifsson (Gudmar); K.K. Tsilidis (Konstantinos); N.K. Arden (Nigel); N. Aslam (Nadim); N. Bellamy (Nicholas); F. Birrell (Fraser); F.J. Blanco; A.J. Carr (Andrew Jonathan); K. Chapman (Kay); A.G. Day-Williams (Aaron); P. Deloukas (Panagiotis); M. Doherty (Michael); G. Engström; H.T. Helgadottir (Hafdis); A. Hofman (Albert); T. Ingvarsson (Torvaldur); H. Jonsson (Helgi); A. Keis (Aime); J.C. Keurentjes (J. Christiaan); M. Kloppenburg (Margreet); P.A. Lind (Penelope); A. McCaskie (Andrew); N.G. Martin; A.L. Milani (Alfredo); G.W. Montgomery; R.G.H.H. Nelissen (Rob); M.C. Nevitt (Michael); P. Nilsson (Peter); W.E.R. Ollier (William); N. Parimi (Neeta); A. Rai (Ashok); S.H. Ralston; M.R. Reed (Mike); J.A. Riancho (José); F. Rivadeneira Ramirez (Fernando); C. Rodriguez-Fontenla (Cristina); L. Southam (Lorraine); U. Thorsteinsdottir (Unnur); A. Tsezou (Aspasia); G.A. Wallis (Gillian); J.M. Wilkinson (Mark); A. Gonzalez (Antonio); N.E. Lane; L.S. Lohmander (Stefan); J. Loughlin (John); A. Metspalu (Andres); A.G. Uitterlinden (André); I. Jonsdottir (Ingileif); J-A. Zwart (John-Anker); P.E. Slagboom (Eline); E. Zeggini (Eleftheria); I. Meulenbelt (Ingrid); J.P.A. Ioannidis (John); T.D. Spector (Timothy); J.B.J. van Meurs (Joyce); A.M. Valdes (Ana Maria)
textabstractObjectives: Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. Methods: We performed a two-stage meta-analysis
Full Text Available In a meta-analysis with multiple end points of interests that are correlated between or within studies, multivariate approach to meta-analysis has a potential to produce more precise estimates of effects by exploiting the correlation structure between end points. However, under random-effects assumption the multivariate estimation is more complex (as it involves estimation of more parameters simultaneously than univariate estimation, and sometimes can produce unrealistic parameter estimates. Usefulness of multivariate approach to meta-analysis of the effects of a genetic variant on two or more correlated traits is not well understood in the area of genetic association studies. In such studies, genetic variants are expected to roughly maintain Hardy-Weinberg equilibrium within studies, and also their effects on complex traits are generally very small to modest and could be heterogeneous across studies for genuine reasons. We carried out extensive simulation to explore the comparative performance of multivariate approach with most commonly used univariate inverse-variance weighted approach under random-effects assumption in various realistic meta-analytic scenarios of genetic association studies of correlated end points. We evaluated the performance with respect to relative mean bias percentage, and root mean square error (RMSE of the estimate and coverage probability of corresponding 95% confidence interval of the effect for each end point. Our simulation results suggest that multivariate approach performs similarly or better than univariate method when correlations between end points within or between studies are at least moderate and between-study variation is similar or larger than average within-study variation for meta-analyses of 10 or more genetic studies. Multivariate approach produces estimates with smaller bias and RMSE especially for the end point that has randomly or informatively missing summary data in some individual studies, when
Martorell-Marugan, Jordi; Toro-Dominguez, Daniel; Alarcon-Riquelme, Marta E; Carmona-Saez, Pedro
Genetic association studies (GAS) aims to evaluate the association between genetic variants and phenotypes. In the last few years, the number of this type of study has increased exponentially, but the results are not always reproducible due to experimental designs, low sample sizes and other methodological errors. In this field, meta-analysis techniques are becoming very popular tools to combine results across studies to increase statistical power and to resolve discrepancies in genetic association studies. A meta-analysis summarizes research findings, increases statistical power and enables the identification of genuine associations between genotypes and phenotypes. Meta-analysis techniques are increasingly used in GAS, but it is also increasing the amount of published meta-analysis containing different errors. Although there are several software packages that implement meta-analysis, none of them are specifically designed for genetic association studies and in most cases their use requires advanced programming or scripting expertise. We have developed MetaGenyo, a web tool for meta-analysis in GAS. MetaGenyo implements a complete and comprehensive workflow that can be executed in an easy-to-use environment without programming knowledge. MetaGenyo has been developed to guide users through the main steps of a GAS meta-analysis, covering Hardy-Weinberg test, statistical association for different genetic models, analysis of heterogeneity, testing for publication bias, subgroup analysis and robustness testing of the results. MetaGenyo is a useful tool to conduct comprehensive genetic association meta-analysis. The application is freely available at http://bioinfo.genyo.es/metagenyo/ .
Berndt, Sonja I; Camp, Nicola J; Skibola, Christine F; Vijai, Joseph; Wang, Zhaoming; Gu, Jian; Nieters, Alexandra; Kelly, Rachel S; Smedby, Karin E; Monnereau, Alain; Cozen, Wendy; Cox, Angela; Wang, Sophia S; Lan, Qing; Teras, Lauren R; Machado, Moara; Yeager, Meredith; Brooks-Wilson, Angela R; Hartge, Patricia; Purdue, Mark P; Birmann, Brenda M; Vajdic, Claire M; Cocco, Pierluigi; Zhang, Yawei; Giles, Graham G; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Montalvan, Rebecca; Burdett, Laurie; Hutchinson, Amy; Ye, Yuanqing; Call, Timothy G; Shanafelt, Tait D; Novak, Anne J; Kay, Neil E; Liebow, Mark; Cunningham, Julie M; Allmer, Cristine; Hjalgrim, Henrik; Adami, Hans-Olov; Melbye, Mads; Glimelius, Bengt; Chang, Ellen T; Glenn, Martha; Curtin, Karen; Cannon-Albright, Lisa A; Diver, W Ryan; Link, Brian K; Weiner, George J; Conde, Lucia; Bracci, Paige M; Riby, Jacques; Arnett, Donna K; Zhi, Degui; Leach, Justin M; Holly, Elizabeth A; Jackson, Rebecca D; Tinker, Lesley F; Benavente, Yolanda; Sala, Núria; Casabonne, Delphine; Becker, Nikolaus; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; McKay, James; Staines, Anthony; Chaffee, Kari G; Achenbach, Sara J; Vachon, Celine M; Goldin, Lynn R; Strom, Sara S; Leis, Jose F; Weinberg, J Brice; Caporaso, Neil E; Norman, Aaron D; De Roos, Anneclaire J; Morton, Lindsay M; Severson, Richard K; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Masala, Giovanna; Weiderpass, Elisabete; Chirlaque, María-Dolores; Vermeulen, Roel C H; Travis, Ruth C; Southey, Melissa C; Milne, Roger L; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Clavel, Jacqueline; Zheng, Tongzhang; Holford, Theodore R; Villano, Danylo J; Maria, Ann; Spinelli, John J; Gascoyne, Randy D; Connors, Joseph M; Bertrand, Kimberly A; Giovannucci, Edward; Kraft, Peter; Kricker, Anne; Turner, Jenny; Ennas, Maria Grazia; Ferri, Giovanni M; Miligi, Lucia; Liang, Liming; Ma, Baoshan; Huang, Jinyan; Crouch, Simon; Park, Ju-Hyun; Chatterjee, Nilanjan; North, Kari E; Snowden, John A; Wright, Josh; Fraumeni, Joseph F; Offit, Kenneth; Wu, Xifeng; de Sanjose, Silvia; Cerhan, James R; Chanock, Stephen J; Rothman, Nathaniel; Slager, Susan L
Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and
Full Text Available Metabolic syndrome (MetS is a complex disorder related to insulin resistance, obesity, and inflammation. Genetic and environmental factors also contribute to the development of MetS, and through genome-wide association studies (GWASs, important susceptibility loci have been identified. However, GWASs focus more on individual single-nucleotide polymorphisms (SNPs, explaining only a small portion of genetic heritability. To overcome this limitation, pathway analyses are being applied to GWAS datasets. The aim of this study is to elucidate the biological pathways involved in the pathogenesis of MetS through pathway analysis. Cohort data from the Korea Associated Resource (KARE was used for analysis, which include 8,842 individuals (age, 52.2 ± 8.9 years; body mass index, 24.6 ± 3.2 kg/m2. A total of 312,121 autosomal SNPs were obtained after quality control. Pathway analysis was conducted using Meta-analysis Gene-Set Enrichment of Variant Associations (MAGENTA to discover the biological pathways associated with MetS. In the discovery phase, SNPs from chromosome 12, including rs11066280, rs2074356, and rs12229654, were associated with MetS (p < 5 × 10-6, and rs11066280 satisfied the Bonferroni-corrected cutoff (unadjusted p < 1.38 × 10-7, Bonferroni-adjusted p < 0.05. Through pathway analysis, biological pathways, including electron carrier activity, signaling by platelet-derived growth factor (PDGF, the mitogen-activated protein kinase kinase kinase cascade, PDGF binding, peroxisome proliferator-activated receptor (PPAR signaling, and DNA repair, were associated with MetS. Through pathway analysis of MetS, pathways related with PDGF, mitogen-activated protein kinase, and PPAR signaling, as well as nucleic acid binding, protein secretion, and DNA repair, were identified. Further studies will be needed to clarify the genetic pathogenesis leading to MetS.
Wang, Z.; McGlynn, K.A.; Rajpert- de Meyts, E.; Bishop, D.T.; Chung, C.C.; Dalgaard, M.D.; Greene, M.H.; Gupta, R; Grotmol, T.; Haugen, T.B.; Karlsson, R.; Litchfield, K.; Mitra, N.; Nielsen, K.; Pyle, L.C.; Schwartz, S.M.; Thorsson, V.; Vardhanabhuti, S.; Wiklund, F.; Turnbull, C.; Chanock, S.J.; Kanetsky, P.A.; Nathanson, K.L.; Kiemeney, B.; Skotheim, R.I.; Zheng, T.
The international Testicular Cancer Consortium (TECAC) combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new susceptibility loci. We conducted a fixed-effects meta-analysis, including, to our knowledge, the first
Wang, Zhaoming; McGlynn, Katherine A.; Rajpert-De Meyts, Ewa
The international Testicular Cancer Consortium (TECAC) combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new susceptibility loci. We conducted a fixed-effects meta-analysis, including, to our knowledge, the fi...
Postmus, Iris; Trompet, Stella; Deshmukh, Harshal A.; Barnes, Michael R.; Li, Xiaohui; Warren, Helen R.; Chasman, Daniel I.; Zhou, Kaixin; Arsenault, Benoit J.; Donnelly, Louise A.; Wiggins, Kerri L.; Avery, Christy L.; Griffin, Paula; Feng, QiPing; Taylor, Kent D.; Li, Guo; Evans, Daniel S.; Smith, Albert V.; de Keyser, Catherine E.; Johnson, Andrew D.; de Craen, Anton J. M.; Stott, David J.; Buckley, Brendan M.; Ford, Ian; Westendorp, Rudi G. J.; Slagboom, P. Eline; Sattar, Naveed; Munroe, Patricia B.; Sever, Peter; Poulter, Neil; Stanton, Alice; Shields, Denis C.; O'Brien, Eoin; Shaw-Hawkins, Sue; Chen, Y.-D. Ida; Nickerson, Deborah A.; Smith, Joshua D.; Dubé, Marie Pierre; Boekholdt, S. Matthijs; Hovingh, G. Kees; Kastelein, John J. P.; McKeigue, Paul M.; Betteridge, John; Neil, Andrew; Durrington, Paul N.; Doney, Alex; Carr, Fiona; Morris, Andrew; McCarthy, Mark I.; Groop, Leif; Ahlqvist, Emma; Bis, Joshua C.; Rice, Kenneth; Smith, Nicholas L.; Lumley, Thomas; Whitsel, Eric A.; Stürmer, Til; Boerwinkle, Eric; Ngwa, Julius S.; O'Donnell, Christopher J.; Vasan, Ramachandran S.; Wei, Wei-Qi; Wilke, Russell A.; Liu, Ching-Ti; Sun, Fangui; Guo, Xiuqing; Heckbert, Susan R.; Post, Wendy; Sotoodehnia, Nona; Arnold, Alice M.; Stafford, Jeanette M.; Ding, Jingzhong; Herrington, David M.; Kritchevsky, Stephen B.; Eiriksdottir, Gudny; Launer, Leonore J.; Harris, Tamara B.; Chu, Audrey Y.; Giulianini, Franco; Macfadyen, Jean G.; Barratt, Bryan J.; Nyberg, Fredrik; Stricker, Bruno H.; Uitterlinden, André G.; Hofman, Albert; Rivadeneira, Fernando; Emilsson, Valur; Franco, Oscar H.; Ridker, Paul M.; Gudnason, Vilmundur; Liu, Yongmei; Denny, Joshua C.; Ballantyne, Christie M.; Rotter, Jerome I.; Adrienne Cupples, L.; Psaty, Bruce M.; Palmer, Colin N. A.; Tardif, Jean-Claude; Colhoun, Helen M.; Hitman, Graham; Krauss, Ronald M.; Wouter Jukema, J.; Caulfield, Mark J.; Donnelly, Peter; Barroso, Ines; Blackwell, Jenefer M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Deloukas, Panos; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Trembath, Richard C.; Viswanathan, Ananth C.; Wood, Nicholas W.; Spencer, Chris C. A.; Band, Gavin; Bellenguez, Céline; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Pearson, Richard; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Langford, Cordelia; Hunt, Sarah E.; Edkins, Sarah; Gwilliam, Rhian; Blackburn, Hannah; Bumpstead, Suzannah J.; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T.; Liddle, Jennifer; Potter, Simon C.; Ravindrarajah, Radhi; Ricketts, Michelle; Waller, Matthew; Weston, Paul; Widaa, Sara; Whittaker, Pamela
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol
Zabalza, Michel; Subirana, Isaac; Lluis-Ganella, Carla; Sayols-Baixeras, Sergi; de Groot, Eric; Arnold, Roman; Cenarro, Ana; Ramos, Rafel; Marrugat, Jaume; Elosua, Roberto
Recent studies have identified several genetic variants associated with coronary artery disease. Some of these genetic variants are not associated with classical cardiovascular risk factors and the mechanism of such associations is unclear. The aim of the study was to determine whether these genetic variants are related to subclinical atherosclerosis measured by carotid intima media thickness, carotid stiffness, and ankle brachial index. A cross-sectional study nested in the follow-up of the REGICOR cohort was undertaken. The study included 2667 individuals. Subclinical atherosclerosis measurements were performed with standardized methods. Nine genetic variants were genotyped to assess associations with subclinical atherosclerosis, individually and in a weighted genetic risk score. A systematic review and meta-analysis of previous studies that analyzed these associations was undertaken. Neither the selected genetic variants nor the genetic risk score were significantly associated with subclinical atherosclerosis. In the meta-analysis, the rs1746048 (CXCL12; n = 10581) risk allele was directly associated with carotid intima-media thickness (β = 0.008; 95% confidence interval, 0.001-0.015), whereas the rs6725887 (WDR12; n = 7801) risk allele was inversely associated with this thickness (β = -0.013; 95% confidence interval, -0.024 to -0.003). The analyzed genetic variants seem to mediate their association with coronary artery disease through different mechanisms. Our results generate the hypothesis that the CXCL12 variant appears to influence coronary artery disease risk through arterial remodeling and thickening, whereas the WDR12 risk variant could be related to higher plaque vulnerability. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.
Evangelou, Evangelos; Kerkhof, Hanneke J; Styrkarsdottir, Unnur; Ntzani, Evangelia E; Bos, Steffan D; Esko, Tonu; Evans, Daniel S; Metrustry, Sarah; Panoutsopoulou, Kalliope; Ramos, Yolande F M; Thorleifsson, Gudmar; Tsilidis, Konstantinos K; Arden, Nigel; Aslam, Nadim; Bellamy, Nicholas; Birrell, Fraser; Blanco, Francisco J; Carr, Andrew; Chapman, Kay; Day-Williams, Aaron G; Deloukas, Panos; Doherty, Michael; Engström, Gunnar; Helgadottir, Hafdis T; Hofman, Albert; Ingvarsson, Thorvaldur; Jonsson, Helgi; Keis, Aime; Keurentjes, J Christiaan; Kloppenburg, Margreet; Lind, Penelope A; McCaskie, Andrew; Martin, Nicholas G; Milani, Lili; Montgomery, Grant W; Nelissen, Rob G H H; Nevitt, Michael C; Nilsson, Peter M; Ollier, William ER; Parimi, Neeta; Rai, Ashok; Ralston, Stuart H; Reed, Mike R; Riancho, Jose A; Rivadeneira, Fernando; Rodriguez-Fontenla, Cristina; Southam, Lorraine; Thorsteinsdottir, Unnur; Tsezou, Aspasia; Wallis, Gillian A; Wilkinson, J Mark; Gonzalez, Antonio; Lane, Nancy E; Lohmander, L Stefan; Loughlin, John; Metspalu, Andres; Uitterlinden, Andre G; Jonsdottir, Ingileif; Stefansson, Kari; Slagboom, P Eline; Zeggini, Eleftheria; Meulenbelt, Ingrid; Ioannidis, John PA; Spector, Tim D; van Meurs, Joyce B J; Valdes, Ana M
Objectives Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. Methods We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for ‘in silico’ or ‘de novo’ replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. Results We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10−9 and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10−8) and follow-up studies (p=7.3×10−4). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10−7, OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10−6, OR=1.27 in male specific analysis). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS. PMID:23989986
Neale, Benjamin M.; Medland, Sarah E.; Ripke, Stephan; Asherson, Philip; Franke, Barbara; Lesch, Klaus-Peter; Faraone, Stephen V.; Nguyen, Thuy Trang; Schafer, Helmut; Holmans, Peter; Daly, Mark; Steinhausen, Hans-Christoph; Freitag, Christine; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Walitza, Susanne; Warnke, Andreas; Meyer, Jobst; Palmason, Haukur; Buitelaar, Jan; Vasquez, Alejandro Arias; Lambregts-Rommelse, Nanda; Gill, Michael; Anney, Richard J. L.; Langely, Kate; O'Donovan, Michael; Williams, Nigel; Owen, Michael; Thapar, Anita; Kent, Lindsey; Sergeant, Joseph; Roeyers, Herbert; Mick, Eric; Biederman, Joseph; Doyle, Alysa; Smalley, Susan; Loo, Sandra; Hakonarson, Hakon; Elia, Josephine; Todorov, Alexandre; Miranda, Ana; Mulas, Fernando; Ebstein, Richard P.; Rothenberger, Aribert; Banaschewski, Tobias; Oades, Robert D.; Sonuga-Barke, Edmund; McGough, James; Nisenbaum, Laura; Middleton, Frank; Hu, Xiaolan; Nelson, Stan
Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of…
Lanktree, Matthew B.; Guo, Yiran; Murtaza, Muhammed; Glessner, Joseph T.; Bailey, Swneke D.; Onland-Moret, N. Charlotte; Lettre, Guillaume; Ongen, Halit; Rajagopalan, Ramakrishnan; Johnson, Toby; Shen, Haiqing; Nelson, Christopher P.; Klopp, Norman; Baumert, Jens; Padmanabhan, Sandosh; Pankratz, Nathan; Pankow, James S.; Shah, Sonia; Taylor, Kira; Barnard, John; Peters, Bas J.; Maloney, Cliona M.; Lobmeyer, Maximilian T.; Stanton, Alice; Zafarmand, M. Hadi; Romaine, Simon P. R.; Mehta, Amar; van Iperen, Erik P. A.; Gong, Yan; Price, Tom S.; Smith, Erin N.; Kim, Cecilia E.; Li, Yun R.; Asselbergs, Folkert W.; Atwood, Larry D.; Bailey, Kristian M.; Bhatt, Deepak; Bauer, Florianne; Behr, Elijah R.; Bhangale, Tushar; Boer, Jolanda M. A.; Boehm, Bernhard O.; Bradfield, Jonathan P.; Brown, Morris; Braund, Peter S.; Burton, Paul R.; Carty, Cara; Chandrupatla, Hareesh R.; Chen, Wei; Connell, John; Dalgeorgou, Chrysoula; de Boer, Anthonius; Drenos, Fotios; Elbers, Clara C.; Fang, James C.; Fox, Caroline S.; Frackelton, Edward C.; Fuchs, Barry; Furlong, Clement E.; Gibson, Quince; Gieger, Christian; Goe, Anuj; Grobbee, Diederik E.; Hastie, Claire; Howard, Philip J.; Huang, Guan-Hua; Johnson, W. Craig; Li, Qing; Kleber, Marcus E.; Klein, Barbara E. K.; Klein, Ronald; Kooperberg, Charles; Ky, Bonnie; LaCroix, Andrea; Lanken, Paul; Lathrop, Mark; Li, Mingyao; Marshal, Vanessa; Melander, Olle; Mentch, Frank D.; Meyer, Nuala J.; Monda, Keri L.; Montpetit, Alexandre; Murugesan, Gurunathan; Nakayama, Karen; Nondah, Dave; Onipinla, Abiodun; Rafelt, Suzanne; Newhouse, Stephen J.; Otieno, F. George; Patel, Sanjey R.; Putt, Mary E.; Rodriguez, Santiago; Safa, Radwan N.; Sawyer, Douglas B.; Schreiner, Pamela J.; Simpson, Claire; Sivapalaratnam, Suthesh; Srinivasan, Sathanur R.; Suver, Christine; Swergold, Gary; Sweitzer, Nancy K.; Thomas, Kelly A.; Thorand, Barbara; Timpson, Nicholas J.; Tischfield, Sam; Tobin, Martin; Tomaszweski, Maciej; Verschuren, W. M. Monique; Wallace, Chris; Winkelmann, Bernhard; Zhang, Haitao; Zheng, Dongling; Zhang, Li; Zmuda, Joseph M.; Clarke, Robert; Balmforth, Anthony J.; Danesh, John; Day, Ian N.; Schork, Nicholas J.; de Bakker, Paul I. W.; Delles, Christian; Duggan, David; Hingorani, Aroon D.; Hirschhorn, Joel N.; Hofker, Marten H.; Humphries, Steve E.; Kivimaki, Mika; Lawlor, Debbie A.; Kottke-Marchant, Kandice; Mega, Jessica L.; Mitchell, Braxton D.; Morrow, David A.; Palmen, Jutta; Redline, Susan; Shields, Denis C.; Shuldiner, Alan R.; Sleiman, Patrick M.; Smith, George Davey; Farrall, Martin; Jamshidi, Yalda; Christiani, David C.; Casas, Juan P.; Hall, Alistair S.; Doevendans, Pieter A.; Christie, Jason D.; Berenson, Gerald S.; Murray, Sarah S.; Illig, Thomas; Dorn, Gerald W.; Cappola, Thomas P.; Boerwinkle, Eric; Sever, Peter; Rader, Daniel J.; Reilly, Muredach P.; Caulfield, Mark; Talmud, Philippa J.; Topol, Eric; Engert, James C.; Wang, Kai; Dominiczak, Anna; Hamsten, Anders; Curtis, Sean P.; Silverstein, Roy L.; Lange, Leslie A.; Sabatine, Marc S.; Trip, Mieke; Saleheen, Danish; Peden, John F.; Cruickshanks, Karen J.; Maerz, Winfried; O'Connell, Jeffrey R.; Klungel, Olaf H.; Wijmenga, Cisca; Maitland-van der Zee, Anke Hilse; Schadt, Eric E.; Johnson, Julie A.; Jarvik, Gail P.; Papanicolaou, George J.; Watkins, Hugh; Grant, Struan F. A.; Munroe, Patricia B.; North, Kari E.; Samani, Nilesh J.; Koenig, Wolfgang; Gaunt, Tom R.; Anand, Sonia S.; van der Schouw, Yvonne T.; Kumari, Meena; Soranzo, Nicole; FitzGerald, Garret A.; Reiner, Alex; Hegele, Robert A.; Hakonarson, Hakon; Keating, Brendan J.
Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and
Babu, Giridhara R; Jotheeswaran, A T; Mahapatra, Tanmay; Mahapatra, Sanchita; Kumar, Ananth; Detels, Roger; Pearce, Neil
Job strain results from a combination of high workload and few decision-making opportunities in the workplace. There is inconsistent evidence regarding the association between job strain and hypertension, and methodological shortcomings preclude firm conclusions. Thus, a meta-analysis of observational studies on hypertension among occupational groups was conducted to determine whether job strain was associated with hypertension. In January 2012, we carried out a comprehensive, topic-specific electronic literature search of the Ovid MEDLINE, EMBASE and PsychoINFO databases complemented by individual help from non-communicable disease experts. Experimental/interventional studies and studies on personality disorders were excluded. Nine of 894 identified studies met the eligibility criteria and were included in the meta-analysis. The pooled OR of the nine studies was 1.29 (95% CI 1.14 to 1.47; pjob strain and hypertension [corrected]. In a subgroup analysis, cohort studies of good methodological quality showed significant associations between job strain and hypertension, while those of poor methodological quality showed no association or subgroup differences. We conclude that despite methodological differences, case-control and cohort studies of good methodological quality showed positive associations between hypertension and job strain.
Full Text Available Brachial circumference (BC, also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p<0.05 in the age-adjusted strata for men and across both sexes. In this first GWAS meta-analysis for BC to date, we have not identified any genome-wide significant signals and do not observe robust association of previously established obesity loci with BC. Large-scale collaborations will be necessary to achieve higher power to detect loci underlying BC.
Xu, T; Zhang, Y-H
Psoriasis is a common, chronic, relapsing, inflammatory skin disorder. Observational studies suggest an association between psoriasis and the incidence of stroke or myocardial infarction (MI). However, whether psoriasis is an independent risk factor for these two vascular events remains controversial. To evaluate the association of psoriasis with stroke and MI by conducting a meta-analysis of cohort studies. Cohort studies were searched in MEDLINE (Pubmed), EMBASE and Cochrane Library from their inception to March 2012. Stroke and MI were considered as a composite endpoint. Two authors independently extracted information on the characteristics of the study participants, follow-up range and control for potential confounding factors. A random-effects model was used to calculate the overall combined risk estimates. Seven cohort studies were included in the meta-analysis. On the basis of cohort characteristics, five of them were considered good quality and two were fair. The overall combined relative risk for psoriasis and composite vascular endpoint was 1·2 (95% confidence interval 1·1-1·31). Subgroup analysis maintained this significance with respect to stroke and MI individually. Sensitivity analysis and 'trim and fill' method yielded similar results. No evidence of publication bias was observed. This meta-analysis of cohort studies suggests that psoriasis significantly increases the risk of stroke and MI. The increase is probably independent of conventional cardiovascular risk factors. © 2012 The Authors. BJD © 2012 British Association of Dermatologists.
Stahl, Eli A.; Raychaudhuri, Soumya; Remmers, Elaine F.; Xie, Gang; Eyre, Stephen; Thomson, Brian P.; Li, Yonghong; Kurreeman, Fina A. S.; Zhernakova, Alexandra; Hinks, Anne; Guiducci, Candace; Chen, Robert; Alfredsson, Lars; Amos, Christopher I.; Ardlie, Kristin G.; Barton, Anne; Bowes, John; Brouwer, Elisabeth; Burtt, Noel P.; Catanese, Joseph J.; Coblyn, Jonathan; Coenen, Marieke J. H.; Costenbader, Karen H.; Criswell, Lindsey A.; Crusius, J. Bart A.; Cui, Jing; de Bakker, Paul I. W.; De Jager, Philip L.; Ding, Bo; Emery, Paul; Flynn, Edward; Harrison, Pille; Hocking, Lynne J.; Huizinga, Tom W. J.; Kastner, Daniel L.; Ke, Xiayi; Lee, Annette T.; Liu, Xiangdong; Martin, Paul; Morgan, Ann W.; Padyukov, Leonid; Posthumus, Marcel D.; Radstake, Timothy R. D. J.; Reid, David M.; Seielstad, Mark; Seldin, Michael F.; Shadick, Nancy A.; Steer, Sophia; Tak, Paul P.; Thomson, Wendy; van der Helm-van Mil, Annette H. M.; van der Horst-Bruinsma, Irene E.; van der Schoot, C. Ellen; van Riel, Piet L. C. M.; Weinblatt, Michael E.; Wilson, Anthony G.; Wolbink, Gert Jan; Wordsworth, B. Paul; Wijmenga, Cisca; Karlson, Elizabeth W.; Toes, Rene E. M.; de Vries, Niek; Begovich, Ann B.; Worthington, Jane; Siminovitch, Katherine A.; Gregersen, Peter K.; Klareskog, Lars; Plenge, Robert M.
To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768
Sullivan, Patrick F.; Daly, Mark J.; Ripke, Stephan; Lewis, Cathryn M.; Lin, Dan-Yu; Wray, Naomi R.; Neale, Benjamin; Levinson, Douglas F.; Breen, Gerome; Byrne, Enda M.; Wray, Naomi R.; Levinson, Douglas F.; Rietschel, Marcella; Hoogendijk, Witte; Ripke, Stephan; Sullivan, Patrick F.; Hamilton, Steven P.; Levinson, Douglas F.; Lewis, Cathryn M.; Ripke, Stephan; Weissman, Myrna M.; Wray, Naomi R.; Breuer, Rene; Cichon, Sven; Degenhardt, Franziska; Frank, Josef; Gross, Magdalena; Herms, Stefan; Hoefels, Susanne; Maier, Wolfgang; Mattheisen, Manuel; Noeethen, Markus M.; Rietschel, Marcella; Schulze, Thomas G.; Steffens, Michael; Treutlein, Jens; Boomsma, Dorret I.; De Geus, Eco J.; Hoogendijk, Witte; Hottenga, Jouke Jan; Jung-Ying, Tzeng; Lin, Dan-Yu; Middeldorp, Christel M.; Nolen, Willem A.; Penninx, Brenda P.; Smit, Johannes H.; Sullivan, Patrick F.; van Grootheest, Gerard; Willemsen, Gonneke; Zitman, Frans G.; Coryell, William H.; Knowles, James A.; Lawson, William B.; Levinson, Douglas F.; Potash, James B.; Scheftner, William A.; Shi, Jianxin; Weissman, Myrna M.; Holsboer, Florian; Muglia, Pierandrea; Tozzi, Federica; Blackwood, Douglas H. R.; Boomsma, Dorret I.; De Geus, Eco J.; Hottenga, Jouke Jan; MacIntyre, Donald J.; McIntosh, Andrew; McLean, Alan; Middeldorp, Christel M.; Penninx, Brenda P.; Ripke, Stephan; Smit, Johannes H.; Sullivan, Patrick F.; van Grootheest, Gerard; Willemsen, Gonneke; Zitman, Frans G.; van den Oord, Edwin J. C. G.; Holsboer, Florian; Lucae, Susanne; Binder, Elisabeth; Mueller-Myhsok, Bertram; Ripke, Stephan; Czamara, Darina; Kohli, Martin A.; Ising, Marcus; Uhr, Manfred; Bettecken, Thomas; Barnes, Michael R.; Breen, Gerome; Craig, Ian W.; Farmer, Anne E.; Lewis, Cathryn M.; McGuffin, Peter; Muglia, Pierandrea; Byrne, Enda; Gordon, Scott D.; Heath, Andrew C.; Henders, Anjali K.; Hickie, Ian B.; Madden, Pamela A. F.; Martin, Nicholas G.; Montgomery, Grant M.; Nyholt, Dale R.; Pergadia, Michele L.; Wray, Naomi R.; Hamilton, Steven P.; McGrath, Patrick J.; Shyn, Stanley I.; Slager, Susan L.; Oskarsson, Hoegni; Sigurdsson, Engilbert; Stefansson, Hreinn; Stefansson, Kari; Steinberg, Stacy; Thorgeirsson, Thorgeir; Levinson, Douglas F.; Potash, James B.; Shi, Jianxin; Weissman, Myrna M.; Guipponi, Michel; Lewis, Glyn; O'Donovan, Michael; Tansey, Katherine E.; Uher, Rudolf; Coryell, William H.; Knowles, James A.; Lawson, William B.; Levinson, Douglas F.; Potash, James B.; Scheftner, William A.; Shi, Jianxin; Weissman, Myrna M.; Castro, Victor M.; Churchill, Susanne E.; Fava, Maurizio; Gainer, Vivian S.; Gallagher, Patience J.; Goryachev, Sergey; Iosifescu, Dan V.; Kohane, Isaac S.; Murphy, Shawn N.; Perlis, Roy H.; Smoller, Jordan W.; Weilburg, Jeffrey B.; Kutalik, Zoltan; Preisig, Martin; Grabe, Hans J.; Nauck, Matthias; Schulz, Andrea; Teumer, Alexander; Voelzke, Henry; Landen, Mikael; Lichtenstein, Paul; Magnusson, Patrik; Pedersen, Nancy; Viktorin, Alexander
Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X
Magi, Reedik; Lindgren, Cecilia M; Morris, Andrew P
Despite the success of genome-wide association studies, much of the genetic contribution to complex human traits is still unexplained. One potential source of genetic variation that may contribute to this "missing heritability" is that which differs in magnitude and/or direction between males and females, which could result from sexual dimorphism in gene expression. Such sex-differentiated effects are common in model organisms, and are becoming increasingly evident in human complex traits through large-scale male- and female-specific meta-analyses. In this article, we review the methodology for meta-analysis of sex-specific genome-wide association studies, and propose a sex-differentiated test of association with quantitative or dichotomous traits, which allows for heterogeneity of allelic effects between males and females. We perform detailed simulations to compare the power of the proposed sex-differentiated meta-analysis with the more traditional "sex-combined" approach, which is ambivalent to gender. The results of this study highlight only a small loss in power for the sex-differentiated meta-analysis when the allelic effects of the causal variant are the same in males and females. However, over a range of models of heterogeneity in allelic effects between genders, our sex-differentiated meta-analysis strategy offers substantial gains in power, and thus has the potential to discover novel loci contributing effects to complex human traits with existing genome-wide association data. © 2010 Wiley-Liss, Inc.
Full Text Available Abstract Background Single Nucleotide Polymorphism (SNP analysis only captures a small proportion of associated genetic variants in Genome-Wide Association Studies (GWAS partly due to small marginal effects. Pathway level analysis incorporating prior biological information offers another way to analyze GWAS's of complex diseases, and promises to reveal the mechanisms leading to complex diseases. Biologically defined pathways are typically comprised of numerous genes. If only a subset of genes in the pathways is associated with disease then a joint analysis including all individual genes would result in a loss of power. To address this issue, we propose a pathway-based method that allows us to test for joint effects by using a pre-selected gene subset. In the proposed approach, each gene is considered as the basic unit, which reduces the number of genetic variants considered and hence reduces the degrees of freedom in the joint analysis. The proposed approach also can be used to investigate the joint effect of several genes in a candidate gene study. Results We applied this new method to a published GWAS of psoriasis and identified 6 biologically plausible pathways, after adjustment for multiple testing. The pathways identified in our analysis overlap with those reported in previous studies. Further, using simulations across a range of gene numbers and effect sizes, we demonstrate that the proposed approach enjoys higher power than several other approaches to detect associated pathways. Conclusions The proposed method could increase the power to discover susceptibility pathways and to identify associated genes using GWAS. In our analysis of genome-wide psoriasis data, we have identified a number of relevant pathways for psoriasis.
Dudley, Joel T.; Chen, Rong; Sanderford, Maxwell; Butte, Atul J.; Kumar, Sudhir
Genome-wide disease association studies contrast genetic variation between disease cohorts and healthy populations to discover single nucleotide polymorphisms (SNPs) and other genetic markers revealing underlying genetic architectures of human diseases. Despite scores of efforts over the past decade, many reproducible genetic variants that explain substantial proportions of the heritable risk of common human diseases remain undiscovered. We have conducted a multispecies genomic analysis of 5,831 putative human risk variants for more than 230 disease phenotypes reported in 2,021 studies. We find that the current approaches show a propensity for discovering disease-associated SNPs (dSNPs) at conserved genomic positions because the effect size (odds ratio) and allelic P value of genetic association of an SNP relates strongly to the evolutionary conservation of their genomic position. We propose a new measure for ranking SNPs that integrates evolutionary conservation scores and the P value (E-rank). Using published data from a large case-control study, we demonstrate that E-rank method prioritizes SNPs with a greater likelihood of bona fide and reproducible genetic disease associations, many of which may explain greater proportions of genetic variance. Therefore, long-term evolutionary histories of genomic positions offer key practical utility in reassessing data from existing disease association studies, and in the design and analysis of future studies aimed at revealing the genetic basis of common human diseases. PMID:22389448
Magosi, Lerato E; Goel, Anuj; Hopewell, Jemma C; Farrall, Martin
Progress in mapping loci associated with common complex diseases or quantitative inherited traits has been expedited by large-scale meta-analyses combining information across multiple studies, assembled through collaborative networks of researchers. Participating studies will usually have been independently designed and implemented in unique settings that are potential sources of phenotype, ancestry or other variability that could introduce between-study heterogeneity into a meta-analysis. Heterogeneity tests based on individual genetic variants (e.g. Q, I2) are not suited to identifying locus-specific from more systematic multi-locus or genome-wide patterns of heterogeneity. We have developed and evaluated an aggregate heterogeneity M statistic that combines between-study heterogeneity information across multiple genetic variants, to reveal systematic patterns of heterogeneity that elude conventional single variant analysis. Application to a GWAS meta-analysis of coronary disease with 48 contributing studies uncovered substantial systematic between-study heterogeneity, which could be partly explained by age-of-disease onset, family-history of disease and ancestry. Future meta-analyses of diseases and traits with multiple known genetic associations can use this approach to identify outlier studies and thereby optimize power to detect novel genetic associations.
Lerato E Magosi
Full Text Available Progress in mapping loci associated with common complex diseases or quantitative inherited traits has been expedited by large-scale meta-analyses combining information across multiple studies, assembled through collaborative networks of researchers. Participating studies will usually have been independently designed and implemented in unique settings that are potential sources of phenotype, ancestry or other variability that could introduce between-study heterogeneity into a meta-analysis. Heterogeneity tests based on individual genetic variants (e.g. Q, I2 are not suited to identifying locus-specific from more systematic multi-locus or genome-wide patterns of heterogeneity. We have developed and evaluated an aggregate heterogeneity M statistic that combines between-study heterogeneity information across multiple genetic variants, to reveal systematic patterns of heterogeneity that elude conventional single variant analysis. Application to a GWAS meta-analysis of coronary disease with 48 contributing studies uncovered substantial systematic between-study heterogeneity, which could be partly explained by age-of-disease onset, family-history of disease and ancestry. Future meta-analyses of diseases and traits with multiple known genetic associations can use this approach to identify outlier studies and thereby optimize power to detect novel genetic associations.
Full Text Available We introduce a new framework for the analysis of association studies, designed to allow untyped variants to be more effectively and directly tested for association with a phenotype. The idea is to combine knowledge on patterns of correlation among SNPs (e.g., from the International HapMap project or resequencing data in a candidate region of interest with genotype data at tag SNPs collected on a phenotyped study sample, to estimate ("impute" unmeasured genotypes, and then assess association between the phenotype and these estimated genotypes. Compared with standard single-SNP tests, this approach results in increased power to detect association, even in cases in which the causal variant is typed, with the greatest gain occurring when multiple causal variants are present. It also provides more interpretable explanations for observed associations, including assessing, for each SNP, the strength of the evidence that it (rather than another correlated SNP is causal. Although we focus on association studies with quantitative phenotype and a relatively restricted region (e.g., a candidate gene, the framework is applicable and computationally practical for whole genome association studies. Methods described here are implemented in a software package, Bim-Bam, available from the Stephens Lab website http://stephenslab.uchicago.edu/software.html.
Chen, Zhongxue; Huang, Hanwen; Ng, Hon Keung Tony
In genome-wide association studies (GWAS), multiple diseases with shared controls is one of the case-control study designs. If data obtained from these studies are appropriately analyzed, this design can have several advantages such as improving statistical power in detecting associations and reducing the time and cost in the data collection process. In this paper, we propose a study design for GWAS which involves multiple diseases but without controls. We also propose corresponding statistical data analysis strategy for GWAS with multiple diseases but no controls. Through a simulation study, we show that the statistical association test with the proposed study design is more powerful than the test with single disease sharing common controls, and it has comparable power to the overall test based on the whole dataset including the controls. We also apply the proposed method to a real GWAS dataset to illustrate the methodologies and the advantages of the proposed design. Some possible limitations of this study design and testing method and their solutions are also discussed. Our findings indicate that the proposed study design and statistical analysis strategy could be more efficient than the usual case-control GWAS as well as those with shared controls. Copyright © 2012 Elsevier B.V. All rights reserved.
Liu, Jibin; Shen, Biao; Shi, Minxin; Cai, Jing
Background Several epidemiological studies have determined the associations between coffee intake level and skin cancer risk; however, the results were not yet conclusive. Herein, we conducted a systematic review and meta-analysis of the cohort and case-control studies for the association between coffee intake level and malignant melanoma (MM) risk. Methods Studies were identified through searching the PubMed and MEDLINE databases (to November, 2015). Study-specific risk estimates were pooled under the random-effects model. Results Two case-control studies (846 MM patients and 843 controls) and five cohort studies (including 844,246 participants and 5,737 MM cases) were identified. For caffeinated coffee, the pooled relative risk (RR) of MM was 0.81 [95% confidential interval (95% CI) = 0.68–0.97; P-value for Q-test = 0.003; I2 = 63.5%] for those with highest versus lowest quantity of intake. In the dose-response analysis, the RR of MM was 0.955 (95% CI = 0.912–0.999) for per 1 cup/day increment of caffeinated coffee consumption and linearity dose-response association was found (P-value for nonlinearity = 0.326). Strikingly, no significant association was found between the decaffeinated coffee intake level and MM risk (pooled RR = 0.92, 95% CI = 0.81–1.05; P-value for Q-test = 0.967; I2 = 0%; highest versus lowest quantity of intake). Conclusions This meta-analysis suggested that caffeinated coffee might have chemo-preventive effects against MM but not decaffeinated coffee. However, larger prospective studies and the intervention studies are warranted to confirm these findings. PMID:26816289
Full Text Available Several epidemiological studies have determined the associations between coffee intake level and skin cancer risk; however, the results were not yet conclusive. Herein, we conducted a systematic review and meta-analysis of the cohort and case-control studies for the association between coffee intake level and malignant melanoma (MM risk.Studies were identified through searching the PubMed and MEDLINE databases (to November, 2015. Study-specific risk estimates were pooled under the random-effects model.Two case-control studies (846 MM patients and 843 controls and five cohort studies (including 844,246 participants and 5,737 MM cases were identified. For caffeinated coffee, the pooled relative risk (RR of MM was 0.81 [95% confidential interval (95% CI = 0.68-0.97; P-value for Q-test = 0.003; I2 = 63.5%] for those with highest versus lowest quantity of intake. In the dose-response analysis, the RR of MM was 0.955 (95% CI = 0.912-0.999 for per 1 cup/day increment of caffeinated coffee consumption and linearity dose-response association was found (P-value for nonlinearity = 0.326. Strikingly, no significant association was found between the decaffeinated coffee intake level and MM risk (pooled RR = 0.92, 95% CI = 0.81-1.05; P-value for Q-test = 0.967; I2 = 0%; highest versus lowest quantity of intake.This meta-analysis suggested that caffeinated coffee might have chemo-preventive effects against MM but not decaffeinated coffee. However, larger prospective studies and the intervention studies are warranted to confirm these findings.
Full Text Available Most common complex traits, such as obesity, hypertension, diabetes, and cancers, are known to be associated with multiple genes, environmental factors, and their epistasis. Recently, the development of advanced genotyping technologies has allowed us to perform genome-wide association studies (GWASs. For detecting the effects of multiple genes on complex traits, many approaches have been proposed for GWASs. Multifactor dimensionality reduction (MDR is one of the powerful and efficient methods for detecting high-order gene-gene (GxG interactions. However, the biological interpretation of GxG interactions identified by MDR analysis is not easy. In order to aid the interpretation of MDR results, we propose a network graph analysis to elucidate the meaning of identified GxG interactions. The proposed network graph analysis consists of three steps. The first step is for performing GxG interaction analysis using MDR analysis. The second step is to draw the network graph using the MDR result. The third step is to provide biological evidence of the identified GxG interaction using external biological databases. The proposed method was applied to Korean Association Resource (KARE data, containing 8838 individuals with 327,632 single-nucleotide polymorphisms, in order to perform GxG interaction analysis of body mass index (BMI. Our network graph analysis successfully showed that many identified GxG interactions have known biological evidence related to BMI. We expect that our network graph analysis will be helpful to interpret the biological meaning of GxG interactions.
Postmus, Iris; Warren, Helen R; Trompet, Stella
BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation. METHODS AND RESULTS: We performed...... a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p
Pereza, Nina; Ostojić, Saša; Kapović, Miljenko; Peterlin, Borut
1) To perform the first comprehensive systematic review of genetic association studies (GASs) in idiopathic recurrent spontaneous abortion (IRSA); 2) to analyze studies according to recurrent spontaneous abortion (RSA) definition and selection criteria for patients and control subjects; and 3) to perform meta-analyses for the association of candidate genes with IRSA. Systematic review and meta-analysis. Not applicable. Couples with IRSA and their spontaneously aborted embryos. Summary odds ratios (ORs) were calculated by means of fixed- or random-effects models. Association of genetic variants with IRSA. The systematic review included 428 case-control studies (1990-2015), which differed substantially regarding RSA definition, clinical evaluation of patients, and selection of control subjects. In women, 472 variants in 187 genes were investigated. Meta-analyses were performed for 36 variants in 16 genes. Association with IRSA defined as three or more spontaneous abortions (SAs) was detected for 21 variants in genes involved in immune response (IFNG, IL10, KIR2DS2, KIR2DS3, KIR2DS4, MBL, TNF), coagulation (F2, F5, PAI-1, PROZ), metabolism (GSTT1, MTHFR), and angiogenesis (NOS3, VEGFA). However, ORs were modest (0.51-2.37), with moderate or weak epidemiologic credibility. Minor differences in summary ORs were detected between IRSA defined as two or more and as three or more SAs. Male partners were included in 12.1% of studies, and one study included spontaneously aborted embryos. Candidate gene studies show moderate associations with IRSA. Owing to large differences in RSA definition and selection criteria for participants, consensus is needed. Future GASs should include both partners and spontaneously aborted embryos. Genome-wide association studies and large-scale replications of identified associations are recommended. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Tang, Fang; Wang, Gangpu; Lian, Ying
Epidemiological studies have repeatedly investigated the association between anxiety and metabolic syndrome (MetS). However, the results have been inconsistent. We performed a meta-analysis of observational studies to summarize the evidence regarding the relation of anxiety and MetS risk. We performed a systematic literature search of all studies published in PubMed and EMBASE from its inception to June 2016. Cross-sectional and cohort studies that reported an association between the two conditions in adults were included. Data on prevalence, incidence, unadjusted or adjusted odds ratio (OR), and 95% CI were extracted or provided independently by the authors. Random effects model was used to report the pooled OR. The I2 statistic was used to assess heterogeneity. Egger's test and Begger's test were used to evaluate the publication bias. The search yielded 18 cross-sectional studies and two cohort studies. The pooled finding from cross-sectional studies showed that anxiety had a significant positive association with MetS (OR 1.07, 95% CI 1.01-1.12), with moderate heterogeneity (I2=45.7%, P=0.018). Findings from two cohort studies indicated that the association between anxiety and MetS was insignificant. Our results suggest that there is an association between anxiety and MetS. In individuals with MetS anxiety should be detected and managed. Further prospective studies are needed to explore the bidirectional association between anxiety and MetS. Copyright © 2016 Elsevier Ltd. All rights reserved.
Vaitsiakhovich, Tatsiana; Drichel, Dmitriy; Herold, Christine; Lacour, André; Becker, Tim
Meta-analysis of summary statistics is an essential approach to guarantee the success of genome-wide association studies (GWAS). Application of the fixed or random effects model to single-marker association tests is a standard practice. More complex methods of meta-analysis involving multiple parameters have not been used frequently, a gap that could be explained by the lack of a respective meta-analysis pipeline. Meta-analysis based on combining p-values can be applied to any association test. However, to be powerful, meta-analysis methods for high-dimensional models should incorporate additional information such as study-specific properties of parameter estimates, their effect directions, standard errors and covariance structure. We modified 'method for the synthesis of linear regression slopes' recently proposed in the educational sciences to the case of multiple logistic regression, and implemented it in a meta-analysis tool called METAINTER. The software handles models with an arbitrary number of parameters, and can directly be applied to analyze the results of single-SNP tests, global haplotype tests, tests for and under gene-gene or gene-environment interaction. Via simulations for two-single nucleotide polymorphisms (SNP) models we have shown that the proposed meta-analysis method has correct type I error rate. Moreover, power estimates come close to that of the joint analysis of the entire sample. We conducted a real data analysis of six GWAS of type 2 diabetes, available from dbGaP (http://www.ncbi.nlm.nih.gov/gap). For each study, a genome-wide interaction analysis of all SNP pairs was performed by logistic regression tests. The results were then meta-analyzed with METAINTER. The software is freely available and distributed under the conditions specified on http://metainter.meb.uni-bonn.de. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e
Gao, Shen; Zhao, Dong; Wang, Miao; Zhao, Fan; Han, Xueyu; Qi, Yue; Liu, Jing
Although basic research has suggested that oxidized low-density lipoprotein (ox-LDL) is involved in the pathogenesis of atherosclerosis, population observational studies have yielded conflicting results about the association between circulating ox-LDL and atherosclerotic cardiovascular disease (ASCVD). Therefore, we performed a systematic review and meta-analysis of currently available observational studies to verify the association between circulating ox-LDL and ASCVD. We systematically searched PubMed and the Cochrane Library from their inception to March 27, 2017, for nested case-control studies, case-cohort studies, and prospective cohort studies on the relationship between ox-LDL and ASCVD. Studies that did not assess the hazard ratio, relative risk, or odds ratio of ox-LDL or did not adjust for other risk factors, or those without examination of ox-LDL before collection of ASCVD occurrences were excluded. The summarized effect size was combined using fixed effect models. Subgroup analyses were performed on the basis of study quality, study design, definition of ASCVD events, effect size types, types of ox-LDL assay, ox-LDL contrast level, and whether low-density lipoprotein cholesterol was adjusted in a multivariate model. A total of 12 included studies consisted of 3 nested case-control studies, 1 case-cohort study, 5 hospital-based cohort studies, and 3 community-based cohort studies. The summary effect size of increased circulating ox-LDL was 1.79 (95% confidence interval, 1.56-2.05) for ASCVD. Similar associations were shown in all subgroups. Our findings indicate that increased levels of circulating ox-LDL are associated with clinical ASCVD events. Further well designed community-based cohort studies or intervention studies are needed to confirm our findings. Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Sun, Yanfa; Liu, Ranran; Zhao, Guiping; Zheng, Maiqing; Sun, Yan; Yu, Xiaoqiong; Li, Peng; Wen, Jie
Polydactyly occurs in some chicken breeds, but the molecular mechanism remains incompletely understood. Combined genome-wide linkage analysis and association study (GWAS) for chicken polydactyly helps identify loci or candidate genes for the trait and potentially provides further mechanistic understanding of this phenotype in chickens and perhaps other species. The linkage analysis and GWAS for polydactyly was conducted using an F2 population derived from Beijing-You chickens and commercial broilers. The results identified two QTLs through linkage analysis and seven single-nucleotide polymorphisms (SNPs) through GWAS, associated with the polydactyly trait. One QTL located at 35 cM on the GGA2 was significant at the 1% genome-wise level and another QTL at the 1% chromosome-wide significance level was detected at 39 cM on GGA19. A total of seven SNPs, four of 5% genome-wide significance (P polydactyly in chickens and other species, and identified others, most of which have not previously been associated with limb development. The genes and associated SNPs revealed here provide detailed information for further exploring the molecular and developmental mechanisms underlying polydactyly. Copyright © 2014 Sun et al.
Manichaikul, Ani; Chen, Wei-Min; Williams, Kayleen; Wong, Quenna; Sale, Michèle M; Pankow, James S; Tsai, Michael Y; Rotter, Jerome I; Rich, Stephen S; Mychaleckyj, Josyf C
Cohort studies typically sample unrelated individuals from a population, although family members of index cases may also be recruited to investigate shared familial risk factors. Recruitment of family members may be incomplete or ancillary to the main cohort, resulting in a mixed sample of independent family units, including unrelated singletons and multiplex families. Multiple methods are available to perform genome-wide association (GWA) analysis of binary or continuous traits in families, but it is unclear whether methods known to perform well on ascertained pedigrees, sibships, or trios are appropriate in analysis of a mixed unrelated cohort and family sample. We present simulation studies based on Multi-Ethnic Study of Atherosclerosis (MESA) pedigree structures to compare the performance of several popular methods of GWA analysis for both quantitative and dichotomous traits in cohort studies. We evaluate approaches suitable for analysis of families, and combined the best performing methods with population-based samples either by meta-analysis, or by pooled analysis of family- and population-based samples (mega-analysis), comparing type 1 error and power. We further assess practical considerations, such as availability of software and ability to incorporate covariates in statistical modeling, and demonstrate our recommended approaches through quantitative and binary trait analysis of HDL cholesterol (HDL-C) in 2,553 MESA family- and population-based African-American samples. Our results suggest linear modeling approaches that accommodate family-induced phenotypic correlation (e.g., variance-component model for quantitative traits or generalized estimating equations for dichotomous traits) perform best in the context of combined family- and population-based cohort GWAS.
Wang, Zhaoming; McGlynn, Katherine A; Rajpert-De Meyts, Ewa; Bishop, D Timothy; Chung, Charles C; Dalgaard, Marlene D; Greene, Mark H; Gupta, Ramneek; Grotmol, Tom; Haugen, Trine B; Karlsson, Robert; Litchfield, Kevin; Mitra, Nandita; Nielsen, Kasper; Pyle, Louise C; Schwartz, Stephen M; Thorsson, Vésteinn; Vardhanabhuti, Saran; Wiklund, Fredrik; Turnbull, Clare; Chanock, Stephen J; Kanetsky, Peter A; Nathanson, Katherine L
The international Testicular Cancer Consortium (TECAC) combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new susceptibility loci. We conducted a fixed-effects meta-analysis, including, to our knowledge, the first analysis of the X chromosome. Eight new loci mapping to 2q14.2, 3q26.2, 4q35.2, 7q36.3, 10q26.13, 15q21.3, 15q22.31, and Xq28 achieved genome-wide significance (P < 5 × 10 -8 ). Most loci harbor biologically plausible candidate genes. We refined previously reported associations at 9p24.3 and 19p12 by identifying one and three additional independent SNPs, respectively. In aggregate, the 39 independent markers identified to date explain 37% of father-to-son familial risk, 8% of which can be attributed to the 12 new signals reported here. Our findings substantially increase the number of known TGCT susceptibility alleles, move the field closer to a comprehensive understanding of the underlying genetic architecture of TGCT, and provide further clues to the etiology of TGCT.
Full Text Available Pancreatic cancer is the fourth leading cause of cancer death in the U.S. and the etiology of this highly lethal disease has not been well defined. To identify genetic susceptibility factors for pancreatic cancer, we conducted pathway analysis of genome-wide association study (GWAS data in 3,141 pancreatic cancer patients and 3,367 controls with European ancestry.Using the gene set ridge regression in association studies (GRASS method, we analyzed 197 pathways identified from the Kyoto Encyclopedia of Genes and Genomes database. We used the logistic kernel machine (LKM test to identify major contributing genes to each pathway. We conducted functional enrichment analysis of the most significant genes (P<0.01 using the Database for Annotation, Visualization, and Integrated Discovery (DAVID.Two pathways were significantly associated with risk of pancreatic cancer after adjusting for multiple comparisons (P<0.00025 and in replication testing: neuroactive ligand-receptor interaction, (Ps<0.00002, and the olfactory transduction pathway (P = 0.0001. LKM test identified four genes that were significantly associated with risk of pancreatic cancer after Bonferroni correction (P<1×10(-5: ABO, HNF1A, OR13C4, and SHH. Functional enrichment analysis using DAVID consistently found the G protein-coupled receptor signaling pathway (including both neuroactive ligand-receptor interaction and olfactory transduction pathways to be the most significant pathway for pancreatic cancer risk in this study population.These novel findings provide new perspectives on genetic susceptibility to and molecular mechanisms of pancreatic cancer.
Koga, Arthur T; Strauss, John; Zai, Clement; Remington, Gary; De Luca, Vincenzo
In recent years, several studies have investigated genetic polymorphisms of antipsychotic drug-metabolizing enzymes and receptors. However, most studies focused on drug response and very few have investigated the genetic influence on antipsychotic dosage. The aim of the present study is to test the association between antipsychotic dosages at genome-wide level. The current dosage of antipsychotic medications was collected from 79 schizophrenia patients. The dosage was standardized using three different methods: chlorpromazine equivalent (CPZe), defined daily dose (DDD), and percentage of maximum dose (PM %). The patients were then genotyped using the Illumina HumanOmni2.5-8 BeadChip Kit. All markers were screened for significance using linear regression, and the p values were visualized using a Manhattan plot. The genome-wide analysis showed that the top Single-Nucleotide Polymorphisms (SNPs) associated with dosage variation were rs981975 on chromosome 14 for CPZe, rs4470690 on chromosome 4 for PM %, and rs79323383 on chromosome 8 for DDD. However, no genome-wide significantly associated SNPs were identified. In this pilot sample, we found promising trends for pharmacodynamic targets associated with antipsychotic dosage. Therefore, studies combining large prescription databases may identify genetic predictors to adjust the dose of antipsychotic medication.
Stahl, Eli A.; Raychaudhuri, Soumya; Remmers, Elaine F.; Xie, Gang; Eyre, Stephen; Thomson, Brian P.; Li, Yonghong; Kurreeman, Fina A. S.; Zhernakova, Alexandra; Hinks, Anne; Guiducci, Candace; Chen, Robert; Alfredsson, Lars; Amos, Christopher I.; Ardlie, Kristin G.; Barton, Anne; Bowes, John; Brouwer, Elisabeth; Burtt, Noel P.; Catanese, Joseph J.; Coblyn, Jonathan; Coenen, Marieke JH; Costenbader, Karen H.; Criswell, Lindsey A.; Crusius, J. Bart A.; Cui, Jing; de Bakker, Paul I.W.; De Jager, Phillip L.; Ding, Bo; Emery, Paul; Flynn, Edward; Harrison, Pille; Hocking, Lynne J.; Huizinga, Tom W. J.; Kastner, Daniel L.; Ke, Xiayi; Lee, Annette T.; Liu, Xiangdong; Martin, Paul; Morgan, Ann W.; Padyukov, Leonid; Posthumus, Marcel D.; Radstake, Timothy RDJ; Reid, David M.; Seielstad, Mark; Seldin, Michael F.; Shadick, Nancy A.; Steer, Sophia; Tak, Paul P.; Thomson, Wendy; van der Helm-van Mil, Annette H. M.; van der Horst-Bruinsma, Irene E.; van der Schoot, C. Ellen; van Riel, Piet LCM; Weinblatt, Michael E.; Wilson, Anthony G.; Wolbink, Gert Jan; Wordsworth, Paul; Wijmenga, Cisca; Karlson, Elizabeth W.; Toes, Rene E. M.; de Vries, Niek; Begovich, Ann B.; Worthington, Jane; Siminovitch, Katherine A.; Gregersen, Peter K.; Klareskog, Lars; Plenge, Robert M.
To identify novel genetic risk factors for rheumatoid arthritis (RA), we conducted a genome-wide association study (GWAS) meta-analysis of 5,539 autoantibody positive RA cases and 20,169 controls of European descent, followed by replication in an independent set of 6,768 RA cases and 8,806 controls. Of 34 SNPs selected for replication, 7 novel RA risk alleles were identified at genome-wide significance (P<5×10−8) in analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5, and PXK. We also refined the risk alleles at two established RA risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed RA risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P<0.05, many of which are validated autoimmune risk alleles, suggesting that most represent bona fide RA risk alleles. PMID:20453842
Full Text Available Abstract Background It is increasingly clear that common human diseases have a complex genetic architecture characterized by both additive and nonadditive genetic effects. The goal of the present study was to determine whether patterns of both additive and nonadditive genetic associations aggregate in specific functional groups as defined by the Gene Ontology (GO. Results We first estimated all pairwise additive and nonadditive genetic effects using the multifactor dimensionality reduction (MDR method that makes few assumptions about the underlying genetic model. Statistical significance was evaluated using permutation testing in two genome-wide association studies of ALS. The detection data consisted of 276 subjects with ALS and 271 healthy controls while the replication data consisted of 221 subjects with ALS and 211 healthy controls. Both studies included genotypes from approximately 550,000 single-nucleotide polymorphisms (SNPs. Each SNP was mapped to a gene if it was within 500 kb of the start or end. Each SNP was assigned a p-value based on its strongest joint effect with the other SNPs. We then used the Exploratory Visual Analysis (EVA method and software to assign a p-value to each gene based on the overabundance of significant SNPs at the α = 0.05 level in the gene. We also used EVA to assign p-values to each GO group based on the overabundance of significant genes at the α = 0.05 level. A GO category was determined to replicate if that category was significant at the α = 0.05 level in both studies. We found two GO categories that replicated in both studies. The first, ‘Regulation of Cellular Component Organization and Biogenesis’, a GO Biological Process, had p-values of 0.010 and 0.014 in the detection and replication studies, respectively. The second, ‘Actin Cytoskeleton’, a GO Cellular Component, had p-values of 0.040 and 0.046 in the detection and replication studies, respectively. Conclusions Pathway
Brett A McKinney
Full Text Available Evidence from human genetic studies of several disorders suggests that interactions between alleles at multiple genes play an important role in influencing phenotypic expression. Analytical methods for identifying Mendelian disease genes are not appropriate when applied to common multigenic diseases, because such methods investigate association with the phenotype only one genetic locus at a time. New strategies are needed that can capture the spectrum of genetic effects, from Mendelian to multifactorial epistasis. Random Forests (RF and Relief-F are two powerful machine-learning methods that have been studied as filters for genetic case-control data due to their ability to account for the context of alleles at multiple genes when scoring the relevance of individual genetic variants to the phenotype. However, when variants interact strongly, the independence assumption of RF in the tree node-splitting criterion leads to diminished importance scores for relevant variants. Relief-F, on the other hand, was designed to detect strong interactions but is sensitive to large backgrounds of variants that are irrelevant to classification of the phenotype, which is an acute problem in genome-wide association studies. To overcome the weaknesses of these data mining approaches, we develop Evaporative Cooling (EC feature selection, a flexible machine learning method that can integrate multiple importance scores while removing irrelevant genetic variants. To characterize detailed interactions, we construct a genetic-association interaction network (GAIN, whose edges quantify the synergy between variants with respect to the phenotype. We use simulation analysis to show that EC is able to identify a wide range of interaction effects in genetic association data. We apply the EC filter to a smallpox vaccine cohort study of single nucleotide polymorphisms (SNPs and infer a GAIN for a collection of SNPs associated with adverse events. Our results suggest an important
Summary Background The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). Methods We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at panalysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10−10), implicating SCN1A, and at 4p15.1 (p=5·44 × 10−9), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10−9), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. Interpretation This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the ultimate aim of assisting in disease classification and prognosis. The data suggest that
Siri-Tarino, Patty W; Sun, Qi; Hu, Frank B; Krauss, Ronald M
A reduction in dietary saturated fat has generally been thought to improve cardiovascular health. The objective of this meta-analysis was to summarize the evidence related to the association of dietary saturated fat with risk of coronary heart disease (CHD), stroke, and cardiovascular disease (CVD; CHD inclusive of stroke) in prospective epidemiologic studies. Twenty-one studies identified by searching MEDLINE and EMBASE databases and secondary referencing qualified for inclusion in this study. A random-effects model was used to derive composite relative risk estimates for CHD, stroke, and CVD. During 5-23 y of follow-up of 347,747 subjects, 11,006 developed CHD or stroke. Intake of saturated fat was not associated with an increased risk of CHD, stroke, or CVD. The pooled relative risk estimates that compared extreme quantiles of saturated fat intake were 1.07 (95% CI: 0.96, 1.19; P = 0.22) for CHD, 0.81 (95% CI: 0.62, 1.05; P = 0.11) for stroke, and 1.00 (95% CI: 0.89, 1.11; P = 0.95) for CVD. Consideration of age, sex, and study quality did not change the results. A meta-analysis of prospective epidemiologic studies showed that there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD or CVD. More data are needed to elucidate whether CVD risks are likely to be influenced by the specific nutrients used to replace saturated fat.
Seung Hoan Choi
Full Text Available Vascular endothelial growth factor (VEGF is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3 and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79 x 10(-13, rs74506613 (JMJD1C, P = 1.17 x 10(-19, rs4782371 (ZFPM1, P = 1.59 x 10(-9 and rs2639990 (ZADH2, P = 1.72 x 10(-8, respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52 x 10(-18; rs7043199, VLDLR-AS1, P = 5.12 x 10(-14 at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39 x 10(-1467; rs1740073, C6orf223, P = 2.34 x 10(-17; rs6993770, ZFPM2, P = 2.44 x 10(-60; rs2375981, KCNV2, P = 1.48 x 10(-100. These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis
Moor, M.H.M. de; Berg, S.M. van den; Verweij, K.J.H.; Krueger, R.F.; Luciano, M.; Vasquez, A.A.; Matteson, L.K.; Derringer, J.; Esko, T.; Amin, N.; Gordon, S.D.; Hansell, N.K.; Hart, A.B.; Seppälä, I.; Huffman, J.E.
IMPORTANCE Neuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63 000 participants (including MDD cases). OBJECTIVES To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide as...
Yang, Xiaohong R; Chang-Claude, Jenny; Goode, Ellen L
Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.......Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors....
Full Text Available Association studies are a staple of genotype-phenotype mapping studies, whether they are based on single markers, haplotypes, candidate genes, genome-wide genotypes, or whole genome sequences. Although genetic epidemiological studies typically contain data collected on multiple traits which themselves are often correlated, most analyses have been performed on single traits. Here, I review several methods that have been developed to perform multiple trait analysis. These methods range from traditional multivariate models for systems of equations to recently developed graphical approaches based on network theory. The application of network theory to genetics is termed systems genetics and has the potential to address long-standing questions in genetics about complex processes such as coordinate regulation, homeostasis, and pleiotropy.
Yu, Jia-Yun; Hu, Fan; Du, Wei; Ma, Xue-Lei; Yuan, Kun
Recently, several studies have investigated the association between polymorphisms in miR-146a rs2910164, miR-196a2 rs11614913, miR-499 rs3746444, miR-149 rs229283, miR-34b/c rs4938723, and hepatocellular carcinoma (HCC), which showed inconclusive results. A publication search was performed in PubMed, ExcerptaMedica Database, Chinese Biomedical Literature Database, and Chinese National Knowledge Infrastructure to collect relevant medical data published through February 2016. The aim of this study was to ascertain the association between HCC and micro-RNAs. A total of 21 studies were included in our study, which showed that miR-146a rs2910164 polymorphism has a significant association with HCC in the allele, recessive, and homozygous models overall [allele model: odds ratio (OR) = 0.927, 95% confidence interval (CI): 0.869-0.988, p = 0.02; recessive model: OR = 0.893, 95% CI: 0.814-0.981, p = 0.018; homozygous model: OR = 0.853, 95% CI: 0.744-0.978, p = 0.023] and in Asian populations (allele model: OR = 0.921, 95% CI: 0.863-0.983, p = 0.014; recessive model: OR = 0.893, 95% CI: 0.814-0.981, p = 0.019; homozygous model: OR = 0.851, 95% CI: 0.741-0.977, p = 0.022). For miR-196a2 rs11614913, significant statistical heterogeneity overall and in Asian populations was identified in the comparison of the allele, recessive, homozygous, and heterozygous models (overall: allele model: OR = 0.889, 95% CI: 0.842-0.94, p risk of HCC in Caucasians in all genetic models except for the heterozygous model (allele model: OR = 0.658, 95% CI: 0.49-0.885, p = 0.006; dominant model: OR = 0.641, 95% CI: 0.418-0.981, p = 0.041; recessive model: OR = 0.489, 95% CI: 0.278-0.862, p = 0.013; homozygous model: OR = 0.414, 95% CI: 0.222-0.772, p = 0.005). Only the recessive models produced a significant association between miR-499 rs3746444 polymorphism and HCC risk (recessive model: OR = 1.283, 95% CI: 1.008-1.632, p = 0.043). The analysis for mi
Full Text Available The analysis of genome-wide association studies (GWAS benefits from the investigation of biologically meaningful gene sets, such as gene-interaction networks (pathways. We propose an extension to a successful kernel-based pathway analysis approach by integrating kernel functions into a powerful algorithmic framework for variable selection, to enable investigation of multiple pathways simultaneously. We employ genetic similarity kernels from the logistic kernel machine test (LKMT as base-learners in a boosting algorithm. A model to explain case-control status is created iteratively by selecting pathways that improve its prediction ability. We evaluated our method in simulation studies adopting 50 pathways for different sample sizes and genetic effect strengths. Additionally, we included an exemplary application of kernel boosting to a rheumatoid arthritis and a lung cancer dataset. Simulations indicate that kernel boosting outperforms the LKMT in certain genetic scenarios. Applications to GWAS data on rheumatoid arthritis and lung cancer resulted in sparse models which were based on pathways interpretable in a clinical sense. Kernel boosting is highly flexible in terms of considered variables and overcomes the problem of multiple testing. Additionally, it enables the prediction of clinical outcomes. Thus, kernel boosting constitutes a new, powerful tool in the analysis of GWAS data and towards the understanding of biological processes involved in disease susceptibility.
Schumacher, Kurt R; Gossett, Jeffrey; Guleserian, Kristine; Naftel, David C; Pruitt, Elizabeth; Dodd, Debra; Carboni, Michael; Lamour, Jacqueline; Pophal, Stephen; Zamberlan, Mary; Gajarski, Robert J
Post-Fontan protein-losing enteropathy (PLE) is associated with significant morbidity and mortality. Although heart transplantation (HTx) can be curative, PLE may increase the risk of morbidity before and after HTx. This study analyzed the influence of PLE influence on waiting list and post-HTx outcomes in a pediatric cohort. Fontan patients listed for HTx and enrolled in the Pediatric Heart Transplant Study from 1999 to 2012 were stratified by a diagnosis of PLE, and the association of PLE with waiting list and post-HTx mortality, rejection, and infection was analyzed. Compared with non-PLE Fontan patients (n = 260), PLE patients listed for HTx (n = 96) were older (11.9 years vs 7.6 years; p = 0.003), had a larger body surface area (1.1 m(2) vs 0.9 m(2); p = 0.0001), had lower serum bilirubin (0.5 vs 0.9 mg/dl; p = 0.01), lower B-type natriuretic peptide (59 vs 227 pg/ml; p = 0.006), and were less likely to be on a ventilator (3% vs 13%; p = 0.006). PLE patients had lower waiting list mortality than non-PLE Fontan patients (p PLE was not independently associated with increased post-HTx mortality at any time point. In this multicenter cohort, the diagnosis of PLE alone was not associated with increased waiting list mortality or post-HTx morbidity or mortality. Given the limitations of our data, this analysis suggests that PLE patients in the pediatric age group have outcomes similar to their non-PLE counterparts. Additional multicenter studies of PLE patients with targeted collection of PLE-specific information will be necessary to fully delineate the risks conferred by PLE for HTx. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
Although prospective logistic regression is the standard method of analysis for case-control data, it has been recently noted that in genetic epidemiologic studies one can use the "retrospective" likelihood to gain major power by incorporating various population genetics model assumptions such as Hardy-Weinberg-Equilibrium (HWE), gene-gene and gene-environment independence. In this article we review these modern methods and contrast them with the more classical approaches through two types of applications (i) association tests for typed and untyped single nucleotide polymorphisms (SNPs) and (ii) estimation of haplotype effects and haplotype-environment interactions in the presence of haplotype-phase ambiguity. We provide novel insights to existing methods by construction of various score-tests and pseudo-likelihoods. In addition, we describe a novel two-stage method for analysis of untyped SNPs that can use any flexible external algorithm for genotype imputation followed by a powerful association test based on the retrospective likelihood. We illustrate applications of the methods using simulated and real data. © Institute of Mathematical Statistics, 2009.
Maria José Penna Maisonnette de Attayde Silva
Full Text Available OBJECTIVE: To evaluate the effect of Chlamydia trachomatis infection during pregnancy on perinatal morbidity and mortality. METHODS: Systematic review and meta-analysis in an electronic database and manual, combining high sensitivity specific descriptors seeking to answer the research objective. The articles considered to be of high methodological quality (score above 6 on the Newcastle-Ottawa Scale were assessed by meta-analysis. RESULTS: Summary estimates of 12 studies were calculated by means of Mantel-Haenszel test with 95% confidence interval. It was observed that Chlamydia infection during pregnancy increased risk of preterm labor (relative risk (RR = 1.35 [1.11, 1.63], low birth weight (RR = 1.52 [1.24, 1.87] and perinatal mortality (RR = 1.84 [1.15, 2.94]. No evidence of increased risk was associated with Chlamydia infection in regard to premature rupture of membranes (RR = 1.13 [0.95, 1.34], abortion and postpartum endometritis (RR = 1.20 [0.65, 2.20] and 0.89 [0.49, 1.61] respectively. CONCLUSION: The diagnosis and treatment of Chlamydia cervicitis during pregnancy can reduce perinatal morbidity and mortality associated with this infection. However, clinical trials are needed to confirm these findings.
Skibola Christine F
Full Text Available Abstract Background B-cell non-Hodgkin lymphoma represents a diverse group of hematological malignancies, of which follicular lymphoma (FL is one of the most common subtypes. Family and epidemiological studies suggest an important genetic role in the etiology of FL. In recent genome-wide association studies (GWAS of FL, several genetic susceptibility loci have been identified on chromosome 6p21.33 (rs6457327 and 6p21.32 (rs10484561, rs2647012 in the human leukocyte antigen class I and class II regions. To identify new genetic variants and further elucidate the genetic basis of FL, a meta-analysis was performed of the top 1000 SNPs associated with FL risk from two GWAS in the US, Denmark and Sweden (592 cases, 1541 controls, with independent validation in 107 cases and 681 controls. Results rs9275517 and rs3117222 in the HLA class II region were validated and inversely associated with FL risk (rs9275517: OR = 0.63, 95% CI = 0.55-0.73, p = 4.03 × 10-11; rs3117222: OR = 0.66, 95% CI = 0.57-0.77, p = 1.45 × 10-7. rs9275517, which is in high linkage disequilibrium with rs2647012 (r2 = 0.9, was no longer associated with FL after conditioning on rs2647012. The rs3117222 association was independent of established FL SNPs, but not of the HLA-DPB1*0301 allele. Using publicly available gene expression profiles with matching genotype information, we found that rs3117222 also was significantly correlated with increased HLA-DPB1 expression. Conclusions By performing a meta-analysis of two GWAS of FL, we further validated the relevance of HLA-DPB1*0301 as a protective allele in the pathogenesis of FL. Moreover, the protective rs3117222 A allele correlated with increased levels of HLA-DPB1, suggesting a possible disease mechanism involving HLA-DPB1 expression regulation. Our results add further support to the major role of HLA genetic variation in the pathogenesis of FL.
...; Yang, Xiaohong R; Chang-Claude, Jenny; Goode, Ellen L; Couch, Fergus J; Nevanlinna, Heli; Milne, Roger L; Gaudet, Mia; Schmidt, Marjanka K; Broeks, Annegien; Cox, Angela; Fasching, Peter A; Hein, Rebecca; Spurdle, Amanda B; Blows, Fiona; ver, Kristy; Flesch-Janys, Dieter; Heinz, Judith; Sinn, Peter; Vrieling, Alina; Heikkinen, Tuomas; Aittomaeki, Kristiina; Heikkilae, Paeivi; Blomqvist, Carl; Lissowska, Jolanta; Peplonska, Beata; Chanock, Stephen; Figueroa, Jonine; Brinton, Louise; Hall, Per; Czene, Kamila; Humphreys, Keith; Darabi, Hatef; Liu, Jianjun; Van 't Veer, Laura J; Van Leeuwen, Flora E; Anulis, Irene L; Glendon, Gord; Knight, Julia A; Mulligan, Anna Marie; O'Malley, Frances P; Weerasooriya, Nayana; John, Esther M; Beckmann, Matthias W; Hartmann, Arndt; Weihbrecht, Sebastian B; Wachter, David L; Jud, Sebastian M. S; Loehberg, Christian R; Baglietto, Laura; English, Dallas R; Giles, Graham G; McLean, Catriona A; Severi, Gianluca; Lambrechts, Diether; Vandorpe, Thijs; Weltens, Caroline; Paridaens, Robert; Smeets, Ann; Neven, Patrick; Wildiers, Hans; Wang, Xianshu; Olson, Janet E; Cafourek, Victoria; Fredericksen, Zachary; Kosel, Matthew; Vachon, Celine; Cramp, Helen E; Connley, Daniel; Cross, Simon S; Balasubramanian, Sabapathy P; Reed, Malcolm W. R; Doerk, Thilo; Bremer, Michael; Meyer, Aneas; Karstens, Johann H; Ay, Aysun; Park-Simon, Tjoung-Won; Hillemanns, Peter; Arias Perez, Jose Ignacio; Menendez Roiguez, Primitiva; Zamora, Pilar; Bentez, Javier; Ko, Yon-Dschun; Fischer, Hans-Peter; Hamann, Ute; Pesch, Beate; Bruening, Thomas; Justenhoven, Christina; Brauch, Hiltrud; Eccles, Diana M; Tapper, William J; Gerty, Sue M; Sawyer, Elinor J; Tomlinson, Ian P; Jones, Angela; Kerin, Michael; Miller, Nicola; McInerney, Niall; Anton-Culver, Hoda; Ziogas, Argyrios
...) and progesterone receptor (PR) expression status of the tumors. Methods We pooled tumor marker and epidemiological risk factor data from 35 568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium...
Shaid, D.J.; Sommer, S.S. (Mayo Clinic/Foundation, Rochester, MN (United States))
Design and analysis methods are presented for studying the association of a candidate gene with a disease by using parental data in place of nonrelated controls. This alternating design eliminates spurious differences in allele frequencies between cases and nonrelated controls resulting from different ethnic origins and population stratification for these two groups. The authors present analysis methods which are based on two genetic relative risks: (1) the relative risk of disease for homozygotes with two copies of the candidate gene versus homozygotes without the candidate gene and (2) the relative risk for heterozygotes with one copy of the candidate gene versus homozygotes without the candidate gene. In addition to estimating the magnitude of these relative risks, likelihood methods allow specific hypotheses to be tested, namely, a test for overall association of the candidate gene with disease, as well as specific genetic hypotheses, such as dominant or recessive inheritance. Two likelihood methods are presented: (1) a likelihood method appropriate when Hardy-Weinberg equilibrium holds and (2) a likelihood method in which the authors condition on parental genotype data when Hardy-Weinberg equilibrium does not hold. The results for the relative efficiency of these two methods suggest that the conditional approach may at times be preferable, even when equilibrium holds. Sample-size and power calculations are presented for a multitiered design. Tier 1 detects the presence of an abnormal sequence for a postulated candidate gene among a small group of cases. Tier 2 tests for association of the abnormal variant with disease, such as by the likelihood methods presented. Tier 3 confirms positive results from tier 2. Results indicate that required sample sizes are smaller when expression of disease is recessive, rather than dominant, and that, for recessive disease and large relative risks, necessary sample sizes may be feasible. 19 refs., 2 figs., 2 tabs.
Full Text Available Background: The link between body weight status and spinal diseases has been suggested by a number of cross-sectional and cohort studies with a limited range of patient populations. No population-representative samples have been used to examine the link between obesity and spinal diseases. The present study is based on a nationally representative sample drawn from the Medical Expenditure Panel Survey. Methods: Using the cross-sectional sample of the 2014 Medical Expenditure Panel Study, we built four weighted logistic regression analyses of the associations between body weight status and the following four spinal diseases: low back pain, spondylosis, other cervical disorders and intervertebral disc disorder (IDD. Each respondent’s body weight status was used as the key independent variable with three categories: normal/underweight, overweight, and obese. We controlled for marital status, gender, age, smoking status, household income, health insurance coverage, educational attainment and the use of health services for other major categories of diseases. Results: A total sample of 23,048 respondents was used in our analysis. Overweight and obese respondents, as compared to normal/underweight respondents, were more likely to develop lower back problems (Overweight: logged odds = 0.218, p < 0.01; Obese: logged odds = 0.395, p < 0.001 and IDD (Overweight: logged odds = 0.441, p < 0.05; Obese: logged odds = 0.528, p < 0.001. The associations between bodyweight status and spondylitis were statistically insignificant (Overweight: logged odds = 0.281, p = 0.442; Obese: logged odds = 0.680, p = 0.104. The associations between body weight status and other cervical disorders (Overweight: logged odds = −0.116, p = 0.304; Obese: logged odds = −0.160, p = 0.865 were statistically insignificant. Conclusions: As the first study using a national sample to study bodyweight and spinal diseases, our paper supports the hypothesis that obesity adds to the burden
Tang, Clara Sze-Man; Gui, Hongsheng; Kapoor, Ashish; Kim, Jeong-Hyun; Luzón-Toro, Berta; Pelet, Anna; Burzynski, Grzegorz; Lantieri, Francesca; So, Man-Ting; Berrios, Courtney; Shin, Hyoung Doo; Fernández, Raquel M; Le, Thuy-Linh; Verheij, Joke B G M; Matera, Ivana; Cherny, Stacey S; Nandakumar, Priyanka; Cheong, Hyun Sub; Antiñolo, Guillermo; Amiel, Jeanne; Seo, Jeong-Meen; Kim, Dae-Yeon; Oh, Jung-Tak; Lyonnet, Stanislas; Borrego, Salud; Ceccherini, Isabella; Hofstra, Robert M W; Chakravarti, Aravinda; Kim, Hyun-Young; Sham, Pak Chung; Tam, Paul K H; Garcia-Barceló, Maria-Mercè
Hirschsprung disease (HSCR) is the most common cause of neonatal intestinal obstruction. It is characterized by the absence of ganglia in the nerve plexuses of the lower gastrointestinal tract. So far, three common disease-susceptibility variants at the RET, SEMA3 and NRG1 loci have been detected through genome-wide association studies (GWAS) in Europeans and Asians to understand its genetic etiologies. Here we present a trans-ethnic meta-analysis of 507 HSCR cases and 1191 controls, combining all published GWAS results on HSCR to fine-map these loci and narrow down the putatively causal variants to 99% credible sets. We also demonstrate that the effects of RET and NRG1 are universal across European and Asian ancestries. In contrast, we detected a European-specific association of a low-frequency variant, rs80227144, in SEMA3 [odds ratio (OR) = 5.2, P = 4.7 × 10-10]. Conditional analyses on the lead SNPs revealed a secondary association signal, corresponding to an Asian-specific, low-frequency missense variant encoding RET p.Asp489Asn (rs9282834, conditional OR = 20.3, conditional P = 4.1 × 10-14). When in trans with the RET intron 1 enhancer risk allele, rs9282834 increases the risk of HSCR from 1.1 to 26.7. Overall, our study provides further insights into the genetic architecture of HSCR and has profound implications for future study designs. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
Full Text Available In the last years, the interest in technologies such as in-memory analytics and associative search has increased. This paper explores how you can use in-memory analytics and an associative model in statistics. The word “associative” puts the emphasis on understanding how datasets relate to one another. The paper presents the main characteristics of “associative” data model. Also, the paper presents how to design an associative model for labor market indicators analysis. The source is the EU Labor Force Survey. Also, this paper presents how to make associative analysis.
Liao, Shu-Yi; Lin, Xihong; Christiani, David C
Single nucleotide polymorphisms have been found to be associated with pulmonary function using genome-wide association studies. However, lung function is a complex trait that is likely to be influenced by multiple gene-gene interactions besides individual genes. Our goal is to build a cellular network to explore the relationship between pulmonary function and genotypes by combining SNP level and network analyses using longitudinal lung function data from the Framingham Heart Study. We analyzed 2,698 genotyped participants from the Offspring cohort that had an average of 3.35 spirometry measurements per person for a mean length of 13 years. Repeated forced expiratory volume in one second (FEV1 ) and the ratio of FEV1 to forced vital capacity (FVC) were used as outcomes. Data were analyzed using linear-mixed models for the association between lung function and alleles by accounting for the correlation among repeated measures over time within the same subject and within-family correlation. Network analyses were performed using dmGWAS and validated with data from the Third Generation cohort. Analyses identified SMAD3, TGFBR2, CD44, CTGF, VCAN, CTNNB1, SCGB1A1, PDE4D, NRG1, EPHB1, and LYN as contributors to pulmonary function. Most of these genes were novel that were not found previously using solely SNP-level analysis. These novel genes are involving the transforming growth factor beta (TGFB)-SMAD pathway, Wnt/beta-catenin pathway, etc. Therefore, combining SNP-level and network analyses using longitudinal lung function data is a useful alternative strategy to identify risk genes. © 2014 WILEY PERIODICALS, INC.
Potkin Steven G
Full Text Available Abstract Background Recently we have witnessed a surge of interest in using genome-wide association studies (GWAS to discover the genetic basis of complex diseases. Many genetic variations, mostly in the form of single nucleotide polymorphisms (SNPs, have been identified in a wide spectrum of diseases, including diabetes, cancer, and psychiatric diseases. A common theme arising from these studies is that the genetic variations discovered by GWAS can only explain a small fraction of the genetic risks associated with the complex diseases. New strategies and statistical approaches are needed to address this lack of explanation. One such approach is the pathway analysis, which considers the genetic variations underlying a biological pathway, rather than separately as in the traditional GWAS studies. A critical challenge in the pathway analysis is how to combine evidences of association over multiple SNPs within a gene and multiple genes within a pathway. Most current methods choose the most significant SNP from each gene as a representative, ignoring the joint action of multiple SNPs within a gene. This approach leads to preferential identification of genes with a greater number of SNPs. Results We describe a SNP-based pathway enrichment method for GWAS studies. The method consists of the following two main steps: 1 for a given pathway, using an adaptive truncated product statistic to identify all representative (potentially more than one SNPs of each gene, calculating the average number of representative SNPs for the genes, then re-selecting the representative SNPs of genes in the pathway based on this number; and 2 ranking all selected SNPs by the significance of their statistical association with a trait of interest, and testing if the set of SNPs from a particular pathway is significantly enriched with high ranks using a weighted Kolmogorov-Smirnov test. We applied our method to two large genetically distinct GWAS data sets of schizophrenia, one
Shi, HaiCun; Yuan, CongHu; Dai, ZhenYu; Ma, HaiRong; Sheng, LiQin
Studies employing voxel-based morphometry (VBM) have reported inconsistent findings on the association of gray matter (GM) abnormalities with fibromyalgia. The aim of the present study is to identify the most prominent and replicable GM areas that involved in fibromyalgia. A systematic search of the PubMed database from January 2000 to September 2015 was performed to identify eligible whole-brain VBM studies. Comprehensive meta-analyses to investigate regional GM abnormalities in fibromyalgia were conducted with the Seed-based d Mapping software package. Seven studies, reporting nine comparisons and including a grand total of 180 fibromyalgia patients and 126 healthy controls, were included in the meta-analyses. In fibromyalgia patients compared with healthy controls, regional GM decreases were consistently found in the bilateral anterior cingulate/paracingulate cortex/medial prefrontal cortex, the bilateral posterior cingulate/paracingulate cortex, the left parahippocampal gyrus/fusiform cortex, and the right parahippocampal gyrus/hippocampus. Regional GM increases were consistently found in the left cerebellum. Meta-regression demonstrated that age was correlated with GM anomalies in fibromyalgia patients. The current meta-analysis identified a characteristic pattern of GM alterations within the medial pain system, default mode network, and cerebro-cerebellar circuits, which further supports the concept that fibromyalgia is a symptom complex involving brain areas beyond those implicated in chronic pain. Copyright © 2016 Elsevier Inc. All rights reserved.
Yang, Xiaohong R.; Chang-Claude, Jenny; Goode, Ellen L.; Couch, Fergus J.; Nevanlinna, Heli; Milne, Roger L.; Gaudet, Mia; Schmidt, Marjanka K.; Broeks, Annegien; Cox, Angela; Fasching, Peter A.; Hein, Rebecca; Spurdle, Amanda B.; Blows, Fiona; Driver, Kristy; Flesch-Janys, Dieter; Heinz, Judith; Sinn, Peter; Vrieling, Alina; Heikkinen, Tuomas; Aittomaeki, Kristiina; Heikkilae, Paeivi; Blomqvist, Carl; Lissowska, Jolanta; Peplonska, Beata; Chanock, Stephen; Figueroa, Jonine; Brinton, Louise; Hall, Per; Czene, Kamila; Humphreys, Keith; Darabi, Hatef; Liu, Jianjun; Van 't Veer, Laura J.; Van Leeuwen, Flora E.; Andrulis, Irene L.; Glendon, Gord; Knight, Julia A.; Mulligan, Anna Marie; O'Malley, Frances P.; Weerasooriya, Nayana; John, Esther M.; Beckmann, Matthias W.; Hartmann, Arndt; Weihbrecht, Sebastian B.; Wachter, David L.; Jud, Sebastian M. S.; Loehberg, Christian R.; Baglietto, Laura; English, Dallas R.; Giles, Graham G.; McLean, Catriona A.; Severi, Gianluca; Lambrechts, Diether; Vandorpe, Thijs; Weltens, Caroline; Paridaens, Robert; Smeets, Ann; Neven, Patrick; Wildiers, Hans; Wang, Xianshu; Olson, Janet E.; Cafourek, Victoria; Fredericksen, Zachary; Kosel, Matthew; Vachon, Celine; Cramp, Helen E.; Connley, Daniel; Cross, Simon S.; Balasubramanian, Sabapathy P.; Reed, Malcolm W. R.; Doerk, Thilo; Bremer, Michael; Meyer, Andreas; Karstens, Johann H.; Ay, Aysun; Park-Simon, Tjoung-Won; Hillemanns, Peter; Arias Perez, Jose Ignacio; Menendez Rodriguez, Primitiva; Zamora, Pilar; Bentez, Javier; Ko, Yon-Dschun; Fischer, Hans-Peter; Hamann, Ute; Pesch, Beate; Bruening, Thomas; Justenhoven, Christina; Brauch, Hiltrud; Eccles, Diana M.; Tapper, William J.; Gerty, Sue M.; Sawyer, Elinor J.; Tomlinson, Ian P.; Jones, Angela; Kerin, Michael; Miller, Nicola; McInerney, Niall; Anton-Culver, Hoda; Ziogas, Argyrios; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Yang, Show-Lin; Yu, Jyh-Cherng; Chen, Shou-Tung; Hsu, Giu-Cheng; Haiman, Christopher A.; Henderson, Brian E.; Le Marchand, Loic; Kolonel, Laurence N.; Lindblom, Annika; Margolin, Sara; Jakubowska, Anna; Lubinski, Jan; Huzarski, Tomasz; Byrski, Tomasz; Gorski, Bohdan; Gronwald, Jacek; Hooning, Maartje J.; Hollestelle, Antoinette; van den Ouweland, Ans M. W.; Jager, Agnes; Kriege, Mieke; Tilanus-Linthorst, Madeleine M. A.; Collee, Margriet; Wang-Gohrke, Shan; Pylkaes, Katri; Jukkola-Vuorinen, Arja; Mononen, Kari; Grip, Mervi; Hirvikoski, Pasi; Winqvist, Robert; Mannermaa, Arto; Kosma, Veli-Matti; Kauppinen, Jaana; Kataja, Vesa; Auvinen, Paeivi; Soini, Ylermi; Sironen, Reijo; Bojesen, Stig E.; Orsted, David Dynnes; Kaur-Knudsen, Diljit; Flyger, Henrik; Nordestgaard, Borge G.; Holland, Helene; Chenevix-Trench, Georgia; Manoukian, Siranoush; Barile, Monica; Radice, Paolo; Hankinson, Susan E.; Hunter, David J.; Tamimi, Rulla; Sangrajrang, Suleeporn; Brennan, Paul; Mckay, James; Odefrey, Fabrice; Gaborieau, Valerie; Devilee, Peter; Huijts, P. E. A.; Tollenaar, R. A. E. M.; Seynaeve, C.; Dite, Gillian S.; Apicella, Carmel; Hopper, John L.; Hammet, Fleur; Tsimiklis, Helen; Smith, Letitia D.; Southey, Melissa C.; Humphreys, Manjeet K.; Easton, Douglas; Pharoah, Paul; Sherman, Mark E.; Garcia-Closas, Montserrat
Background Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. Methods We pooled tumor marker and epidemiological risk factor data from 35 568 invasive breast cancer case patients
Murabito, Joanne M.; White, Charles C.; Kavousi, Maryam; Sun, Yan V.; Feitosa, Mary F.; Nambi, Vijay; Lamina, Claudia; Schillert, Arne; Coassin, Stefan; Bis, Joshua C.; Broer, Linda; Crawford, Dana C.; Franceschini, Nora; Frikke-Schmidt, Ruth; Haun, Margot; Holewijn, Suzanne; Huffman, Jennifer E.; Hwang, Shih-Jen; Kiechl, Stefan; Kollerits, Barbara; Montasser, May E.; Nolte, Ilja M.; Rudock, Megan E.; Senft, Andrea; Teumer, Alexander; van der Harst, Pim; Vitart, Veronique; Waite, Lindsay L.; Wood, Andrew R.; Wassel, Christina L.; Absher, Devin M.; Allison, Matthew A.; Amin, Najaf; Arnold, Alice; Asselbergs, Folkert W.; Aulchenko, Yurii; Bandinelli, Stefania; Barbalic, Maja; Boban, Mladen; Brown-Gentry, Kristin; Couper, David J.; Criqui, Michael H.; Dehghan, Abbas; den Heijer, Martin; Dieplinger, Benjamin; Ding, Jingzhong; Doerr, Marcus; Espinola-Klein, Christine; Felix, Stephan B.; Ferrucci, Luigi; Folsom, Aaron R.; Fraedrich, Gustav; Gibson, Quince; Goodloe, Robert; Gunjaca, Grgo; Haltmayer, Meinhard; Heiss, Gerardo; Hofman, Albert; Kieback, Arne; Kiemeney, Lambertus A.; Kolcic, Ivana; Kullo, Iftikhar J.; Kritchevsky, Stephen B.; Lackner, Karl J.; Li, Xiaohui; Lieb, Wolfgang; Lohman, Kurt; Meisinger, Christa; Melzer, David; Mohler, Emile R.; Mudnic, Ivana; Mueller, Thomas; Navis, Gerjan; Oberhollenzer, Friedrich; Olin, Jeffrey W.; O'Connell, Jeff; O'Donnell, Christopher J.; Palmas, Walter; Penninx, Brenda W.; Petersmann, Astrid; Polasek, Ozren; Psaty, Bruce M.; Rantner, Barbara; Rice, Ken; Rivadeneira, Fernando; Rotter, Jerome I.; Seldenrijk, Adrie; Stadler, Marietta; Summerer, Monika; Tanaka, Toshiko; Tybjaerg-Hansen, Anne; Uitterlinden, Andre G.; van Gilst, Wiek H.; Vermeulen, Sita H.; Wild, Sarah H.; Wild, Philipp S.; Willeit, Johann; Zeller, Tanja; Zemunik, Tatijana; Zgaga, Lina; Assimes, Themistocles L.; Blankenberg, Stefan; Campbell, Harry; Boerwinkle, Eric; Cooke, John P.; de Graaf, Jacqueline; Herrington, David; Kardia, Sharon L. R.; Mitchell, Braxton D.; Murray, Anna; Muenzel, Thomas; Newman, Anne B.; Oostra, Ben A.; Rudan, Igor; Shuldiner, Alan R.; Snieder, Harold; van Duijn, Cornelia M.; Voelker, Uwe; Wright, Alan F.; Wichmann, H. -Erich; Wilson, James F.; Witteman, Jacqueline C. M.; Liu, Yongmei; Hayward, Caroline; Borecki, Ingrid B.; Ziegler, Andreas; North, Kari E.; Cupples, L. Adrienne; Kronenberg, Florian; Dorr, M.; Munzel, T.; Volker, U.
Background-Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
Amin Al Olama, Ali; Kote-Jarai, Zsofia; Schumacher, Fredrick R
Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS inc...
Zaitlen, Noah; Pasaniuc, Bogdan; Patterson, Nick; Pollack, Samuela; Voight, Benjamin; Groop, Leif; Altshuler, David; Henderson, Brian E.; Laurence N Kolonel; Le Marchand, Loic; Waters, Kevin; Haiman, Christopher A.; Stranger, Barbara E.; Dermitzakis, Emmanouil; Kraft, Peter
Motivation: The question of how to best use information from known associated variants when conducting disease association studies has yet to be answered. Some studies compute a marginal P-value for each Several Nucleotide Polymorphisms independently, ignoring previously discovered variants. Other studies include known variants as covariates in logistic regression, but a weakness of this standard conditioning strategy is that it does not account for disease prevalence and non-random ascertain...
van den Berg, Stéphanie M; de Moor, Marleen H M; Verweij, K. J. H.
Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively ...
Li, Qiudan; Zhan, Yongcheng; Wang, Lei; Leischow, Scott J; Zeng, Daniel Dajun
The electronic cigarette (e-cigarette) market has grown rapidly in recent years. However, causes of e-cigarette related symptoms among users and their impact on health remain uncertain. This research aims to mine the potential relationships between symptoms and e-liquid components, such as propylene glycol (PG), vegetable glycerine (VG), flavor extracts, and nicotine, using user-generated data collected from Reddit. A total of 3605 e-liquid related posts from January 1st, 2011 to June 30th, 2015 were collected from Reddit. Then the patterns of VG/PG distribution among different flavors were analyzed. Next, the relationship between throat hit, which was a typical symptom of e-cigarette use, and e-liquid components was studied. Finally, other symptoms were examined based on e-liquid components and user sentiment. We discovered 3 main sets of findings: 1) We identified three groups of flavors in terms of VG/PG ratios. Fruits, cream, and nuts flavors were similar. Sweet, menthol, and seasonings flavors were classified into one group. Tobacco and beverages flavors were the third group. 2) Throat hit was analyzed and we found that menthol and tobacco flavors, as well as high ratios of PG and nicotine level, could produce more throat hit. 3) A total of 9 systems of 25 symptoms were identified and analyzed. Components including VG/PG ratio, flavor, and nicotine could be possible reasons for these symptoms. E-liquid components shown to be associated with e-cigarette use symptomology were VG/PG ratios, flavors, and nicotine levels. Future analysis could be conducted based on the structure of e-liquid components categories built in this study. Information revealed in this study could be utilized by e-cigarette users to understand the relationship between e-liquid type and symptoms experienced, by vendors to choose appropriate recipes of e-liquid, and by policy makers to develop new regulations.
Full Text Available Abstract Background The electronic cigarette (e-cigarette market has grown rapidly in recent years. However, causes of e-cigarette related symptoms among users and their impact on health remain uncertain. This research aims to mine the potential relationships between symptoms and e-liquid components, such as propylene glycol (PG, vegetable glycerine (VG, flavor extracts, and nicotine, using user-generated data collected from Reddit. Methods A total of 3605 e-liquid related posts from January 1st, 2011 to June 30th, 2015 were collected from Reddit. Then the patterns of VG/PG distribution among different flavors were analyzed. Next, the relationship between throat hit, which was a typical symptom of e-cigarette use, and e-liquid components was studied. Finally, other symptoms were examined based on e-liquid components and user sentiment. Results We discovered 3 main sets of findings: 1 We identified three groups of flavors in terms of VG/PG ratios. Fruits, cream, and nuts flavors were similar. Sweet, menthol, and seasonings flavors were classified into one group. Tobacco and beverages flavors were the third group. 2 Throat hit was analyzed and we found that menthol and tobacco flavors, as well as high ratios of PG and nicotine level, could produce more throat hit. 3 A total of 9 systems of 25 symptoms were identified and analyzed. Components including VG/PG ratio, flavor, and nicotine could be possible reasons for these symptoms. Conclusions E-liquid components shown to be associated with e-cigarette use symptomology were VG/PG ratios, flavors, and nicotine levels. Future analysis could be conducted based on the structure of e-liquid components categories built in this study. Information revealed in this study could be utilized by e-cigarette users to understand the relationship between e-liquid type and symptoms experienced, by vendors to choose appropriate recipes of e-liquid, and by policy makers to develop new regulations.
Shohet, Ralph V; Vega, Gloria L; Bersot, Thomas P; Mahley, Robert W; Grundy, Scott M; Guerra, Rudy; Cohen, Jonathan C
Genetic association studies have been widely used to identify loci that influence plasma lipoprotein concentrations, but few of the associations reported have proved consistently reproducible across different study populations. This lack of consistency is a widely recognized limitation of association studies, and is often ascribed to inadequate statistical power, population substructure, and population-specific linkage disequilibrium. However, few studies have assessed the causes of variability underlying a given genotype-phenotype association. We have examined two possible sources of variability in the association between the -514 polymorphism in hepatic lipase (LIPC) and plasma HDL-C concentrations. First, we compared the association between this polymorphism and hepatic lipase activity in four populations. A single copy of the -514C allele was associated with a 10 mmol.hr(-1).l(-1) increase in hepatic lipase activity in white American and Turkish men but only approximately 5 mmol.hr(-1).l(-1) in Chinese and African-American men. Second, we tested the effects of a stanozolol-induced increase in hepatic lipase activity on plasma HDL-C concentrations in men with normal (G, and -2880G>C). Copyright 2002 Wiley-Liss, Inc.
Chang-Claude, Jenny; Goode, Ellen L.; Couch, Fergus J.; Nevanlinna, Heli; Milne, Roger L.; Gaudet, Mia; Schmidt, Marjanka K.; Broeks, Annegien; Cox, Angela; Fasching, Peter A.; Hein, Rebecca; Spurdle, Amanda B.; Blows, Fiona; Driver, Kristy; Flesch-Janys, Dieter; Heinz, Judith; Sinn, Peter; Vrieling, Alina; Heikkinen, Tuomas; Aittomäki, Kristiina; Heikkilä, Päivi; Blomqvist, Carl; Lissowska, Jolanta; Peplonska, Beata; Chanock, Stephen; Figueroa, Jonine; Brinton, Louise; Hall, Per; Czene, Kamila; Humphreys, Keith; Darabi, Hatef; Liu, Jianjun; Van ‘t Veer, Laura J.; van Leeuwen, Flora E.; Andrulis, Irene L.; Glendon, Gord; Knight, Julia A.; Mulligan, Anna Marie; O’Malley, Frances P.; Weerasooriya, Nayana; John, Esther M.; Beckmann, Matthias W.; Hartmann, Arndt; Weihbrecht, Sebastian B.; Wachter, David L.; Jud, Sebastian M.; Loehberg, Christian R.; Baglietto, Laura; English, Dallas R.; Giles, Graham G.; McLean, Catriona A.; Severi, Gianluca; Lambrechts, Diether; Vandorpe, Thijs; Weltens, Caroline; Paridaens, Robert; Smeets, Ann; Neven, Patrick; Wildiers, Hans; Wang, Xianshu; Olson, Janet E.; Cafourek, Victoria; Fredericksen, Zachary; Kosel, Matthew; Vachon, Celine; Cramp, Helen E.; Connley, Daniel; Cross, Simon S.; Balasubramanian, Sabapathy P.; Reed, Malcolm W. R.; Dörk, Thilo; Bremer, Michael; Meyer, Andreas; Karstens, Johann H.; Ay, Aysun; Park-Simon, Tjoung-Won; Hillemanns, Peter; Arias Pérez, Jose Ignacio; Rodríguez, Primitiva Menéndez; Zamora, Pilar; Benítez, Javier; Ko, Yon-Dschun; Fischer, Hans-Peter; Hamann, Ute; Pesch, Beate; Brüning, Thomas; Justenhoven, Christina; Brauch, Hiltrud; Eccles, Diana M.; Tapper, William J.; Gerty, Sue M.; Sawyer, Elinor J.; Tomlinson, Ian P.; Jones, Angela; Kerin, Michael; Miller, Nicola; McInerney, Niall; Anton-Culver, Hoda; Ziogas, Argyrios; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Yu, Jyh-Cherng; Chen, Shou-Tung; Hsu, Giu-Cheng; Haiman, Christopher A.; Henderson, Brian E.; Le Marchand, Loic; Kolonel, Laurence N.; Lindblom, Annika; Margolin, Sara; Jakubowska, Anna; Lubiński, Jan; Huzarski, Tomasz; Byrski, Tomasz; Górski, Bohdan; Gronwald, Jacek; Hooning, Maartje J.; Hollestelle, Antoinette; van den Ouweland, Ans M. W.; Jager, Agnes; Kriege, Mieke; Tilanus-Linthorst, Madeleine M. A.; Collée, Margriet; Wang-Gohrke, Shan; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Mononen, Kari; Grip, Mervi; Hirvikoski, Pasi; Winqvist, Robert; Mannermaa, Arto; Kosma, Veli-Matti; Kauppinen, Jaana; Kataja, Vesa; Auvinen, Päivi; Soini, Ylermi; Sironen, Reijo; Bojesen, Stig E.; Dynnes Ørsted, David; Kaur-Knudsen, Diljit; Flyger, Henrik; Nordestgaard, Børge G.; Holland, Helene; Chenevix-Trench, Georgia; Manoukian, Siranoush; Barile, Monica; Radice, Paolo; Hankinson, Susan E.; Hunter, David J.; Tamimi, Rulla; Sangrajrang, Suleeporn; Brennan, Paul; McKay, James; Odefrey, Fabrice; Gaborieau, Valerie; Devilee, Peter; Huijts, P.E.A.; Tollenaar, RAEM.; Seynaeve, C.; Dite, Gillian S.; Apicella, Carmel; Hopper, John L.; Hammet, Fleur; Tsimiklis, Helen; Smith, Letitia D.; Southey, Melissa C.; Humphreys, Manjeet K.; Easton, Douglas; Pharoah, Paul; Sherman, Mark E.; Garcia-Closas, Montserrat
Background Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. Methods We pooled tumor marker and epidemiological risk factor data from 35 568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case–case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case–control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. Results In case–case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR− than PR+ tumors (P = .001). Nulliparity (P = 3 × 10−6) and increasing age at first birth (P = 2 × 10−9) were less frequent in ER− than in ER+ tumors. Obesity (body mass index [BMI] ≥ 30 kg/m2) in younger women (≤50 years) was more frequent in ER−/PR− than in ER+/PR+ tumors (P = 1 × 10−7), whereas obesity in older women (>50 years) was less frequent in PR− than in PR+ tumors (P = 6 × 10−4). The triple-negative (ER−/PR−/HER2−) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6+ and/or epidermal growth factor receptor [EGFR]+) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case–control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER+ or PR+ tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95
Lin, Yan; Wang, Changjun; Zhong, Ying; Huang, Xin; Peng, Li; Shan, Guangliang; Wang, Ke; Sun, Qiang
Purpose The association between striking life events, an important stress and acute anxiety disorder, and the occurrence of primary breast cancer is unclear. The current meta-analysis was designed to assess the relationship between striking life events and primary breast cancer incidence in women. Methods Systematic computerized searching of the PubMed, ScienceDirect, Embase, and BMJ databases with the combinations of controlled descriptors from Mesh, including breast cancer, breast tumor, ca...
Neale, B.M.; Medland, S.E.; Ripke, S.; Asherson, P.; Franke, B.; Lesch, K.P.; Faraone, S.V.; Nguyen, T.T.; Schafer, H.; Holmans, P.; Daly, M.; Steinhausen, H.C.; Freitag, C.; Reif, A.; Renner, T.J.; Romanos, M.; Romanos, J.; Walitza, S.; Warnke, A.; Meyer, J.; Palmason, H.; Buitelaar, J.K.; Arias Vasquez, A.; Lambregts-Rommelse, N.N.J.; Gill, M.; Anney, R.J.; Langely, K.; O'Donovan, M.; Williams, N.; Owen, M.; Thapar, A.; Kent, L.; Sergeant, J.A.; Roeyers, H.; Mick, E.; Biederman, J.; Doyle, A.; Smalley, S.; Loo, S.; Hakonarson, H.; Elia, J.; Todorov, A.A.; Miranda, A.; Mulas, F.; Ebstein, R.P.; Rothenberger, A.; Banaschewski, T.; Oades, R.D.; Sonuga-Barke, E.J.S.; McGough, J.; Nisenbaum, L.; Middleton, F.; Hu, X.; Nelson, S.
OBJECTIVE: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded
Tan, Qihua; Christiansen, Lene; Brasch-Andersen, Charlotte
with that of the case-only model. RESULTS: Results from our simulation study indicate that our retrospective model exhibits high power in capturing even relatively small effect with reasonable sample sizes. Application of our method to data from an association study on the catalase -262C/T promoter polymorphism...
Full Text Available BACKGROUND: Bovine paratuberculosis (ParaTB also known as Johne's disease, is a contagious fatal disease resulting from infection by Mycobacterium avium subspecies paratuberculosis (MAP. Previous studies have identified loci associated with ParaTB using different measurements to define cases and controls. The objective of this study was to combine the data from two recent studies to identify genetic loci associated with MAP tissue infection and humoral immune response, defined by MAP ELISA-positive cattle, by comparing cases and control animals for one or both measures of infection. METHODOLOGY/PRINCIPAL FINDINGS: The two populations used for the association analyses were a cohort of MAP tissue infected animals and control Holstein cows from the USA and the second cohort composed of ELISA-positive and ELISA-negative Holstein cows from Italy. Altogether 1190 cattle were genotyped with the Illumina BovineSNP50 BeadChip. SNP markers were removed if the minor allele frequency 5%. Animals were removed with >5% genotyping failure. Whole genome association analyses were conducted with the GRAMMAR-CG method using two different definitions of control populations. CONCLUSION/SIGNIFICANCE: The analyses identified several loci (P<5 e-05 associated with ParaTB, defined by positive ELISA and presence of bacteria in tissue compared to ELISA and tissue negative animals, on chromosomes 1, 12 and 15 and one unassigned SNP. These results confirmed associations on chromosome 12 and the unassigned SNP with ParaTB which had been found in the Italian population alone. Furthermore, several additional genomic regions were found associated with ParaTB when ELISA and tissue positive animals were compared with tissue negative samples. These loci were on chromosomes 1, 6, 7, 13, 16, 21,23 and 25 (P<5 e-05. The results clearly indicate the importance of the phenotype definition when seeking to identify markers associated with different disease responses.
Full Text Available Library classification schemes are mostly organized based on disciplines with a hierarchical structure. From the user point of view, some highly related yet non-hierarchical classes may not be easy to perceive in these schemes. This paper is to discover hidden associations between classes by analyzing users’ usage of library collections. The proposed approach employs collaborative filtering techniques to discover associated classes based on the circulation patterns of similar users. Many associated classes scattered across different subject hierarchies could be discovered from the circulation patterns of similar users. The obtained association norms between classes were found to be useful in understanding users' subject preferences for a given class. Classification schemes can, therefore, be made more adaptable to changes of users and the uses of different library collections. There are implications for applications in information organization and retrieval as well. For example, catalogers could refer to the ranked associated classes when they perform multi-classification, and users could also browse the associated classes for related subjects in an enhanced OPAC system. In future research, more empirical studies will be needed to validate the findings, and methods for obtaining user-oriented associations can still be improved.[Article content in Chinese
Yan, Dandan; Zhao, Enfa; Zhang, Hong; Luo, Xiaohui; Du, Yajuan
A potential association between type 1 diabetes mellitus and subsequent epilepsy emerged in recent studies. This study aimed to evaluate the possible relationship between type 1 diabetes mellitus and epilepsy using meta-analysis. Pubmed, ISI Web of Knowledge, Embase and Cochrane Library were searched for potential studies of the association between type 1 diabetes mellitus and epilepsy from inception to February 1, 2017. Two investigators independently screened studies for inclusion and extracted related data; discrepancies were solved by consensus. Random effects model of Hazard Ratio (HR) was used to estimate the strength of association. We identified 13 papers from potentially relevant articles of which 3 cohort studies met the inclusion criteria. Random effects meta-analysis showed that type 1 diabetes mellitus was associated with an increased risk of epilepsy with HR = 3.29 (95% CI: 2.61-4.14; I2 = 0, p = 0.689). Similar results were observed in type 1 diabetes mellitus patents younger than 18-years-old with HR = 2.96 (95% CI: 2.28-3.84; I2 = 0, p = 0.571). Meta-analysis of 2 studies that adjusted for potential confounders yielded an increased risk of epilepsy with HR = 2.89 (95% CI: 2.26-3.70; I2 = 0, p = 0.831). The meta-analysis indicates that type 1 diabetes mellitus is associated with a statistically significant increased risk for epilepsy compared to those without type 1 diabetes mellitus.
Minozzi, Giulietta; Williams, John L; Stella, Alessandra; Strozzi, Francesco; Luini, Mario; Settles, Matthew L; Taylor, Jeremy F; Whitlock, Robert H; Zanella, Ricardo; Neibergs, Holly L
Bovine paratuberculosis (ParaTB) also known as Johne's disease, is a contagious fatal disease resulting from infection by Mycobacterium avium subspecies paratuberculosis (MAP). Previous studies have identified loci associated with ParaTB using different measurements to define cases and controls. The objective of this study was to combine the data from two recent studies to identify genetic loci associated with MAP tissue infection and humoral immune response, defined by MAP ELISA-positive cattle, by comparing cases and control animals for one or both measures of infection. The two populations used for the association analyses were a cohort of MAP tissue infected animals and control Holstein cows from the USA and the second cohort composed of ELISA-positive and ELISA-negative Holstein cows from Italy. Altogether 1190 cattle were genotyped with the Illumina BovineSNP50 BeadChip. SNP markers were removed if the minor allele frequency 5%. Animals were removed with >5% genotyping failure. Whole genome association analyses were conducted with the GRAMMAR-CG method using two different definitions of control populations. The analyses identified several loci (Pdefinition when seeking to identify markers associated with different disease responses.
Goudey, Benjamin; Abedini, Mani; Hopper, John L; Inouye, Michael; Makalic, Enes; Schmidt, Daniel F; Wagner, John; Zhou, Zeyu; Zobel, Justin; Reumann, Matthias
Genome-wide association studies (GWAS) are a common approach for systematic discovery of single nucleotide polymorphisms (SNPs) which are associated with a given disease. Univariate analysis approaches commonly employed may miss important SNP associations that only appear through multivariate analysis in complex diseases. However, multivariate SNP analysis is currently limited by its inherent computational complexity. In this work, we present a computational framework that harnesses supercomputers. Based on our results, we estimate a three-way interaction analysis on 1.1 million SNP GWAS data requiring over 5.8 years on the full "Avoca" IBM Blue Gene/Q installation at the Victorian Life Sciences Computation Initiative. This is hundreds of times faster than estimates for other CPU based methods and four times faster than runtimes estimated for GPU methods, indicating how the improvement in the level of hardware applied to interaction analysis may alter the types of analysis that can be performed. Furthermore, the same analysis would take under 3 months on the currently largest IBM Blue Gene/Q supercomputer "Sequoia" at the Lawrence Livermore National Laboratory assuming linear scaling is maintained as our results suggest. Given that the implementation used in this study can be further optimised, this runtime means it is becoming feasible to carry out exhaustive analysis of higher order interaction studies on large modern GWAS.
Calati, Raffaella; Porcelli, Stefano; Giegling, Ina; Hartmann, Annette M; Möller, Hans-Jürgen; De Ronchi, Diana; Serretti, Alessandro; Rujescu, Dan
Suicide is one of the leading causes of death among young adults. Both genetic and personality factors plausibly have a role on suicidal behavior. We focused on the catechol-O-methyltransferase gene (COMT) and we performed: a review of studies investigating the association between COMT and both suicidal behavior and personality; a meta-analysis of studies investigating the association between suicidal behavior and COMT rs4680 polymorphism; an association study investigating the link between seven COMT polymorphisms (rs737865, rs5844402, rs5993883, rs4680, rs4633, rs165599 and rs9332377) and both personality traits and suicidal behavior. For the review and the meta-analysis we performed an electronic search to identify studies focused on the association between COMT and both suicidal behavior and personality. The sample of the association study was composed of three groups: 289 German healthy controls, 111 German suicide attempters and 70 Italian mood disorder patients. From the review, the meta-analysis and the association study no relationship emerged between COMT and suicidal behavior. Nevertheless, from both review and association study several links were found between COMT and personality traits. In particular, in the association study we found a significant correlation between rs4633 and Reward Dependence (Temperament and Character Inventory). As secondary results we found an association between rs737865 and Angry Reaction (State-Trait Anger Expression Inventory) and between rs9332377 and Irritability (Questionnaire for Measuring Factors of Aggression). Our findings suggested that COMT variants may not be directly implicated in suicidal behavior, however evidence of a COMT role in the modulation of personality traits has been found. Copyright © 2010 Elsevier Ltd. All rights reserved.
Teruel, María; McKinney, Cushla; Balsa, Alejandro; Pascual-Salcedo, Dora; Rodriguez-Rodriguez, Luis; Ortiz, Ana M.; Gómez-Vaquero, Carmen; González-Gay, Miguel A.; Smith, Malcolm; Witte, Torsten; Merriman, Tony; Lie, Benedicte A.; Martin, Javier
Given the role of CD247 in the response of the T cells, its entailment in autoimmune diseases and in order to better clarify the role of this gene in RA susceptibility, we aimed to analyze CD247 gene variants previously associated with other autoimmune diseases (rs1052237, rs2056626 and rs864537) in a large independent European Caucasian population. However, no evidence of association was found for the analyzed CD247 single-nucleotide polymorphisms (SNPs) with RA and with the presence/absence of anti-cyclic citrullinated polypeptide. We performed a meta-analysis including previously published GWAS data from the rs864537 variant, revealing an overall genome-wide significant association between this CD247 SNP and RA with anti-CCP (OR = 0.90, CI 95% = 0.87–0.93, Poverall = 2.1×10−10). Our results show for first time a GWAS-level association between this CD247 polymorphism and RA risk. PMID:23861880
Full Text Available Given the role of CD247 in the response of the T cells, its entailment in autoimmune diseases and in order to better clarify the role of this gene in RA susceptibility, we aimed to analyze CD247 gene variants previously associated with other autoimmune diseases (rs1052237, rs2056626 and rs864537 in a large independent European Caucasian population. However, no evidence of association was found for the analyzed CD247 single-nucleotide polymorphisms (SNPs with RA and with the presence/absence of anti-cyclic citrullinated polypeptide. We performed a meta-analysis including previously published GWAS data from the rs864537 variant, revealing an overall genome-wide significant association between this CD247 SNP and RA with anti-CCP (OR = 0.90, CI 95% = 0.87-0.93, Poverall = 2.1×10(-10. Our results show for first time a GWAS-level association between this CD247 polymorphism and RA risk.
Pork quality plays an important role in the meat processing industry, thus different methodologies have been implemented to elucidate the genetic architecture of traits affecting meat quality. One of the most common and widely used approaches is to perform genome-wide association (GWA) studies. Howe...
Pork quality is a critical concern in the meat industry. Implementation of genome-wide association studies (GWA) allows identification of genomic regions that explain a substantial portion of the variation of relevant traits. It is also important to determine the consistency of results of GWA across...
Horan, Mary K
Micronutrients are necessary for fetal growth. However increasingly pregnant women are nutritionally replete and little is known about the effect of maternal micronutrient intakes on fetal adiposity in mothers with increased BMI. The aim of this study was to examine the association of maternal dietary micronutrient intake with neonatal size and adiposity in a cohort at risk of macrosomia.
Oostenbrug, L.E.; Nolte, I.M.; Oosterom, E.; Steege, G. van der; Meerman, G.J. te; Dullemen, H.M. van; Drenth, J.P.H.; Jong, D.J. de; Linde, K. van der; Jansen, P.L.M.; Kleibeuker, J.H.
BACKGROUND: Three major polymorphisms of the Caspase-Activation Recruitment Domain containing protein 15 gene have been described to be associated with Crohn's disease. Genotype-phenotype studies reported in literature provide conflicting data on disease localisation and behaviour. We investigated
Oostenbrug, L. E.; Nolte, I. M.; Oosterom, E.; van der Steege, G.; te Meerman, G. J.; van Dullemen, H. M.; Drenth, J. P. H.; de Jong, D. J.; van der Linde, K.; Jansen, P. L. M.; Kleibeuker, J. H.
BACKGROUND: Three major polymorphisms of the Caspase-Activation Recruitment Domain containing protein 15 gene have been described to be associated with Crohn's disease. Genotype-phenotype studies reported in literature provide conflicting data on disease localisation and behaviour. We investigated
Full Text Available Romdhane Rekaya,1–3 Shannon Smith,4 El Hamidi Hay,5 Nourhene Farhat,6 Samuel E Aggrey3,7 1Department of Animal and Dairy Science, College of Agricultural and Environmental Sciences, 2Department of Statistics, Franklin College of Arts and Sciences, 3Institute of Bioinformatics, The University of Georgia, Athens, GA, 4Zoetis, Kalamazoo, MI, 5United States Department of Agriculture, Agricultural Research Service, Beltsville, MD, 6Carolinas HealthCare System Blue Ridge, Morganton, NC, 7Department of Poultry Science, College of Agricultural and Environmental Sciences, University of Georgia, Athens, GA, USA Abstract: Errors in the binary status of some response traits are frequent in human, animal, and plant applications. These error rates tend to differ between cases and controls because diagnostic and screening tests have different sensitivity and specificity. This increases the inaccuracies of classifying individuals into correct groups, giving rise to both false-positive and false-negative cases. The analysis of these noisy binary responses due to misclassification will undoubtedly reduce the statistical power of genome-wide association studies (GWAS. A threshold model that accommodates varying diagnostic errors between cases and controls was investigated. A simulation study was carried out where several binary data sets (case–control were generated with varying effects for the most influential single nucleotide polymorphisms (SNPs and different diagnostic error rate for cases and controls. Each simulated data set consisted of 2000 individuals. Ignoring misclassification resulted in biased estimates of true influential SNP effects and inflated estimates for true noninfluential markers. A substantial reduction in bias and increase in accuracy ranging from 12% to 32% was observed when the misclassification procedure was invoked. In fact, the majority of influential SNPs that were not identified using the noisy data were captured using the
Bønnelykke, Klaus; Matheson, Melanie C; Pers, Tune Hannes
and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may......Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up...... the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2...
Full Text Available For genome-wide association studies in family-based designs, we propose a new, universally applicable approach. The new test statistic exploits all available information about the association, while, by virtue of its design, it maintains the same robustness against population admixture as traditional family-based approaches that are based exclusively on the within-family information. The approach is suitable for the analysis of almost any trait type, e.g. binary, continuous, time-to-onset, multivariate, etc., and combinations of those. We use simulation studies to verify all theoretically derived properties of the approach, estimate its power, and compare it with other standard approaches. We illustrate the practical implications of the new analysis method by an application to a lung-function phenotype, forced expiratory volume in one second (FEV1 in 4 genome-wide association studies.
Babu, Giridhara R; Murthy, G V S; Ana, Yamuna; Patel, Prital; Deepa, R; Neelon, Sara E Benjamin; Kinra, Sanjay; Reddy, K Srinath
To perform a meta-analysis of the association of obesity with hypertension and type 2 diabetes mellitus (T2DM) in India among adults. To conduct meta-analysis, we performed comprehensive, electronic literature search in the PubMed, CINAHL Plus, and Google Scholar. We restricted the analysis to studies with documentation of some measure of obesity namely; body mass index, waist-hip ratio, waist circumference and diagnosis of hypertension or diagnosis of T2DM. By obtaining summary estimates of all included studies, the meta-analysis was performed using both RevMan version 5 and "metan" command STATA version 11. Heterogeneity was measured by I2 statistic. Funnel plot analysis has been done to assess the study publication bias. Of the 956 studies screened, 18 met the eligibility criteria. The pooled odds ratio between obesity and hypertension was 3.82 (95%CI: 3.39 to 4.25). The heterogeneity around this estimate (I2 statistic) was 0%, indicating low variability. The pooled odds ratio from the included studies showed a statistically significant association between obesity and T2DM (OR = 1.14, 95%CI: 1.04 to 1.24) with a high degree of variability. Despite methodological differences, obesity showed significant, potentially plausible association with hypertension and T2DM in studies conducted in India. Being a modifiable risk factor, our study informs setting policy priority and intervention efforts to prevent debilitating complications.
Guo, Vivian Yawei; Cao, Bing; Wu, Xinyin; Lee, Jack Jock Wai; Zee, Benny Chung-Ying
Diabetic retinopathy (DR) is linked to increased risk of cardiovascular (CV) disease. However, the effect size of the association was not consistent. In this study, we performed a systematic review and meta-analysis of available cohort studies to determine the association between DR and CV disease, and to investigate the factors that influence the association. Terms related to DR and CV disease were searched from MEDLINE and EMBASE database. High-quality articles (Newcastle-Ottawa scales above 6) conducted in cohort studies reporting the association between DR and CV disease were identified. Study-specific estimates were pooled using random effects with inverse variance meta-analysis. Subgroup analysis was performed according to diabetes types. Heterogeneity of included studies was assessed using the I(2) test. The cause of the heterogeneity was examined using metaregression analyses. A total of 13 studies representing 17,611 patients without CV disease at baseline were included. At follow-up, there were 1457 CV disease-related incidences. Overall, DR was associated with increased risk of CV disease (relative risk [RR]: 2.42, 95% confidence interval [CI]: 1.77-3.31) in diabetes. Specifically, the RR was 3.59 (95% CI: 1.79-7.20) for type 1 diabetes and 1.81 (95% CI: 1.47-2.23) for type 2 diabetes. Significant heterogeneity was found in studies with type 1 diabetes. Metaregression analysis showed that baseline systolic blood pressure was a key factor leading to the heterogeneity. In conclusion, DR is significantly associated with CV disease incidence and CV disease-related mortality in diabetes. Patients with DR may need more intensive management to control future CV disease attacks. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Joshi, Amit D; Andersson, Charlotte; Buch, Stephan
BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis o......BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta......-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease. METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10...... discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62...
Newman, Anne B; Walter, Stefan; Lunetta, Kathryn L
BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity. METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart...... Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1...... significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10...
Zhao, Enfa; Zhang, Yafei; Zeng, Xianling; Liu, Baomin
Increasing studies suggest that gestational diabetes mellitus (GDM) and pre-gestational diabetes mellitus (PGDM) may be associated with an increased risk of major congenital malformations (MCM) in the offspring. To determine whether GDM or PGDM is associated with an increased risk of congenital malformations, we performed a meta-analysis of cohort studies. We systematically searched the PubMed, Web of Science and Cochrane Library (from January, 1990 to October, 2014) and reviewed the reference lists of included papers to search for additional studies. Meta-analysis tools were used to summarize results. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with random-effects models or fixed-effects models. Study quality was assessed using the Newcastle-Ottawa scale. A total of 21 cohort studies were included in the meta-analysis. Analysis of all studies showed that both PGDM and GDM were associated with an increased risk of MCM (RR=2.44, 95% CI=1.92-3.10, I2=78.3%, p=0.342; RR=1.11, 95% CI=1.11-1.27, I2=9.9%, pcohort studies are needed to test the effect of PGDM and GDM on specific congenital malformations risk.
Springelkamp, Henriet; Hoehn, Rene; Mishra, Aniket; Hysi, Pirro G.; Khor, Chiea-Chuen; Loomis, Stephanie J.; Bailey, Jessica N. Cooke; Gibson, Jane; Thorleifsson, Gudmar; Janssen, Sarah F.; Luo, Xiaoyan; Ramdas, Wishal D.; Vithana, Eranga; Nongpiur, Monisha E.; Montgomery, GrantW.; Xu, Liang; Mountain, Jenny E.; Gharahkhani, Puya; Lu, Yi; Amin, Najaf; Karssen, Lennart C.; Sim, Kar-Seng; van Leeuwen, Elisabeth M.; Iglesias, Adriana I.; Verhoeven, Virginie J. M.; Hauser, Michael A.; Loon, Seng-Chee; Despriet, Dominiek D. G.; Nag, Abhishek; Venturini, Cristina; Sanfilippo, Paul G.; Schillert, Arne; Kang, Jae H.; Landers, John; Jonasson, Fridbert; Cree, Angela J.; van Koolwijk, Leonieke M. E.; Rivadeneira, Fernando; Souzeau, Emmanuelle; Jonsson, Vesteinn; Menon, Geeta; Weinreb, Robert N.; de Jong, Paulus T. V. M.; Oostra, Ben A.; Uitterlinden, Andre G.; Hofman, Albert; Ennis, Sarah; Thorsteinsdottir, Unnur; Burdon, Kathryn P.; Spector, Timothy D.; Mirshahi, Alireza; Saw, Seang-Mei; Vingerling, Johannes R.; Teo, Yik-Ying; Haines, Jonathan L.; Wolfs, Roger C. W.; Lemij, Hans G.; Tai, E-Shyong; Jansonius, Nomdo M.; Jonas, Jost B.; Cheng, Ching-Yu; Aung, Tin; Viswanathan, Ananth C.; Klaver, Caroline C. W.; Craig, Jamie E.; Macgregor, Stuart; Mackey, David A.; Lotery, Andrew J.; Stefansson, Kari; Bergen, Arthur A. B.; Young, Terri L.; Wiggs, Janey L.; Pfeiffer, Norbert; Wong, Tien-Yin; Pasquale, Louis R.; Hewitt, Alex W.; van Duijn, Cornelia M.; Hammond, Christopher J.
Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important
H. Springelkamp (Henriët); R. Höhn (René); A. Mishra (Aniket); P.G. Hysi (Pirro); C.C. Khor; S.J. Loomis (Stephanie J.); J.N.C. Bailey (Jessica N. Cooke); J. Gibson (Jane); G. Thorleifsson (Gudmar); S.F. Janssen (Sarah); X. Luo (Xiaoyan); W.D. Ramdas (Wishal); E.N. Vithana (Eranga); M.E. Nongpiur (Monisha E.); G.W. Montgomery (Grant); L. Xu (Liang); J.E. Mountain (Jenny E.); P. Gharahkhani (Puya); Y. Lu (Yi); N. Amin (Najaf); L.C. Karssen (Lennart); K.S. Sim; E.M. van Leeuwen (Elisa); A.I. Iglesias González (Adriana); V.J.M. Verhoeven (Virginie); M.A. Hauser (Michael); S.-C. Loon (Seng-Chee); D.D.G. Despriet (Dominique); A. Nag (Abhishek); C. Venturini (Cristina); P.G. Sanfilippo (Paul G.); A. Schillert (Arne); J.H. Kang (Jae H.); J. Landers (John); F. Jonasson (Fridbert); A.J. Cree (Angela); L.M.E. van Koolwijk (Leonieke); F. Rivadeneira Ramirez (Fernando); E. Souzeau (Emmanuelle); V. Jonsson (Vesteinn); G. Menon (Geeta); P. Mitchell (Paul); J.J. Wang (Jie Jin); E. Rochtchina (Elena); J. Attia (John); R. Scott (Rodney); E.G. Holliday (Elizabeth); P.N. Baird (Paul); J. Xie (Jing); M. Inouye (Michael); A.C. Viswanathan (Ananth); X. Sim (Xueling); R.N. Weinreb (Robert N.); P.T.V.M. de Jong (Paulus); B.A. Oostra (Ben); A.G. Uitterlinden (André); A. Hofman (Albert); S. Ennis (Sarah); U. Thorsteinsdottir (Unnur); K.P. Burdon (Kathryn); T.D. Spector (Timothy); A. Mirshahi (Alireza); S-M. Saw (Seang-Mei); J.R. Vingerling (Hans); Y.Y. Teo (Yik Ying); R.C.W. Wolfs (Roger); H.G. Lemij (Hans); E.S. Tai (Shyong); N.M. Jansonius (Nomdo); J.B. Jonas (Jost B.); C-Y. Cheng (Ching-Yu); T. Aung (Tin); C.C.W. Klaver (Caroline); J.E. Craig (Jamie); S. MacGregor (Stuart); D.A. Mackey (David); A.J. Lotery (Andrew); J-A. Zwart (John-Anker); A.A.B. Bergen (Arthur); T.L. Young (Terri); J.L. Wiggs (Janey); A.F.H. Pfeiffer (Andreas); T.Y. Wong (Tien Yin); L.R. Pasquale (Louis); A.W. Hewit (Alex); C.M. van Duijn (Cornelia); C.J. Hammond (Christopher)
textabstractGlaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an
Springelkamp, Henriët; Höhn, René; Mishra, Aniket; Hysi, Pirro G; Khor, Chiea-Chuen; Loomis, Stephanie J; Bailey, Jessica N Cooke; Gibson, Jane; Thorleifsson, Gudmar; Janssen, Sarah F; Luo, Xiaoyan; Ramdas, Wishal D; Vithana, Eranga; Nongpiur, Monisha E; Montgomery, Grant W; Xu, Liang; Mountain, Jenny E; Gharahkhani, Puya; Lu, Yi; Amin, Najaf; Karssen, Lennart C; Sim, Kar-Seng; van Leeuwen, Elisabeth M; Iglesias, Adriana I; Verhoeven, Virginie J M; Hauser, Michael A; Loon, Seng-Chee; Despriet, Dominiek D G; Nag, Abhishek; Venturini, Cristina; Sanfilippo, Paul G; Schillert, Arne; Kang, Jae H; Landers, John; Jonasson, Fridbert; Cree, Angela J; van Koolwijk, Leonieke M E; Rivadeneira, Fernando; Souzeau, Emmanuelle; Jonsson, Vesteinn; Menon, Geeta; Weinreb, Robert N; de Jong, Paulus T V M; Oostra, Ben A; Uitterlinden, André G; Hofman, Albert; Ennis, Sarah; Thorsteinsdottir, Unnur; Burdon, Kathryn P; Spector, Timothy D; Mirshahi, Alireza; Saw, Seang-Mei; Vingerling, Johannes R; Teo, Yik-Ying; Haines, Jonathan L; Wolfs, Roger C W; Lemij, Hans G; Tai, E-Shyong; Jansonius, Nomdo M; Jonas, Jost B; Cheng, Ching-Yu; Aung, Tin; Viswanathan, Ananth C; Klaver, Caroline C W; Craig, Jamie E; Macgregor, Stuart; Mackey, David A; Lotery, Andrew J; Stefansson, Kari; Bergen, Arthur A B; Young, Terri L; Wiggs, Janey L; Pfeiffer, Norbert; Wong, Tien-Yin; Pasquale, Louis R; Hewitt, Alex W; van Duijn, Cornelia M; Hammond, Christopher J
Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important
I. G. Solovyeva
Full Text Available When studying functional features of immune system, a lot of quantitative and functional parameters are determined. A multifactorial analysis allows of detecting interdependent immunological parameters and defining them as significant factors. In present study, four factors are revealed, which are associated with certain clinical characteristics of gastric cancer (tumor invasion depth, lymph node status and distant metastases, tumor stage, histological type. The data obtained are of interest, with regard of systemic approach to functional studies of immune functions.
P. A. Starikov
Full Text Available The paper demonstrates the sociological research findings concerning the students’ ideas of creativity based on the questionnaires and testing of the students of the natural science, humanities and technical profiles at Siberian Federal University over the period of 2007-2011.The author suggests a new method of semantic association analysis in order to identify the latent groups of notions related to the concept of creativity. The range of students’ common opinions demonstrate the obvious trend for humanizing the idea of creativity, considering it as the perfect mode of human existence, which coincide with the ideas of K. Rogers, A. Maslow and other scholars. Today’s students associate creativity primarily with pleasure, self-development, self-expression, inspiration, improvisation, spontaneity; and the resulting semantic complex incorporates such characteristics of creative work as goodness, abundance of energy, integrity, health, freedom and independence, self-development and spirituality.The obtained data prove the importance of the inspiration experience in creative pedagogy; the research outcomes along with the continuing monitoring of students attitude to creativity development can optimize the learning process. The author emphasizes the necessity of introducing some special courses, based on the integral approach (including social, philosophical, psychological, psycho-social and technical aspects, and aimed at developing students’ creative competence.
Subirana, Isaac; González, Juan R
A new method is described to assess the interactions of imputed SNPs (single nucleotide polymorphisms) in case-control and follow-up studies, properly incorporating SNP imputation uncertainty in the likelihood model. Using simulation studies and analysis of real data obtained from the Framingham study cohort, we compare the performance of this new method to DOSAGE and NAIVE (also known as Best-Guess) methods, developed and commonly used in the context of single SNP and extended to SNP-by-SNP interaction. The results show that only our new method is unbiased under all examined scenarios regarding allele frequencies, imputation uncertainty degree, and interaction effect size. In addition, our method achieves at least as much power as the other two, and exceeds their statistical power in certain follow-up analysis situations. This method is fast enough to perform Genome Wide Interaction Studies (GWIS) with hundreds of thousands of interactions. By performing an exhaustive simulation study let us to provide recommendations for selecting the most appropriated method depending on MAF, interaction effect size, and uncertainty degree. In general, DOSAGE and our proposed method are recommended in most situations being our method more powerful and accurate when uncertainty and effect increase. © 2015 Wiley Periodicals, Inc.
Full Text Available Abstract Background The etiology of multifactorial human diseases involves complex interactions between numerous environmental factors and alleles of many genes. Efficient statistical tools are demanded in identifying the genetic and environmental variants that affect the risk of disease development. This paper introduces a retrospective polytomous logistic regression model to measure both the main and interaction effects in genetic association studies of human discrete and continuous complex traits. In this model, combinations of genotypes at two interacting loci or of environmental exposure and genotypes at one locus are treated as nominal outcomes of which the proportions are modeled as a function of the disease trait assigning both main and interaction effects and with no assumption of normality in the trait distribution. Performance of our method in detecting interaction effect is compared with that of the case-only model. Results Results from our simulation study indicate that our retrospective model exhibits high power in capturing even relatively small effect with reasonable sample sizes. Application of our method to data from an association study on the catalase -262C/T promoter polymorphism and aging phenotypes detected significant main and interaction effects for age-group and allele T on individual's cognitive functioning and produced consistent results in estimating the interaction effect as compared with the popular case-only model. Conclusion The retrospective polytomous logistic regression model can be used as a convenient tool for assessing both main and interaction effects in genetic association studies of human multifactorial diseases involving genetic and non-genetic factors as well as categorical or continuous traits.
Gan, Yong; Li, Liqing; Zhang, Liangwen; Yan, Shijiao; Gao, Chao; Hu, Sai; Qiao, Yan; Tang, Sha; Wang, Chao; Lu, Zuxun
Observational studies suggest that shift work may be associated with prostate cancer. However, the results are inconsistent. The objective of this study is to quantitatively assess the association between shift work and the risk of prostate cancer. Relevant studies were identified by a comprehensive search of the PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases to September 2017. We also reviewed the reference lists from retrieved articles. Observational studies that reported relative risk (RR) with 95% confidence intervals (CIs) for the association between shift work and the risk of prostate cancer were included. A linear and nonlinear dose-response meta-analysis was performed. Fifteen studies with 16 independent reports involving 2,546,822 individuals and 10,715 patients with prostate cancer were included. The pooled adjusted RR for the association between ever exposure to shift work and prostate cancer risk was 1.23 (95% CI, 1.08-1.41; Pshift work was identified (P for nonlinearity=0.001). Subgroup analysis demonstrated that a higher pooled RR of prostate cancer for studies among Asian populations (RR=1.98, 95% CI, 1.34-2.93; P=0.618). A positive association was observed in rotating shift groups (RR=1.10, 95% CI, 1.00-1.26; P=0.156), but not in other shift groups. Integrated evidence from this meta-analysis suggests that shift work is significantly associated with an increased risk of prostate cancer, and a nonlinear association between duration of shift work and prostate cancer was found. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com.
Background Cognitive impairment, including dementia, is a major health concern with the increasing aging population. Preventive measures to delay cognitive decline are of utmost importance. Alzheimer’s disease (AD) is the most frequent cause of dementia, increasing in prevalence from 40% above 85 years of age. Methods We systematically reviewed selected modifiable factors such as education, smoking, alcohol, physical activity, caffeine, antioxidants, homocysteine (Hcy), n-3 fatty acids that were studied in relation to various cognitive health outcomes, including incident AD. We searched MEDLINE for published literature (January 1990 through October 2012), including cross-sectional and cohort studies (sample sizes > 300). Analyses compared study finding consistency across factors, study designs and study-level characteristics. Selecting studies of incident AD, our meta-analysis estimated pooled risk ratios (RR), population attributable risk percent (PAR%) and assessed publication bias. Results In total, 247 studies were retrieved for systematic review. Consistency analysis for each risk factor suggested positive findings ranging from ~38.9% for caffeine to ~89% for physical activity. Education also had a significantly higher propensity for “a positive finding” compared to caffeine, smoking and antioxidant-related studies. Meta-analysis of 31 studies with incident AD yielded pooled RR for low education (RR = 1.99; 95% CI: 1.30-3.04), high Hcy (RR = 1.93; 95% CI: 1.50-2.49), and current/ever smoking status (RR = 1.37; 95% CI: 1.23-1.52) while indicating protective effects of higher physical activity and n-3 fatty acids. Estimated PAR% were particularly high for physical activity (PAR% = 31.9; 95% CI: 22.7-41.2) and smoking (PAR%=31.09%; 95% CI: 17.9-44.3). Overall, no significant publication bias was found. Conclusions Higher Hcy levels, lower educational attainment, and decreased physical activity were particularly strong predictors of
Ivor M D′Souza
Full Text Available Introduction: Transverse deficiency of the maxilla is a common clinical problem in orthodontics and dentofacial orthopedics. Transverse maxillary deficiency, isolated or associated with other dentofacial deformities, results in esthetic and functional impairment giving rise to several clinical manifestations such as asymmetrical facial growth, positional and functional mandibular deviations, altered dentofacial esthetics, adverse periodontal responses, unstable dental tipping, and other functional problems. Orthopedic maxillary expansion is the preferred treatment approach to increase the maxillary transverse dimension in young patients by splitting of the mid palatal suture. This orthopedic procedure has lately been subject of renewed interest in orthodontic treatment mechanics because of its potential for increasing arch perimeter to alleviate crowding in the maxillary arch without adversely affecting facial profile. Hence, the present investigation was conducted to establish a correlation between transverse expansion and changes in the arch perimeter, arch width and arch length. Methods: For this purpose, 10 subjects (five males, five females were selected who had been treated by rapid maxillary expansion (RME using hyrax rapid palatal expander followed by fixed mechanotherapy (PEA. Pretreatment (T1, postexpansion (T2, and posttreatment (T3 dental models were compared for dental changes brought about by RME treatment and its stability at the end of fixed mechanotherapy. After model measurements were made, the changes between T1-T2, T2-T3 and T1-T3 were determined for each patient. The mean difference between T1-T2, T2-T3 and T1-T3 were compared to assess the effects of RME on dental arch measurements. Results are expressed as mean ± standard deviation and are compared by repeated measures analysis of variance followed by a post-hoc test. Arch perimeter changes are correlated with changes in arch widths at the canine, premolar and molar
Wijndaele, Katrien; Brage, Søren; Besson, Hervé; Khaw, Kay-Tee; Sharp, Stephen J.; Luben, Robert; Bhaniani, Amit; Wareham, Nicholas J.; Ekelund, Ulf
Background Although television viewing time is detrimentally associated with intermediate cardiovascular risk factors, the relationship with incident total (i.e. combined fatal and non-fatal) cardiovascular disease (CVD), non-fatal CVD and coronary heart disease is largely unknown. This study examined whether television viewing time is associated with these three outcomes, independently of physical activity energy expenditure and other confounding variables. Methodology/Principal Findings A population-based cohort of 12,608 men and women (aged 61.4±9.0), free from stroke, myocardial infarction and cancer at baseline in 1998–2000 were followed up until 2007 (6.9±1.9 years). Participants self-reported education, smoking, alcohol use, antihypertensive, lipid lowering and antidepressant medication, disease history, total energy intake, sleep duration, physical activity and television viewing. BMI, waist circumference, blood pressure, triglycerides, HDL cholesterol and glycated haemoglobin (HbA1c) were measured by standardized procedures; a clustered metabolic risk score was constructed. Every one hour/day increase in television viewing was associated with an increased hazard for total (HR = 1.06, 95%CI = 1.03–1.08; 2,620 cases), non-fatal CVD (HR = 1.06, 95%CI = 1.03–1.09; 2,134 cases), and coronary heart disease (HR = 1.08, 95%CI = 1.03–1.13; 940 cases), independent of gender, age, education, smoking, alcohol, medication, diabetes status, CVD family history, sleep duration and physical activity energy expenditure. Energy intake, BMI, waist circumference, blood pressure, triglycerides, HDL cholesterol, HbA1c and the clustered metabolic risk score only partially mediated these associations. Conclusions These results indicate that the most prevalent leisure time (sedentary) behaviour, television viewing, independently contributes to increased CVD risk. Recommendations on reducing television viewing time should be considered. PMID
Full Text Available BACKGROUND: Although television viewing time is detrimentally associated with intermediate cardiovascular risk factors, the relationship with incident total (i.e. combined fatal and non-fatal cardiovascular disease (CVD, non-fatal CVD and coronary heart disease is largely unknown. This study examined whether television viewing time is associated with these three outcomes, independently of physical activity energy expenditure and other confounding variables. METHODOLOGY/PRINCIPAL FINDINGS: A population-based cohort of 12,608 men and women (aged 61.4±9.0, free from stroke, myocardial infarction and cancer at baseline in 1998-2000 were followed up until 2007 (6.9±1.9 years. Participants self-reported education, smoking, alcohol use, antihypertensive, lipid lowering and antidepressant medication, disease history, total energy intake, sleep duration, physical activity and television viewing. BMI, waist circumference, blood pressure, triglycerides, HDL cholesterol and glycated haemoglobin (HbA(1c were measured by standardized procedures; a clustered metabolic risk score was constructed. Every one hour/day increase in television viewing was associated with an increased hazard for total (HR = 1.06, 95%CI = 1.03-1.08; 2,620 cases, non-fatal CVD (HR = 1.06, 95%CI = 1.03-1.09; 2,134 cases, and coronary heart disease (HR = 1.08, 95%CI = 1.03-1.13; 940 cases, independent of gender, age, education, smoking, alcohol, medication, diabetes status, CVD family history, sleep duration and physical activity energy expenditure. Energy intake, BMI, waist circumference, blood pressure, triglycerides, HDL cholesterol, HbA(1c and the clustered metabolic risk score only partially mediated these associations. CONCLUSIONS: These results indicate that the most prevalent leisure time (sedentary behaviour, television viewing, independently contributes to increased CVD risk. Recommendations on reducing television viewing time should be considered.
Johan Håkon Bjørngaard
Full Text Available While high body mass index is associated with an increased risk of depression and anxiety, cumulative evidence indicates that it is a protective factor for suicide. The associations from conventional observational studies of body mass index with mental health outcomes are likely to be influenced by reverse causality or confounding by ill-health. In the present study, we investigated the associations between offspring body mass index and parental anxiety, depression and suicide in order to avoid problems with reverse causality and confounding by ill-health.We used data from 32,457 mother-offspring and 27,753 father-offspring pairs from the Norwegian HUNT-study. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale and suicide death from national registers. Associations between offspring and own body mass index and symptoms of anxiety and depression and suicide mortality were estimated using logistic and Cox regression. Causal effect estimates were estimated with a two sample instrument variable approach using offspring body mass index as an instrument for parental body mass index.Both own and offspring body mass index were positively associated with depression, while the results did not indicate any substantial association between body mass index and anxiety. Although precision was low, suicide mortality was inversely associated with own body mass index and the results from the analysis using offspring body mass index supported these results. Adjusted odds ratios per standard deviation body mass index from the instrumental variable analysis were 1.22 (95% CI: 1.05, 1.43 for depression, 1.10 (95% CI: 0.95, 1.27 for anxiety, and the instrumental variable estimated hazard ratios for suicide was 0.69 (95% CI: 0.30, 1.63.The present study's results indicate that suicide mortality is inversely associated with body mass index. We also found support for a positive association between body mass index and depression, but not
Bjørngaard, Johan Håkon; Carslake, David; Lund Nilsen, Tom Ivar; Linthorst, Astrid C E; Davey Smith, George; Gunnell, David; Romundstad, Pål Richard
While high body mass index is associated with an increased risk of depression and anxiety, cumulative evidence indicates that it is a protective factor for suicide. The associations from conventional observational studies of body mass index with mental health outcomes are likely to be influenced by reverse causality or confounding by ill-health. In the present study, we investigated the associations between offspring body mass index and parental anxiety, depression and suicide in order to avoid problems with reverse causality and confounding by ill-health. We used data from 32,457 mother-offspring and 27,753 father-offspring pairs from the Norwegian HUNT-study. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale and suicide death from national registers. Associations between offspring and own body mass index and symptoms of anxiety and depression and suicide mortality were estimated using logistic and Cox regression. Causal effect estimates were estimated with a two sample instrument variable approach using offspring body mass index as an instrument for parental body mass index. Both own and offspring body mass index were positively associated with depression, while the results did not indicate any substantial association between body mass index and anxiety. Although precision was low, suicide mortality was inversely associated with own body mass index and the results from the analysis using offspring body mass index supported these results. Adjusted odds ratios per standard deviation body mass index from the instrumental variable analysis were 1.22 (95% CI: 1.05, 1.43) for depression, 1.10 (95% CI: 0.95, 1.27) for anxiety, and the instrumental variable estimated hazard ratios for suicide was 0.69 (95% CI: 0.30, 1.63). The present study's results indicate that suicide mortality is inversely associated with body mass index. We also found support for a positive association between body mass index and depression, but not for anxiety.
Ma, Wangqian; Yang, Jia; Li, Peiwei; Lu, Xinliang; Cai, Jianting
We aimed to assess the association between allergic conditions and risk/mortality of colorectal cancer (CRC). A systematic literature search was conducted using Pubmed and Embase to identify relevant studies. Prospective studies assessing the association between allergic conditions and risk/mortality of CRC were included. Risk ratios (RRs) were pooled with either a fixed- or a random-effects model according to heterogeneity. A total of 515379 participants and 10345 CRC cases from 12 studies were included in the analysis of CRC risk, while four studies with 1484741 individuals and 30040 CRC deaths were included in the analysis of CRC mortality. The pooled RR for the association between allergic conditions and CRC risk was 0.88 (95% CI 0.83-0.92). The inverse association was observed both in colon cancer (pooled RR = 0.83, 95% CI 0.72-0.97) and rectal cancer (pooled RR = 0.83, 95% CI 0.74-0.93). Moreover, no gender difference was observed in the analysis of CRC risk (for males, pooled RR = 0.88, 95% CI 0.81-0.96; for females, pooled RR = 0.88, 95% CI 0.82-0.95). And allergic conditions were also found to be inversely associated with CRC mortality (pooled RR = 0.88, 95% CI 0.83-0.92). In conclusion, the current meta-analysis provides further evidence that allergic conditions were inversely associated with CRC risk and mortality.
Barrett, Jeffrey C; Clayton, David G; Concannon, Patrick
Type 1 diabetes (T1D) is a common autoimmune disorder that arises from the action of multiple genetic and environmental risk factors. We report the findings of a genome-wide association study of T1D, combined in a meta-analysis with two previously published studies. The total sample set included 7......-pair (ASP) families. Of these, 18 regions were replicated (P
Ervasti, J; Kivimäki, M; Dray-Spira, R; Head, J; Goldberg, M; Pentti, J; Jokela, M; Vahtera, J; Zins, M; Virtanen, M
To examine the extent to which adverse psychosocial factors, such as living alone, psychological distress, job strain and low support from supervisor, increase the risk of work disability (sickness absence and disability pension) among employees with diabetes. In this pooled analysis of individual-participant data from three occupational cohort studies (the Finnish Public Sector Study, the British Whitehall II study, and the French GAZEL study), 1088 women and 949 men with diabetes were followed up to determine the duration (number of days) and frequency (number of spells) of work disability. The mean follow-up periods were 3.2 years in the GAZEL study, 4.6 years in the Whitehall II study and 4.7 years in the Finnish Public Sector Study. Psychosocial factors and potential confounding factors were assessed at baseline using standard questionnaires. Study-specific estimates were pooled using fixed-effects meta-analysis. In analysis adjusted for sociodemographic factors, health behaviours and comorbidities, participants with psychological distress had longer (rate ratio 1.66; 95% CI 1.31-2.09) and more frequent absences (rate ratio 1.33; 95% CI 1.19-1.49) compared with those with no psychological distress. Job strain was associated with slightly increased absence frequency (rate ratio 1.19 95% CI 1.05-1.35), but not with absence duration. Living alone and low supervisor support were not associated with absence duration or frequency. We observed no sex differences in these associations. Psychological distress was associated with increased duration and frequency of work disability among employees with diabetes. Job strain was associated with increased absence frequency but not with absence duration. © 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.
Wang, Ye-Tao; Gou, Ya-Wen; Jin, Wen-Wen; Xiao, Mei; Fang, Hua-Ying
Studies examining the association between alcohol intake and the risk of pancreatic cancer have given inconsistent results. The purpose of this study was to summarize and examine the evidence regarding the association between alcohol intake and pancreatic cancer risk based on results from prospective cohort studies. We searched electronic databases consisting of PubMed, Ovid, Embase, and the Cochrane Library identifying studies published up to Aug 2015. Only prospective studies that reported effect estimates with 95% confidence intervals (CIs) for the risk of pancreatic cancer, examining different alcohol intake categories compared with a low alcohol intake category were included. Results of individual studies were pooled using a random-effects model. We included 19 prospective studies (21 cohorts) reporting data from 4,211,129 individuals. Low-to-moderate alcohol intake had little or no effect on the risk of pancreatic cancer. High alcohol intake was associated with an increased risk of pancreatic cancer (risk ratio [RR], 1.15; 95% CI: 1.06-1.25). Pooled analysis also showed that high liquor intake was associated with an increased risk of pancreatic cancer (RR, 1.43; 95% CI: 1.17-1.74). Subgroup analyses suggested that high alcohol intake was associated with an increased risk of pancreatic cancer in North America, when the duration of follow-up was greater than 10 years, in studies scored as high quality, and in studies with adjustments for smoking status, body mass index, diabetes mellitus, and energy intake.. Low-to-moderate alcohol intake was not significantly associated with the risk of pancreatic cancer, whereas high alcohol intake was associated with an increased risk of pancreatic cancer. Furthermore, liquor intake in particular was associated with an increased risk of pancreatic cancer.
Full Text Available BACKGROUND: The associations between vitamin D receptor (VDR gene polymorphisms and breast cancer risk were comprehensively investigated to clarify issues that remain controversial. METHODOLOGY/PRINCIPAL FINDINGS: An electronic search was conducted of several databases, including PubMed, the Cochrane library, Web of Science, EMBASE, CBM and CNKI, for papers that describe the association between Fok1, poly-A repeat, Bsm1, Taq1 or Apa1 polymorphisms of the VDR gene and breast cancer risk. Summary odds ratios and 95% confidence intervals (CI were estimated based on a fixed-effect model (FEM or random-effect model (REM, depending on the absence or presence of significant heterogeneity. A total of 39 studies met the inclusion criteria. A meta-analysis of high-quality studies showed that the Fok1 polymorphism of the VDR gene was associated with an increased risk of breast cancer (ff vs. Ff+FF, OR: 1.09, 95%CI: 1.02 to 1.16, p = 0.007. No significant associations were observed between the other polymorphisms and breast cancer risk. No positive results were detected by pooling the results of all relevant studies. CONCLUSION: A meta-analysis of high-quality studies demonstrated that the Fok1 polymorphism of the VDR gene was closely associated with breast cancer risk.
Cho, Yoon Shin; Chen, Chien-Hsiun; Hu, Cheng; Long, Jirong; Ong, Rick Twee Hee; Sim, Xueling; Takeuchi, Fumihiko; Wu, Ying; Go, Min Jin; Yamauchi, Toshimasa; Chang, Yi-Cheng; Kwak, Soo Heon; Ma, Ronald C.W.; Yamamoto, Ken; Adair, Linda S.; Aung, Tin; Cai, Qiuyin; Chang, Li-Ching; Chen, Yuan-Tsong; Gao, Yutang; Hu, Frank B.; Kim, Hyung-Lae; Kim, Sangsoo; Kim, Young Jin; Lee, Jeannette Jen-Mai; Lee, Nanette R.; Li, Yun; Liu, Jian Jun; Lu, Wei; Nakamura, Jiro; Nakashima, Eitaro; Ng, Daniel Peng-Keat; Tay, Wan Ting; Tsai, Fuu-Jen; Wong, Tien Yin; Yokota, Mitsuhiro; Zheng, Wei; Zhang, Rong; Wang, Congrong; So, Wing Yee; Ohnaka, Keizo; Ikegami, Hiroshi; Hara, Kazuo; Cho, Young Min; Cho, Nam H; Chang, Tien-Jyun; Bao, Yuqian; Hedman, Åsa K.; Morris, Andrew P.; McCarthy, Mark I.; Takayanagi, Ryoichi; Park, Kyong Soo; Jia, Weiping; Chuang, Lee-Ming; Chan, Juliana C.N.; Maeda, Shiro; Kadowaki, Takashi; Lee, Jong-Young; Wu, Jer-Yuarn; Teo, Yik Ying; Tai, E Shyong; Shu, Xiao Ou; Mohlke, Karen L.; Kato, Norihiro; Han, Bok-Ghee; Seielstad, Mark
We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in East Asian populations. The first stage meta-analysis of eight T2D genome-wide association studies (6,952 cases and 11,865 controls) was followed by a second stage in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which were mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, involved in pancreatic beta cell development and insulin gene expression1,2, is known for its association with fasting glucose levels3,4. The evidence of T2D association for PEPD5 and HNF4A6,7 has been detected in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings derived from East Asians provide new perspectives on the etiology of T2D. PMID:22158537
Cho, Yoon Shin; Chen, Chien-Hsiun; Hu, Cheng
We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis...... (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3....... GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion...
Amin Al Olama, Ali; Kote-Jarai, Zsofia; Schumacher, Fredrick R; Wiklund, Fredrik; Berndt, Sonja I; Benlloch, Sara; Giles, Graham G; Severi, Gianluca; Neal, David E; Hamdy, Freddie C; Donovan, Jenny L; Hunter, David J; Henderson, Brian E; Thun, Michael J; Gaziano, Michael; Giovannucci, Edward L; Siddiq, Afshan; Travis, Ruth C; Cox, David G; Canzian, Federico; Riboli, Elio; Key, Timothy J; Andriole, Gerald; Albanes, Demetrius; Hayes, Richard B; Schleutker, Johanna; Auvinen, Anssi; Tammela, Teuvo L J; Weischer, Maren; Stanford, Janet L; Ostrander, Elaine A; Cybulski, Cezary; Lubinski, Jan; Thibodeau, Stephen N; Schaid, Daniel J; Sorensen, Karina D; Batra, Jyotsna; Clements, Judith A; Chambers, Suzanne; Aitken, Joanne; Gardiner, Robert A; Maier, Christiane; Vogel, Walther; Dörk, Thilo; Brenner, Hermann; Habuchi, Tomonori; Ingles, Sue; John, Esther M; Dickinson, Joanne L; Cannon-Albright, Lisa; Teixeira, Manuel R; Kaneva, Radka; Zhang, Hong-Wei; Lu, Yong-Jie; Park, Jong Y; Cooney, Kathleen A; Muir, Kenneth R; Leongamornlert, Daniel A; Saunders, Edward; Tymrakiewicz, Malgorzata; Mahmud, Nadiya; Guy, Michelle; Govindasami, Koveela; O'Brien, Lynne T; Wilkinson, Rosemary A; Hall, Amanda L; Sawyer, Emma J; Dadaev, Tokhir; Morrison, Jonathan; Dearnaley, David P; Horwich, Alan; Huddart, Robert A; Khoo, Vincent S; Parker, Christopher C; Van As, Nicholas; Woodhouse, Christopher J; Thompson, Alan; Dudderidge, Tim; Ogden, Chris; Cooper, Colin S; Lophatonanon, Artitaya; Southey, Melissa C; Hopper, John L; English, Dallas; Virtamo, Jarmo; Le Marchand, Loic; Campa, Daniele; Kaaks, Rudolf; Lindstrom, Sara; Diver, W Ryan; Gapstur, Susan; Yeager, Meredith; Cox, Angela; Stern, Mariana C; Corral, Roman; Aly, Markus; Isaacs, William; Adolfsson, Jan; Xu, Jianfeng; Zheng, S Lilly; Wahlfors, Tiina; Taari, Kimmo; Kujala, Paula; Klarskov, Peter; Nordestgaard, Børge G; Røder, M Andreas; Frikke-Schmidt, Ruth; Bojesen, Stig E; FitzGerald, Liesel M; Kolb, Suzanne; Kwon, Erika M; Karyadi, Danielle M; Orntoft, Torben Falck; Borre, Michael; Rinckleb, Antje; Luedeke, Manuel; Herkommer, Kathleen; Meyer, Andreas; Serth, Jürgen; Marthick, James R; Patterson, Briony; Wokolorczyk, Dominika; Spurdle, Amanda; Lose, Felicity; McDonnell, Shannon K; Joshi, Amit D; Shahabi, Ahva; Pinto, Pedro; Santos, Joana; Ray, Ana; Sellers, Thomas A; Lin, Hui-Yi; Stephenson, Robert A; Teerlink, Craig; Muller, Heiko; Rothenbacher, Dietrich; Tsuchiya, Norihiko; Narita, Shintaro; Cao, Guang-Wen; Slavov, Chavdar; Mitev, Vanio; Chanock, Stephen; Gronberg, Henrik; Haiman, Christopher A; Kraft, Peter; Easton, Douglas F; Eeles, Rosalind A
Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.
Liu, Xuejiao; Zhang, Dongdong; Liu, Yu; Sun, Xizhuo; Han, Chengyi; Wang, Bingyuan; Ren, Yongcheng; Zhou, Junmei; Zhao, Yang; Shi, Yuanyuan; Hu, Dongsheng; Zhang, Ming
Despite the inverse association between physical activity (PA) and incident hypertension, a comprehensive assessment of the quantitative dose-response association between PA and hypertension has not been reported. We performed a meta-analysis, including dose-response analysis, to quantitatively evaluate this association. We searched PubMed and Embase databases for articles published up to November 1, 2016. Random effects generalized least squares regression models were used to assess the quantitative association between PA and hypertension risk across studies. Restricted cubic splines were used to model the dose-response association. We identified 22 articles (29 studies) investigating the risk of hypertension with leisure-time PA or total PA, including 330 222 individuals and 67 698 incident cases of hypertension. The risk of hypertension was reduced by 6% (relative risk, 0.94; 95% confidence interval, 0.92-0.96) with each 10 metabolic equivalent of task h/wk increment of leisure-time PA. We found no evidence of a nonlinear dose-response association of PA and hypertension (Pnonlinearity=0.094 for leisure-time PA and 0.771 for total PA). With the linear cubic spline model, when compared with inactive individuals, for those who met the guidelines recommended minimum level of moderate PA (10 metabolic equivalent of task h/wk), the risk of hypertension was reduced by 6% (relative risk, 0.94; 95% confidence interval, 0.92-0.97). This meta-analysis suggests that additional benefits for hypertension prevention occur as the amount of PA increases. © 2017 American Heart Association, Inc.
Background Genome-wide association studies (GWAS) have successfully identified genes associated with complex human diseases. Although much of the heritability remains unexplained, combining single nucleotide polymorphism (SNP) genotypes from multiple studies for meta-analysis will increase the statistical power to identify new disease-associated variants. Meta-analysis requires same allele definition (nomenclature) and genome build among individual studies. Similarly, imputation, commonly-used prior to meta-analysis, requires the same consistency. However, the genotypes from various GWAS are generated using different genotyping platforms, arrays or SNP-calling approaches, resulting in use of different genome builds and allele definitions. Incorrect assumptions of identical allele definition among combined GWAS lead to a large portion of discarded genotypes or incorrect association findings. There is no published tool that predicts and converts among all major allele definitions. Results In this study, we have developed a tool, GACT, which stands for Genome build and Allele definition Conversion Tool, that predicts and inter-converts between any of the common SNP allele definitions and between the major genome builds. In addition, we assessed several factors that may affect imputation quality, and our results indicated that inclusion of singletons in the reference had detrimental effects while ambiguous SNPs had no measurable effect. Unexpectedly, exclusion of genotypes with missing rate > 0.001 (40% of study SNPs) showed no significant decrease of imputation quality (even significantly higher when compared to the imputation with singletons in the reference), especially for rare SNPs. Conclusion GACT is a new, powerful, and user-friendly tool with both command-line and interactive online versions that can accurately predict, and convert between any of the common allele definitions and between genome builds for genome-wide meta-analysis and imputation of
Sophie van der Sluis
Full Text Available To date, the genome-wide association study (GWAS is the primary tool to identify genetic variants that cause phenotypic variation. As GWAS analyses are generally univariate in nature, multivariate phenotypic information is usually reduced to a single composite score. This practice often results in loss of statistical power to detect causal variants. Multivariate genotype-phenotype methods do exist but attain maximal power only in special circumstances. Here, we present a new multivariate method that we refer to as TATES (Trait-based Association Test that uses Extended Simes procedure, inspired by the GATES procedure proposed by Li et al (2011. For each component of a multivariate trait, TATES combines p-values obtained in standard univariate GWAS to acquire one trait-based p-value, while correcting for correlations between components. Extensive simulations, probing a wide variety of genotype-phenotype models, show that TATES's false positive rate is correct, and that TATES's statistical power to detect causal variants explaining 0.5% of the variance can be 2.5-9 times higher than the power of univariate tests based on composite scores and 1.5-2 times higher than the power of the standard MANOVA. Unlike other multivariate methods, TATES detects both genetic variants that are common to multiple phenotypes and genetic variants that are specific to a single phenotype, i.e. TATES provides a more complete view of the genetic architecture of complex traits. As the actual causal genotype-phenotype model is usually unknown and probably phenotypically and genetically complex, TATES, available as an open source program, constitutes a powerful new multivariate strategy that allows researchers to identify novel causal variants, while the complexity of traits is no longer a limiting factor.
Full Text Available BACKGROUND: Red and processed meat was concluded as a limited-suggestive risk factor of gastric cancer by the World Cancer Research Fund. However, recent epidemiological studies have yielded inconclusive results. METHODS: We searched Medline, EMBASE, and the Cochrane Library from their inception to April 2013 for both cohort and case-control studies which assessed the association between red and/or processed meat intake and gastric cancer risk. Study-specific relative risk estimates were polled by random-effect or fixed-effect models. RESULTS: Twelve cohort and thirty case-control studies were included in the meta-analysis. Significant associations were found between both red (RR: 1.45, 95% CI: 1.22-1.73 and processed (RR: 1.45, 95% CI: 1.26-1.65 meat intake and gastric cancer risk generally. Positive findings were also existed in the items of beef (RR: 1.28, 95% CI: 1.04-1.57, bacon (RR: 1.37, 95% CI: 1.17-1.61, ham (RR: 1.44, 95% CI: 1.00-2.06, and sausage (RR: 1.33, 95% CI: 1.16-1.52. When conducted by study design, the association was significant in case-control studies (RR: 1.63, 95% CI: 1.33-1.99 but not in cohort studies (RR: 1.02, 95% CI: 0.90-1.17 for red meat. Increased relative risks were seen in high-quality, adenocarcinoma, cardia and European-population studies for red meat. And most subgroup analysis confirmed the significant association between processed meat intake and gastric cancer risk. CONCLUSIONS: Our findings indicate that consumption of red and/or processed meat contributes to increased gastric cancer risk. However, further investigation is needed to confirm the association, especially for red meat.
Zhu, Hongcheng; Yang, Xi; Zhang, Chi; Zhu, Chen; Tao, Guangzhou; Zhao, Lianjun; Tang, Shaowen; Shu, Zheng; Cai, Jing; Dai, Shengbin; Qin, Qin; Xu, Liping; Cheng, Hongyan; Sun, Xinchen
Red and processed meat was concluded as a limited-suggestive risk factor of gastric cancer by the World Cancer Research Fund. However, recent epidemiological studies have yielded inconclusive results. We searched Medline, EMBASE, and the Cochrane Library from their inception to April 2013 for both cohort and case-control studies which assessed the association between red and/or processed meat intake and gastric cancer risk. Study-specific relative risk estimates were polled by random-effect or fixed-effect models. Twelve cohort and thirty case-control studies were included in the meta-analysis. Significant associations were found between both red (RR: 1.45, 95% CI: 1.22-1.73) and processed (RR: 1.45, 95% CI: 1.26-1.65) meat intake and gastric cancer risk generally. Positive findings were also existed in the items of beef (RR: 1.28, 95% CI: 1.04-1.57), bacon (RR: 1.37, 95% CI: 1.17-1.61), ham (RR: 1.44, 95% CI: 1.00-2.06), and sausage (RR: 1.33, 95% CI: 1.16-1.52). When conducted by study design, the association was significant in case-control studies (RR: 1.63, 95% CI: 1.33-1.99) but not in cohort studies (RR: 1.02, 95% CI: 0.90-1.17) for red meat. Increased relative risks were seen in high-quality, adenocarcinoma, cardia and European-population studies for red meat. And most subgroup analysis confirmed the significant association between processed meat intake and gastric cancer risk. Our findings indicate that consumption of red and/or processed meat contributes to increased gastric cancer risk. However, further investigation is needed to confirm the association, especially for red meat.
Contreras-Soto, Rodrigo Iván; Mora, Freddy; de Oliveira, Marco Antônio Rott; Higashi, Wilson; Scapim, Carlos Alberto; Schuster, Ivan
Mapping quantitative trait loci through the use of linkage disequilibrium (LD) in populations of unrelated individuals provides a valuable approach for dissecting the genetic basis of complex traits in soybean (Glycine max). The haplotype-based genome-wide association study (GWAS) has now been proposed as a complementary approach to intensify benefits from LD, which enable to assess the genetic determinants of agronomic traits. In this study a GWAS was undertaken to identify genomic regions that control 100-seed weight (SW), plant height (PH) and seed yield (SY) in a soybean association mapping panel using single nucleotide polymorphism (SNP) markers and haplotype information. The soybean cultivars (N = 169) were field-evaluated across four locations of southern Brazil. The genome-wide haplotype association analysis (941 haplotypes) identified eleven, seventeen and fifty-nine SNP-based haplotypes significantly associated with SY, SW and PH, respectively. Although most marker-trait associations were environment and trait specific, stable haplotype associations were identified for SY and SW across environments (i.e., haplotypes Gm12_Hap12). The haplotype block 42 on Chr19 (Gm19_Hap42) was confirmed to be associated with PH in two environments. These findings enable us to refine the breeding strategy for tropical soybean, which confirm that haplotype-based GWAS can provide new insights on the genetic determinants that are not captured by the single-marker approach.
C.E. Elks (Cathy); J.R.B. Perry (John); P. Sulem (Patrick); D.I. Chasman (Daniel); N. Franceschini (Nora); C. He (Chunyan); K.L. Lunetta (Kathryn); J.A. Visser (Jenny); E.M. Byrne (Enda); D.L. Cousminer (Diana); D.F. Gudbjartsson (Daniel); T. Esko (Tõnu); B. Feenstra (Bjarke); J.J. Hottenga (Jouke Jan); D.L. Koller (Daniel); Z. Kutalik (Zoltán); P. Lin (Peng); M. Mangino (Massimo); M. Marongiu (Mara); P.F. McArdle (Patrick); A.V. Smith (Albert Vernon); L. Stolk (Lisette); S. van Wingerden (Sophie); J.H. Zhao (Jing Hua); E. Albrecht (Eva); T. Corre (Tanguy); E. Ingelsson (Erik); C. Hayward (Caroline); P.K. Magnusson (Patrik); S. Ulivi (Shelia); N.M. Warrington (Nicole); L. Zgaga (Lina); H. Alavere (Helene); N. Amin (Najaf); T. Aspelund (Thor); S. Bandinelli (Stefania); I. Barroso (Inês); G. Berenson (Gerald); S.M. Bergmann (Sven); H. Blackburn (Hannah); E.A. Boerwinkle (Eric); J.E. Buring (Julie); F. Busonero; H. Campbell (Harry); S.J. Chanock (Stephen); W. Chen (Wei); M. Cornelis (Marilyn); D.J. Couper (David); A.D. Coviello (Andrea); P. d' Adamo (Pio); U. de Faire (Ulf); E.J.C. de Geus (Eco); P. Deloukas (Panagiotis); A. Döring (Angela); D.F. Easton (Douglas); G. Eiriksdottir (Gudny); V. Emilsson (Valur); J.G. Eriksson (Johan); L. Ferrucci (Luigi); A.R. Folsom (Aaron); T. Foroud (Tatiana); M. Garcia (Melissa); P. Gasparini (Paolo); F. Geller (Frank); C. Gieger (Christian); V. Gudnason (Vilmundur); A.S. Hall (Alistair); S.E. Hankinson (Susan); L. Ferreli (Liana); A.C. Heath (Andrew); D.G. Hernandez (Dena); A. Hofman (Albert); F.B. Hu (Frank); T. Illig (Thomas); M.R. Järvelin; A.D. Johnson (Andrew); D. Karasik (David); K-T. Khaw (Kay-Tee); D.P. Kiel (Douglas); T.O. Kilpelänen (Tuomas); I. Kolcic (Ivana); P. Kraft (Peter); L.J. Launer (Lenore); J.S.E. Laven (Joop); S. Li (Shengxu); J. Liu (Jianjun); D. Levy (Daniel); N.G. Martin (Nicholas); M. Melbye (Mads); V. Mooser (Vincent); J.C. Murray (Jeffrey); M.A. Nalls (Michael); P. Navarro (Pau); M. Nelis (Mari); A.R. Ness (Andrew); K. Northstone (Kate); B.A. Oostra (Ben); M. Peacock (Munro); C. Palmer (Cameron); A. Palotie (Aarno); G. Paré (Guillaume); A.N. Parker (Alex); N.L. Pedersen (Nancy); L. Peltonen (Leena Johanna); C.E. Pennell (Craig); P.D.P. Pharoah (Paul); O. Polasek (Ozren); A.S. Plump (Andrew); A. Pouta (Anneli); E. Porcu (Eleonora); T. Rafnar (Thorunn); J.P. Rice (John); S.M. Ring (Susan); F. Rivadeneira Ramirez (Fernando); I. Rudan (Igor); C. Sala (Cinzia); V. Salomaa (Veikko); S. Sanna (Serena); D. Schlessinger; N.J. Schork (Nicholas); A. Scuteri (Angelo); A.V. Segrè (Ayellet); A.R. Shuldiner (Alan); N. Soranzo (Nicole); U. Sovio (Ulla); S.R. Srinivasan (Sathanur); D.P. Strachan (David); M.L. Tammesoo; E. Tikkanen (Emmi); D. Toniolo (Daniela); K. Tsui (Kim); L. Tryggvadottir (Laufey); J.P. Tyrer (Jonathan); M. Uda (Manuela); R.M. van Dam (Rob); J.B.J. van Meurs (Joyce); P. Vollenweider (Peter); G. Waeber (Gérard); N.J. Wareham (Nick); D. Waterworth (Dawn); H.E. Wichmann (Heinz Erich); G.A.H.M. Willemsen (Gonneke); J.F. Wilson (James); A.F. Wright (Alan); L. Young (Lauren); G. Zhai (Guangju); W.V. Zhuang; L.J. Bierut (Laura); D.I. Boomsma (Dorret); H.A. Boyd (Heather); L. Crisponi (Laura); E.W. Demerath (Ellen); P. Tikka-Kleemola (Päivi); M.J. Econs (Michael); T.B. Harris (Tamara); D. Hunter (David); R.J.F. Loos (Ruth); A. Metspalu (Andres); G.W. Montgomery (Grant); P.M. Ridker (Paul); T.D. Spector (Tim); E.A. Streeten (Elizabeth); K. Stefansson (Kari); U. Thorsteinsdottir (Unnur); A.G. Uitterlinden (André); E. Widen (Elisabeth); J. Murabito (Joanne); K. Ong (Ken); M.N. Weedon (Michael)
textabstractTo identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10 -60) and 9q31.2 (P = 2.2 × 10 -33), we identified 30
Elks, Cathy E; Perry, John R B; Sulem, Patrick
To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarc...
DANIEL SOTO MUÑOZ
Full Text Available This article delimits the borders de of the associative crime, by using as the main study case the Tarantino’s film “Pulp Fiction” (1994. By means of the analysis and cinematographic interpretation, the main characteristics that shape the “organized crime” are described and illustrated: the existence of a solid organization, the criminal profitable ends and the employment of violence as a criminal method.
Schürks, Markus; Buring, Julie E.; Kurth, Tobias
Aims Migraine has a wide clinical spectrum. Our aim was to group information on migraine characteristics into meaningful components and to identify key components of the migraine phenotype. Methods We performed two principal component analyses, one among participants in the Women's Health Study enrolment cohort and one in a sub-cohort with additional migraine-specific information. Results Among the 9,427 women with migraine attack-related information at enrolment, the three most important components pertained to central nervous system (CNS) sensitization, attack frequency/pain location, and aura/visual phenomena. In the sub-group of 1,675 women with more detailed information, food triggers and unspecific symptoms constituted two principal components that explain more of the variance of the migraine phenotype than the three attack-related components. Conclusions Our results indicate that information on migraine-associated features, symptoms, and triggers is highly correlated allowing the extraction of principal components. Migraine attack-related symptoms are best summarized by symptoms related to CNS sensitization, attack frequency/pain location, and aura/visual phenomena. Taking a more general view, unspecific symptoms and food triggers appear to carry stronger importance in characterizing the migraine phenotype. These components are useful for future research on the pathophysiology and genetics of migraine and may have implications for diagnosing and treating patients. PMID:21398421
Hernández-Roca, José Joaquín; García-Vázquez, Elisa; Hernández, Alicia; Canteras, Manuel; Herrero, José Antonio; Cascales, Eva; Mené-Fenor, Enrique; Gómez-Gómez, Joaquín
Bacteraemia (B) accounts for a considerable proportion (0.36%) of all hospital admissions due to infections diseases and it is associated to increased hospital costs. The aim of this study is to describe a cohort of patients with bacteraemia at a second level hospital, to analyze factors associated to mortality and its economical impact during hospital admission. Observational study of a cohort of adult patients with bacteraemia admitted at a second level hospital during 2010. Data collection from clinical records has been done according to a standard protocol: epidemiological and clinical variables and factors associated to mortality were analysed. Total economical cost per patient was estimated. 148 patients were included: 80 community B (55.4%), 23 health care associated B (15.5%) and 45 nosocomial B (28.5%). The incidence was 9 cases 10.000 persons/year. Mean age was 69 years and the global mortality was 24%. In bivariate analysis smoking, diabetes mellitus, McCabe Jackson score type I-II, Pitt Index ≥ 3, APACHE ≥ 20, Glasgow ≤ 9, shock, respiratory distress, invasive procedures, nosocomial bacteraemia and inadequate empiric or definitive antibiotic treatment were associated to mortality (pcost per patient was 9,459 € for community acquired bacteriemia, 5,656 € for health care associated bacteraemia and 41,680€ for nosocomial bacteraemia. Comorbidity, inadequate empiric antibiotic treatment and haemodialysis during acute phase are statistically significantly in our cohort of patients with bacteraemia.
Tsuji, Takashi; Matsumoto, Morio; Nakamura, Masaya; Ishii, Ken; Fujita, Nobuyuki; Chiba, Kazuhiro; Watanabe, Kota
The aim of the present study was to investigate the factors associated with C5 palsy by focusing on radiological parameters using multivariable analysis. The authors retrospectively assessed 190 patients with cervical spondylotic myelopathy treated by open-door laminoplasty. Four radiographic parameters-the number of expanded lamina, C3-C7 angle, lamina open angle and space anterior to the spinal cord-were evaluated to clarify the factors associated with C5 palsy. Of the 190 patients, 11 developed C5 palsy, giving an overall incidence of 5.8%. Although the number of expanded lamina, lamina open angle and space anterior to the spinal cord were significantly larger in C5 palsy group than those in non-palsy group, a multiple logistic regression analysis revealed that only the space anterior to the spinal cord (odds ratio 2.60) was a significant independent factor associated with C5 palsy. A multiple linear regression analysis indicated that the lamina open angle was associated with the space anterior to the spinal cord and the analysis identified the following equation: space anterior to the spinal cord (mm) = 1.54 + 0.09 × lamina open angle (degree). A cut-off value of 53.5° for the lamina open angle predicted the development of C5 palsy with a sensitivity of 72.7% and a specificity of 83.2%. The larger postoperative space anterior to the spinal cord, which was associated with the lamina open angle, was positively correlated with the higher incidence of C5 palsy.
Full Text Available Abstract Background Last years' mapping of diverse genomes has generated huge amounts of biological data which are currently dispersed through many databases. Integration of the information available in the various databases is required to unveil possible associations relating already known data. Biological data are often imprecise and noisy. Fuzzy set theory is specially suitable to model imprecise data while association rules are very appropriate to integrate heterogeneous data. Results In this work we propose a novel fuzzy methodology based on a fuzzy association rule mining method for biological knowledge extraction. We apply this methodology over a yeast genome dataset containing heterogeneous information regarding structural and functional genome features. A number of association rules have been found, many of them agreeing with previous research in the area. In addition, a comparison between crisp and fuzzy results proves the fuzzy associations to be more reliable than crisp ones. Conclusion An integrative approach as the one carried out in this work can unveil significant knowledge which is currently hidden and dispersed through the existing biological databases. It is shown that fuzzy association rules can model this knowledge in an intuitive way by using linguistic labels and few easy-understandable parameters.
Lopez, Francisco J; Blanco, Armando; Garcia, Fernando; Cano, Carlos; Marin, Antonio
Last years' mapping of diverse genomes has generated huge amounts of biological data which are currently dispersed through many databases. Integration of the information available in the various databases is required to unveil possible associations relating already known data. Biological data are often imprecise and noisy. Fuzzy set theory is specially suitable to model imprecise data while association rules are very appropriate to integrate heterogeneous data. In this work we propose a novel fuzzy methodology based on a fuzzy association rule mining method for biological knowledge extraction. We apply this methodology over a yeast genome dataset containing heterogeneous information regarding structural and functional genome features. A number of association rules have been found, many of them agreeing with previous research in the area. In addition, a comparison between crisp and fuzzy results proves the fuzzy associations to be more reliable than crisp ones. An integrative approach as the one carried out in this work can unveil significant knowledge which is currently hidden and dispersed through the existing biological databases. It is shown that fuzzy association rules can model this knowledge in an intuitive way by using linguistic labels and few easy-understandable parameters.
Full Text Available Aims. Published data on the associations of VEGF polymorphisms with diabetic retinopathy (DR susceptibility are inconclusive. A systematic meta-analysis was undertaken to clarify this topic. Methods. Data were collected from the following electronic databases: PubMed, Embase, OVID, Web of Science, Elsevier Science Direct, Excerpta Medica Database (EMBASE, and Cochrane Library with the last report up to January 10, 2014. ORs and 95% CIs were calculated for VEGF–2578C/A (rs699947, –1154G/A (rs1570360, –460T/C (rs833061, −634G>C (rs2010963, and +936C/T (rs3025039 in at least two published studies. Meta-analysis was performed in a fixed/random effect model by using the software STATA 12.0. Results. A total of 11 studies fulfilling the inclusion criteria were included in this meta-analysis. A significant relationship between VEGF+936C/T (rs3025039 polymorphism and DR was found in a recessive model (OR = 3.19, 95% CI = 1.20–8.41, and P(z=0.01 in Asian and overall populations, while a significant association was also found between –460T/C (rs833061 polymorphism and DR risk under a recessive model (OR = 2.12, 95% CI = 1.12–4.01, and P(z=0.02. Conclusions. Our meta-analysis demonstrates that +936C/T (rs3025039 is likely to be associated with susceptibility to DR in Asian populations, and the recessive model of –460T/C (rs833061 is associated with elevated DR susceptibility.
Full Text Available Background: Acne vulgaris is one of the most common skin diseases with a multifactorial pathogenesis. Examination of the literature regarding the contribution of smoking to acne shows contradictory results. The aim of this study was to undertake a systematic review of the literature and meta-analysis about the association between acne and smoking. Methods: A systematic review and meta-analysis, when possible were performed. The literature review was based on Pubmed, Scopus and Google Scholar searches using the keywords “(smoking OR tobacco OR nicotine OR cigarettes AND acne”. Only cross-sectional studies were included. Meta-analyses were performed using the RevMan software version 5 for Windows. Four different meta-analyses were carried out: one evaluating the association between smoking habit and acne, one including data stratified by gender, one for studies with a quality score > 6, and one relating to acne classification. Results: Six studies were selected. The first meta-analysis, including all studies, showed a non significant role of smoke in the development of acne: OR 1.05 (95% CI: 0.66–1.67 with random effect estimate. The second meta-analyses, including data stratified by gender, showed a OR=0.99 (95% CI: 0.57–1.73 for males and a OR of 1.45 (95% CI: 0.08–24.64 for females, using random effect for the heterogeneity in both cases. The third meta-analysis, included studies with a quality score >6 resulted in an estimated OR= 0.69 (95% CI: 0.55–0.85: in this case it was possible to use the fixed effect estimate. The last meta-analysis, concerning the severity grading, showed a non-significant result: OR=1.09 (95% CI: 0.61–1.95 using the random effect approach. Conclusions: The first two meta-analyses found no signification association between smoking and
Background: Acne vulgaris is one of the most common skin diseases with a multifactorial pathogenesis. Examination of the literature regarding the contribution of smoking to acne shows contradictory results. The aim of this study was to undertake a systematic review of the literature and meta-analysis about the association between acne and smoking.
Methods: A systematic review and meta-analysis, when possible were performed. The literature review was based on Pubmed, Scopus and Google Scholar searches using the keywords “(smoking OR tobacco OR nicotine OR cigarettes AND acne”. Only cross-sectional studies were included. Meta-analyses were performed using the RevMan software version 5 for Windows. Four different meta-analyses were carried out: one evaluating the association between smoking habit and acne, one including data stratified by gender, one for studies with a quality score > 6, and one relating to acne classification.
Results: Six studies were selected. The first meta-analysis, including all studies, showed a non significant role of smoke in the development of acne: OR 1.05 (95% CI: 0.66–1.67 with random effect estimate. The second meta-analyses, including data stratified by gender, showed a OR=0.99 (95% CI: 0.57–1.73 for males and a OR of 1.45 (95% CI: 0.08–24.64 for females, using random effect for the heterogeneity in both cases. The third meta-analysis, included studies with a quality score >6 resulted in an estimated OR= 0.69 (95% CI: 0.55–0.85: in this case it was possible to use the fixed effect estimate. The last meta-analysis, concerning the severity grading, showed a non-significant result: OR=1.09 (95% CI: 0.61–1.95 using the random effect approach.
Conclusions: The first two meta-analyses found no signification association between smoking and
Full Text Available BACKGROUND: Excision repair cross-complimentary group 1 (ERCC1 is an essential component of the nucleotide excision repair system that is responsible for repairing damaged DNA. Functional genetic variations in the ERCC1 gene may alter DNA repair capacity and modulate cancer risk. The putative roles of ERCC1 gene polymorphisms in lung cancer susceptibility have been widely investigated. However, the results remain controversial. OBJECTIVES: An updated meta-analysis was conducted to explore whether lung cancer risk could be attributed to the following ERCC1 polymorphisms: rs11615 (T>C, rs3212986 (C>A, rs3212961 (A>C, rs3212948 (G>C, rs2298881 (C>A. METHODS: Several major databases (MEDLINE, EMBASE and Scopus and the Chinese Biomedical database were searched for eligible studies. Crude odds ratios (ORs with 95% confidence intervals (CIs were used to measure the strength of associations. RESULTS: Sixteen studies with 10,106 cases and 13,238 controls were included in this meta-analysis. Pooled ORs from 11 eligible studies (8,215 cases vs. 11,402 controls suggested a significant association of ERCC1 rs11615 with increased risk for lung cancer (homozygous: CC versus TT, OR = 1.24, 95% CI: 1.04-1.48, P = 0.02. However, such an association was disproportionately driven by a single study. Removal of that study led to null association. Moreover, initial analyses suggested that ERCC1 rs11615 exerts a more profound effect on the susceptibility of non-smokers to lung cancer than that of smokers. Moreover, no statistically significant association was found between remaining ERCC1 polymorphisms of interest and lung cancer risk, except for rs3212948 variation (heterozygous: CG vs.GG, OR = 0.78, 95% CI: 0.67-0.90, P = 0.001; dominant: CG/CC vs.GG, OR = 0.79, 95% CI: 0.69-0.91, P = 0.001. CONCLUSION: Overall, this meta-analysis suggests that ERCC1 rs3212948 G>C, but not others, is a lung cancer risk-associated polymorphism. Carefully
Evangelou, Marina; Smyth, Deborah J; Fortune, Mary D; Burren, Oliver S; Walker, Neil M; Guo, Hui; Onengut-Gumuscu, Suna; Chen, Wei-Min; Concannon, Patrick; Rich, Stephen S; Todd, John A; Wallace, Chris
Pathway analysis can complement point-wise single nucleotide polymorphism (SNP) analysis in exploring genomewide association study (GWAS) data to identify specific disease-associated genes that can be candidate causal genes. We propose a straightforward methodology that can be used for conducting a gene-based pathway analysis using summary GWAS statistics in combination with widely available reference genotype data. We used this method to perform a gene-based pathway analysis of a type 1 diabetes (T1D) meta-analysis GWAS (of 7,514 cases and 9,045 controls). An important feature of the conducted analysis is the removal of the major histocompatibility complex gene region, the major genetic risk factor for T1D. Thirty-one of the 1,583 (2%) tested pathways were identified to be enriched for association with T1D at a 5% false discovery rate. We analyzed these 31 pathways and their genes to identify SNPs in or near these pathway genes that showed potentially novel association with T1D and attempted to replicate the association of 22 SNPs in additional samples. Replication P-values were skewed (P=9.85×10-11) with 12 of the 22 SNPs showing Passociated variants in genes ITGB7 (rs11170466, P=7.86×10-9), NRP1 (rs722988, 4.88×10-8), BAD (rs694739, 2.37×10-7), CTSB (rs1296023, 2.79×10-7), FYN (rs11964650, P=5.60×10-7), UBE2G1 (rs9906760, 5.08×10-7), MAP3K14 (rs17759555, 9.67×10-7), ITGB1 (rs1557150, 1.93×10-6), and IL7R (rs1445898, 2.76×10-6). The proposed methodology can be applied to other GWAS datasets for which only summary level data are available. © 2014 The Authors. ** Genetic Epidemiology published by Wiley Periodicals, Inc.
Foster Meredith C
Full Text Available Abstract Background Ectopic fat accumulation in the renal sinus is associated with chronic kidney disease and hypertension. The genetic contributions to renal sinus fat accumulation in humans have not been well characterized. Methods The present analysis consists of participants from the Framingham Offspring and Third Generation who underwent computed tomography; renal sinus fat and visceral adipose tissue (VAT were quantified. Renal sinus fat was natural log transformed and sex- and cohort-specific residuals were created, adjusted for (1 age, (2 age and body mass index (BMI, and (3 age and VAT. Residuals were pooled and used to calculate heritability using variance-components analysis in SOLAR. A genome-wide association study (GWAS for renal sinus fat was performed using an additive model with approximately 2.5 million imputed single nucleotide polymorphisms (SNPs. Finally, we identified the associations of renal sinus fat in our GWAS results with validated SNPs for renal function (n = 16, BMI (n = 32, and waist-to-hip ratio (WHR, n = 14, and applied a multi-SNP genetic risk score method to determine if the SNPs for each renal and obesity trait were in aggregate associated with renal sinus fat. Results The heritability of renal sinus fat was 39% (p Conclusions Renal sinus fat is a heritable trait, even after accounting for generalized and abdominal adiposity. This provides support for further research into the genetic determinants of renal sinus fat. While our study was underpowered to detect genome-wide significant loci, our candidate gene BMI risk score results suggest that variability in renal sinus fat may be associated with SNPs previously known to be associated with generalized adiposity.
Mick, Paul; Parfyonov, Maksim; Wittich, Walter; Phillips, Natalie; Kathleen Pichora-Fuller, M
To determine if hearing loss, vision loss, and dual sensory loss were associated with social network diversity, social participation, availability of social support, and loneliness, respectively, in a population-based sample of older Canadians and to determine whether age or sex modified the associations. Cross-sectional population-based study. Canada. The sample included 21 241 participants in the Canadian Longitudinal Study on Aging tracking cohort. The sample was nationally representative of English- and French-speaking, non-institutionalized 45- to 89-year-old Canadians who did not live on First Nations reserves and who had normal cognition. Participants with missing data for any of the variables in the multivariable regression models were excluded from analysis. Hearing and vision loss were determined by self-report. Dual sensory loss was defined as reporting both hearing and vision loss. Univariate analyses were performed to assess cross-sectional associations between hearing, vision, and dual sensory loss, and social, demographic, and medical variables. Multivariable regression models were used to analyze cross-sectional associations between each type of sensory loss and social network diversity, social participation, availability of social support, and loneliness. Vision loss (in men) and dual sensory loss (in 65- to 85-year-olds) were independently associated with reduced social network diversity. Vision loss and dual sensory loss (in 65- to 85-year-olds) were each independently associated with reduced social participation. All forms of sensory loss were associated with both low availability of social support and loneliness. Sensory impairment is associated with reduced social function in older Canadians. Interventions and research that address the social needs of older individuals with sensory loss are needed. Copyright© the College of Family Physicians of Canada.
Full Text Available Abstract Background Elevated levels of factor VIII (FVIII and von Willebrand Factor (vWF are well-established risk factors for cardiovascular diseases, in particular venous thrombosis. Although high, the heritability of these traits is poorly explained by the genetic factors known so far. The aim of this work was to identify novel single nucleotide polymorphisms (SNPs that could influence the variability of these traits. Methods Three independent genome-wide association studies for vWF plasma levels and FVIII activity were conducted and their results were combined into a meta-analysis totalling 1,624 subjects. Results No single nucleotide polymorphism (SNP reached the study-wide significance level of 1.12 × 10-7 that corresponds to the Bonferroni correction for the number of tested SNPs. Nevertheless, the recently discovered association of STXBP5, STX2, TC2N and CLEC4M genes with vWF levels and that of SCARA5 and STAB2 genes with FVIII levels were confirmed in this meta-analysis. Besides, among the fifteen novel SNPs showing promising association at p -5 with either vWF or FVIII levels in the meta-analysis, one located in ACCN1 gene also showed weak association (P = 0.0056 with venous thrombosis in a sample of 1,946 cases and 1,228 controls. Conclusions This study has generated new knowledge on genomic regions deserving further investigations in the search for genetic factors influencing vWF and FVIII plasma levels, some potentially implicated in VT, as well as providing some supporting evidence of previously identified genes.
Jiang, Wei; Yu, Weichuan
In genome-wide association studies (GWASs) of common diseases/traits, we often analyze multiple GWASs with the same phenotype together to discover associated genetic variants with higher power. Since it is difficult to access data with detailed individual measurements, summary-statistics-based meta-analysis methods have become popular to jointly analyze datasets from multiple GWASs. In this paper, we propose a novel summary-statistics-based joint analysis method based on controlling the joint local false discovery rate (Jlfdr). We prove that our method is the most powerful summary-statistics-based joint analysis method when controlling the false discovery rate at a certain level. In particular, the Jlfdr-based method achieves higher power than commonly used meta-analysis methods when analyzing heterogeneous datasets from multiple GWASs. Simulation experiments demonstrate the superior power of our method over meta-analysis methods. Also, our method discovers more associations than meta-analysis methods from empirical datasets of four phenotypes. The R-package is available at: http://bioinformatics.ust.hk/Jlfdr.html . firstname.lastname@example.org. Supplementary data are available at Bioinformatics online.
Bjørngaard, Johan Håkon; Carslake, David; Lund Nilsen, Tom Ivar; Linthorst, Astrid C. E.; Davey Smith, George; Gunnell, David; Romundstad, Pål Richard
Objective While high body mass index is associated with an increased risk of depression and anxiety, cumulative evidence indicates that it is a protective factor for suicide. The associations from conventional observational studies of body mass index with mental health outcomes are likely to be influenced by reverse causality or confounding by ill-health. In the present study, we investigated the associations between offspring body mass index and parental anxiety, depression and suicide in order to avoid problems with reverse causality and confounding by ill-health. Methods We used data from 32,457 mother-offspring and 27,753 father-offspring pairs from the Norwegian HUNT-study. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale and suicide death from national registers. Associations between offspring and own body mass index and symptoms of anxiety and depression and suicide mortality were estimated using logistic and Cox regression. Causal effect estimates were estimated with a two sample instrument variable approach using offspring body mass index as an instrument for parental body mass index. Results Both own and offspring body mass index were positively associated with depression, while the results did not indicate any substantial association between body mass index and anxiety. Although precision was low, suicide mortality was inversely associated with own body mass index and the results from the analysis using offspring body mass index supported these results. Adjusted odds ratios per standard deviation body mass index from the instrumental variable analysis were 1.22 (95% CI: 1.05, 1.43) for depression, 1.10 (95% CI: 0.95, 1.27) for anxiety, and the instrumental variable estimated hazard ratios for suicide was 0.69 (95% CI: 0.30, 1.63). Conclusion The present study’s results indicate that suicide mortality is inversely associated with body mass index. We also found support for a positive association between body mass index
Gan, Yong; Wu, Jiang; Zhang, Shengchao; Li, Liqing; Cao, Shiyi; Mkandawire, Naomie; Ji, Kun; Herath, Chulani; Gao, Chao; Xu, Hong; Zhou, Yanfeng; Song, Xingyue; Chen, Shanquan; Chen, Yawen; Yang, Tingting; Li, Jing; Qiao, Yan; Hu, Sai; Yin, Xiaoxv; Lu, Zuxun
A meta-analysis was performed to assess the association of coffee consumption with colorectal cancer and to investigate the shape of the association. Relevant prospective cohort studies were identified by a comprehensive search of the PubMed, Embase and Web of Science databases from their inception through August 2015. Either a random-effects model or fixed-effects model was used to compute the pooled risk estimates when appropriate. Linear and nonlinear dose-response meta-analyses were also performed. Nineteen prospective cohort studies involving 2,046,575 participants and 22,629 patients with colorectal cancer were included. The risk of colon cancer was decreased by 7% for every 4 cups per day of coffee (RR=0.93, 95%CI, 0.88-0.99; P=0.199). There was a threshold approximately five cups of coffee per day, and the inverse association for colorectal cancer appeared to be stronger at a higher range of intake. However, a nonlinear association of rectal cancer with coffee consumption was not observed (P for nonlinearity = 0.214). In conclusion, coffee consumption is significantly associated with a decreased risk of colorectal cancer at ≥ 5 cups per day of coffee consumption. The findings support the recommendations of including coffee as a healthy beverage for the prevention of colorectal cancer.
Zhang, Shengchao; Li, Liqing; Cao, Shiyi; Mkandawire, Naomie; Ji, Kun; Herath, Chulani; Gao, Chao; Xu, Hong; Zhou, Yanfeng; Song, Xingyue; Chen, Shanquan; Chen, Yawen; Yang, Tingting; Li, Jing; Qiao, Yan; Hu, Sai; Yin, Xiaoxv; Lu, Zuxun
A meta-analysis was performed to assess the association of coffee consumption with colorectal cancer and to investigate the shape of the association. Relevant prospective cohort studies were identified by a comprehensive search of the PubMed, Embase and Web of Science databases from their inception through August 2015. Either a random-effects model or fixed-effects model was used to compute the pooled risk estimates when appropriate. Linear and nonlinear dose-response meta-analyses were also performed. Nineteen prospective cohort studies involving 2,046,575 participants and 22,629 patients with colorectal cancer were included. The risk of colon cancer was decreased by 7% for every 4 cups per day of coffee (RR=0.93, 95%CI, 0.88-0.99; P=0.199). There was a threshold approximately five cups of coffee per day, and the inverse association for colorectal cancer appeared to be stronger at a higher range of intake. However, a nonlinear association of rectal cancer with coffee consumption was not observed (P for nonlinearity = 0.214). In conclusion, coffee consumption is significantly associated with a decreased risk of colorectal cancer at ≥ 5 cups per day of coffee consumption. The findings support the recommendations of including coffee as a healthy beverage for the prevention of colorectal cancer. PMID:27078843
Ujihara, Tomomi; Hayashi, Nobuyuki
Associations between catechin molecules were investigated by (1)H NMR titration experiments. Eight green tea catechins formed self-assembled dimers in water, and gallate-type catechins had a greater tendency to self-associate than non-gallate-type catechins. All eight catechins also associated as 1:1 heterodimer complexes. Investigation of complex formation of epigallocatechin-3-O-gallate (EGCg) and epigallocatechin (EGC) with the other catechins showed that the affinity between EGCg and 2,3-trans-gallate-type catechins was remarkably high, and the binding affinity of EGCg for ECg was also rather strong. In contrast, the non-gallate-type catechin EGC exhibited generally low binding affinity for other catechins. Structural analyses of the complexes by ROESY experiments and density functional theory calculations demonstrated that the higher binding abilities of gallate-type catechins are due to providing multiple intermolecular interactions that remain effective in an aqueous environment, such as aromatic/aromatic or CH/π interactions.
Mayorga Luis S
Full Text Available Abstract Background The FABP2 gene encodes for the intestinal FABP (IFABP protein, which is expressed only in intestinal enterocytes. A polymorphism at codon 54 in exon 2 of the FABP2 gene exchanges an Alanine (Ala, in the small helical region of the protein, for Threonine (Thr. Given the potential physiological role of the Ala54Thr FABP2 polymorphism, we assess in this study the local population frequency and analyze possible associations with five selected markers, i.e. glycemia, total cholesterol, body mass index (BMI, hypertension, and high Cardiovascular Risk Index (CVR index. Methods We studied 86 men and 116 women. DNA was extracted from a blood drop for genotype analysis. Allele frequencies were calculated by direct counting. Hardy Weinberg Equilibrium was evaluated using a Chi-square goodness of fit test. For the polymorphism association analysis, five markers were selected, i.e. blood pressure, Framingham Risk Index, total cholesterol, BMI, and glycemia. For each marker, the Odds Ratio (OR was calculated by an online statistic tool. Results Our results reveal a similar population polymorphism frequency as in previous European studies, with q = 0.277 (95% confidence limits 0.234–0.323. No significant association was found with any of the tested markers in the context of our Argentine nutritional and cultural habits. We did, however, observe a tendency for increased Cholesterol and high BMI in Thr54 carriers. Conclusion This is the first study to look at the population frequency of the Thr54 allele in Argentina. The obtained result does not differ from previously reported frequencies in European populations. Moreover, we found no association between the Thr54 allele and any of the five selected markers. The observed tendency to increased total cholesterol and elevated BMI in Thr54 carriers, even though not significant for p
Praestegaard, Camilla; Jensen, Allan; Jensen, Signe M; Nielsen, Thor S S; Webb, Penelope M; Nagle, Christina M; DeFazio, Anna; Høgdall, Estrid; Rossing, Mary Anne; Doherty, Jennifer A; Wicklund, Kristine G; Goodman, Marc T; Modugno, Francesmary; Moysich, Kirsten; Ness, Roberta B; Edwards, Robert; Matsuo, Keitaro; Hosono, Satoyo; Goode, Ellen L; Winham, Stacey J; Fridley, Brooke L; Cramer, Daniel W; Terry, Kathryn L; Schildkraut, Joellen M; Berchuck, Andrew; Bandera, Elisa V; Paddock, Lisa E; Massuger, Leon F; Wentzensen, Nicolas; Pharoah, Paul; Song, Honglin; Whittemore, Alice; McGuire, Valerie; Sieh, Weiva; Rothstein, Joseph; Anton-Culver, Hoda; Ziogas, Argyrios; Menon, Usha; Gayther, Simon A; Ramus, Susan J; Gentry-Maharaj, Alexandra; Wu, Anna H; Pearce, Celeste L; Pike, Malcolm; Lee, Alice W; Sutphen, Rebecca; Chang-Claude, Jenny; Risch, Harvey A; Kjaer, Susanne K
Cigarette smoking is associated with an increased risk of developing mucinous ovarian tumors but whether it is associated with ovarian cancer survival overall or for the different histotypes is unestablished. Furthermore, it is unknown whether the association between cigarette smoking and survival differs according to strata of ovarian cancer stage at diagnosis. In a large pooled analysis, we evaluated the association between various measures of cigarette smoking and survival among women with epithelial ovarian cancer. We obtained data from 19 case-control studies in the Ovarian Cancer Association Consortium (OCAC), including 9,114 women diagnosed with ovarian cancer. Cox regression models were used to estimate adjusted study-specific hazard ratios (HRs), which were combined into pooled hazard ratios (pHR) with corresponding 95% confidence intervals (CIs) under random effects models. Overall, 5,149 (57%) women died during a median follow-up period of 7.0 years. Among women diagnosed with ovarian cancer, both current (pHR = 1.17, 95% CI: 1.08-1.28) and former smokers (pHR = 1.10, 95% CI: 1.02-1.18) had worse survival compared with never smoking women. In histotype-stratified analyses, associations were observed for mucinous (current smoking: pHR = 1.91, 95% CI: 1.01-3.65) and serous histotypes (current smoking: pHR = 1.11, 95% CI: 1.00-1.23; former smoking: pHR = 1.12, 95% CI: 1.04-1.20). Further, our results suggested that current smoking has a greater impact on survival among women with localized than disseminated disease. The identification of cigarette smoking as a modifiable factor associated with survival has potential clinical importance as a focus area to improve ovarian cancer prognosis. © 2017 UICC.
Minster, Ryan L; Sanders, Jason L; Singh, Jatinder
Health Study and Framingham Heart Study. Linkage results revealed significant evidence (log-odds score = 3.36) for a quantitative trait locus for mortality-optimized HAI in women on chromosome 9p24-p23. However, results of fine-mapping studies did not implicate any specific candidate genes within...
Cui, Hong; Gong, Ting-Ting; Liu, Cai-Xia; Wu, Qi-Jun
Previous studies investigating the relationship between passive maternal smoking and preterm birth reveal inconsistent results. We conducted the current meta-analysis of observational studies to evaluate the relationship between passive maternal smoking and preterm birth. We identified relevant studies by searching PubMed, EMBASE, and ISI Web of Science databases. We used random-effects models to estimate summary odds ratios (SORs) and 95% confidence intervals (CIs) for aforementioned association. For the analysis, we included 24 studies that involved a total of 5607 women who experienced preterm birth. Overall, the SORs of preterm birth for women who were ever exposed to passive smoking versus women who had never been exposed to passive smoking at any place and at home were 1.20 (95%CI = 1.07-1.34,I(2) = 36.1%) and 1.16 (95%CI = 1.04-1.30,I(2) = 4.4%), respectively. When we conducted a stratified analysis according to study design, the risk estimate was slightly weaker in cohort studies (SOR = 1.10, 95%CI = 1.00-1.21,n = 16) than in cross-sectional studies (SOR = 1.47, 95%CI = 1.23-1.74,n = 5). Additionally, the associations between passive maternal smoking and preterm birth were statistically significant for studies conducted in Asia (SOR = 1.26, 95%CI = 1.05-1.52), for studies including more than 100 cases of preterm birth (SOR = 1.22, 95%CI = 1.05-1.41), and for studies adjusted for maternal age (SOR = 1.27,95%CI = 1.09-1.47), socioeconomic status and/or education (SOR = 1.28, 95%CI = 1.10-1.49), body mass index (SOR = 1.33, 95%CI = 1.04-1.71), and parity (SOR = 1.27, 95%CI = 1.13-1.43). Our findings demonstrate that passive maternal smoking is associated with an increased risk of preterm birth. Future prospective cohort studies are warranted to provide more detailed results stratified by passive maternal smoking during different trimesters of pregnancy and by different types and causes of preterm birth.
Pearce, Celeste Leigh; Templeman, Claire; Rossing, Mary Anne; Lee, Alice; Near, Aimee M; Webb, Penelope M; Nagle, Christina M; Doherty, Jennifer A; Cushing-Haugen, Kara L; Wicklund, Kristine G; Chang-Claude, Jenny; Hein, Rebecca; Lurie, Galina; Wilkens, Lynne R; Carney, Michael E; Goodman, Marc T; Moysich, Kirsten; Kjaer, Susanne K; Hogdall, Estrid; Jensen, Allan; Goode, Ellen L; Fridley, Brooke L; Larson, Melissa C; Schildkraut, Joellen M; Palmieri, Rachel T; Cramer, Daniel W; Terry, Kathryn L; Vitonis, Allison F; Titus, Linda J; Ziogas, Argyrios; Brewster, Wendy; Anton-Culver, Hoda; Gentry-Maharaj, Alexandra; Ramus, Susan J; Anderson, A Rebecca; Brueggmann, Doerthe; Fasching, Peter A; Gayther, Simon A; Huntsman, David G; Menon, Usha; Ness, Roberta B; Pike, Malcolm C; Risch, Harvey; Wu, Anna H; Berchuck, Andrew
Endometriosis is a risk factor for epithelial ovarian cancer; however, whether this risk extends to all invasive histological subtypes or borderline tumours is not clear. We undertook an international collaborative study to assess the association between endometriosis and histological subtypes of ovarian cancer. Data from 13 ovarian cancer case-control studies, which were part of the Ovarian Cancer Association Consortium, were pooled and logistic regression analyses were undertaken to assess the association between self-reported endometriosis and risk of ovarian cancer. Analyses of invasive cases were done with respect to histological subtypes, grade, and stage, and analyses of borderline tumours by histological subtype. Age, ethnic origin, study site, parity, and duration of oral contraceptive use were included in all analytical models. 13 226 controls and 7911 women with invasive ovarian cancer were included in this analysis. 818 and 738, respectively, reported a history of endometriosis. 1907 women with borderline ovarian cancer were also included in the analysis, and 168 of these reported a history of endometriosis. Self-reported endometriosis was associated with a significantly increased risk of clear-cell (136 [20·2%] of 674 cases vs 818 [6·2%] of 13 226 controls, odds ratio 3·05, 95% CI 2·43-3·84, pSmith Foundation, European Community's Seventh Framework Programme, German Federal Ministry of Education and Research of Germany, Programme of Clinical Biomedical Research, German Cancer Research Centre, Eve Appeal, Oak Foundation, UK National Institute of Health Research, National Health and Medical Research Council of Australia, US Army Medical Research and Materiel Command, Cancer Council Tasmania, Cancer Foundation of Western Australia, Mermaid 1, Danish Cancer Society, and Roswell Park Alliance Foundation. Copyright © 2012 Elsevier Ltd. All rights reserved.
Full Text Available Abstract Background Several methods have been presented for the analysis of complex interactions between genetic polymorphisms and/or environmental factors. Despite the available methods, there is still a need for alternative methods, because no single method will perform well in all scenarios. The aim of this work was to evaluate the performance of three selected rule based classifier algorithms, RIPPER, RIDOR and PART, for the analysis of genetic association studies. Methods Overall, 42 datasets were simulated with three different case-control models, a varying number of subjects (300, 600, SNPs (500, 1500, 3000 and noise (5%, 10%, 20%. The algorithms were applied to each of the datasets with a set of algorithm-specific settings. Results were further investigated with respect to a the Model, b the Rules, and c the Attribute level. Data analysis was performed using WEKA, SAS and PERL. Results The RIPPER algorithm discovered the true case-control model at least once in >33% of the datasets. The RIDOR and PART algorithm performed poorly for model detection. The RIPPER, RIDOR and PART algorithm discovered the true case-control rules in more than 83%, 83% and 44% of the datasets, respectively. All three algorithms were able to detect the attributes utilized in the respective case-control models in most datasets. Conclusions The current analyses substantiate the utility of rule based classifiers such as RIPPER, RIDOR and PART for the detection of gene-gene/gene-environment interactions in genetic association studies. These classifiers could provide a valuable new method, complementing existing approaches, in the analysis of genetic association studies. The methods provide an advantage in being able to handle both categorical and continuous variable types. Further, because the outputs of the analyses are easy to interpret, the rule based classifier approach could quickly generate testable hypotheses for additional evaluation. Since the algorithms are
Feng, Mei; Zhu, Jing; Liang, Liqun; Zeng, Ni; Wu, Yanqiu; Wan, Chun; Shen, Yongchun; Wen, Fuqiang
Pleural effusion is one of the most common complications of lung adenocarcinoma and is diagnostically challenging. This study aimed to investigate the diagnostic performance of carcinoembryonic antigen (CEA), cytokeratin fragment (CYFRA) 21-1, and cancer antigen (CA) 19-9 for lung adenocarcinoma-associated malignant pleural effusion (MPE) through a validation study and meta-analysis. Pleural effusion samples were collected from 81 lung adenocarcinoma-associated MPEs and 96 benign pleural effusions. CEA, CYFRA 21-1, and CA19-9 were measured by electrochemiluminescence immunoassay. The capacity of tumor markers was assessed with receiver operating characteristic curve analyses and the area under the curve (AUC) was calculated. Standard methods for meta-analysis of diagnostic studies were used to summarize the diagnostic performance of CEA, CYFRA 21-1, and CA19-9 for lung adenocarcinoma-associated MPE. The pleural levels of CEA, CYFRA 21-1, and CA19-9 were significantly increased in lung adenocarcinoma-associated MPE compared to benign pleural effusion. The cut-off points for CEA, CYFRA 21-1, and CA19-9 were optimally set at 4.55 ng/ml, 43.10 μg/ml, and 12.89 U/ml, and corresponding AUCs were 0.93, 0.85, and 0.81, respectively. The combination of CEA, CYFRA 21-1, and CA19-9 increased the sensitivity to 95.06%, with an AUC of 0.95. Eight studies were included in this meta-analysis. CEA showed the best diagnostic performance with pooled sensitivity, specificity, positive/negative likelihood ratio, and diagnostic odds ratio of 0.75, 0.96, 16.01, 0.23, and 81.49, respectively. The AUC was 0.93. CEA, CYFRA 21-1, and CA19-9 play a role in the diagnosis of lung adenocarcinoma-associated MPE. The combination of these tumor markers increases the diagnostic accuracy.
Siri-Tarino, Patty W; Sun, Qi; Hu, Frank B
Background: A reduction in dietary saturated fat has generally been thought to improve cardiovascular health. Objective: The objective of this meta-analysis was to summarize the evidence related to the association of dietary saturated fat with risk of coronary heart disease (CHD), stroke, and cardiovascular disease (CVD; CHD inclusive of stroke) in prospective epidemiologic studies. Design: Twenty-one studies identified by searching MEDLINE and EMBASE databases and secondary referencing qualified for inclusion in this study. A random-effects model was used to derive composite relative risk estimates for CHD, stroke, and CVD. Results: During 5–23 y of follow-up of 347,747 subjects, 11,006 developed CHD or stroke. Intake of saturated fat was not associated with an increased risk of CHD, stroke, or CVD. The pooled relative risk estimates that compared extreme quantiles of saturated fat intake were 1.07 (95% CI: 0.96, 1.19; P = 0.22) for CHD, 0.81 (95% CI: 0.62, 1.05; P = 0.11) for stroke, and 1.00 (95% CI: 0.89, 1.11; P = 0.95) for CVD. Consideration of age, sex, and study quality did not change the results. Conclusions: A meta-analysis of prospective epidemiologic studies showed that there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD or CVD. More data are needed to elucidate whether CVD risks are likely to be influenced by the specific nutrients used to replace saturated fat. PMID:20071648
Sun, Jiang-Wei; Zhao, Long-Gang; Yang, Yang; Ma, Xiao; Wang, Ying-Ying; Xiang, Yong-Bing
Findings on the association between television (TV) viewing and all-cause mortality in epidemiologic studies have been inconsistent. Therefore, we conducted a meta-analysis of data from prospective cohort studies to quantify this association. Relevant articles were identified by searching MEDLINE (PubMed; National Library of Medicine, Bethesda, Maryland) and EMBASE (Elsevier B.V., Amsterdam, the Netherlands) from inception to March 1, 2015, and reviewing the reference lists of retrieved articles. Study-specific results were pooled using a random-effects model. Of 2,578 citations identified by the search strategy, 10 cohort studies (61,494 deaths among 647,475 individuals) met the inclusion criteria. The summary relative risk of all-cause mortality for the highest category of TV viewing time versus the lowest was 1.33 (95% confidence interval: 1.20, 1.47), with heterogeneity among studies (I(2) = 66.7%, P(heterogeneity) = 0.001). In dose-response meta-analysis, TV viewing time was statistically significantly associated with all-cause mortality risk in a J-shaped fashion (P(nonlinearity) = 0.001). These results indicate that prolonged TV viewing time might increase the risk of all-cause mortality. Given the high prevalence of excessive TV viewing, public health recommendations or interventions aimed at decreasing the amount of TV viewing time in modern societies are warranted. © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: email@example.com.
Full Text Available Pathway-based analysis, used in conjunction with genome-wide association study (GWAS techniques, is a powerful tool to detect subtle but systematic patterns in genome that can help elucidate complex diseases, like cancers. Here, we stepped back from genetic polymorphisms at a single locus and examined how multiple association signals can be orchestrated to find pathways related to lung cancer susceptibility. We used single-nucleotide polymorphism (SNP array data from 869 non-small cell lung cancer (NSCLC cases from a previous GWAS at the National Cancer Center and 1,533 controls from the Korean Association Resource project for the pathway-based analysis. After mapping single-nucleotide polymorphisms to genes, considering their coding region and regulatory elements (±20 kbp, multivariate logistic regression of additive and dominant genetic models were fitted against disease status, with adjustments for age, gender, and smoking status. Pathway statistics were evaluated using Gene Set Enrichment Analysis (GSEA and Adaptive Rank Truncated Product (ARTP methods. Among 880 pathways, 11 showed relatively significant statistics compared to our positive controls (PGSEA≤0.025, false discovery rate≤0.25. Candidate pathways were validated using the ARTP method and similarities between pathways were computed against each other. The top-ranked pathways were ABC Transporters (PGSEA<0.001, PARTP = 0.001, VEGF Signaling Pathway (PGSEA<0.001, PARTP = 0.008, G1/S Check Point (PGSEA = 0.004, PARTP = 0.013, and NRAGE Signals Death through JNK (PGSEA = 0.006, PARTP = 0.001. Our results demonstrate that pathway analysis can shed light on post-GWAS research and help identify potential targets for cancer susceptibility.
Gao, H; Wu, Y; Zhang, T; Wu, Y; Jiang, L; Zhan, J; Li, J; Yang, R
Given the drawbacks of implementing multivariate analysis for mapping multiple traits in genome-wide association study (GWAS), principal component analysis (PCA) has been widely used to generate independent 'super traits' from the original multivariate phenotypic traits for the univariate analysis. However, parameter estimates in this framework may not be the same as those from the joint analysis of all traits, leading to spurious linkage results. In this paper, we propose to perform the PCA for residual covariance matrix instead of the phenotypical covariance matrix, based on which multiple traits are transformed to a group of pseudo principal components. The PCA for residual covariance matrix allows analyzing each pseudo principal component separately. In addition, all parameter estimates are equivalent to those obtained from the joint multivariate analysis under a linear transformation. However, a fast least absolute shrinkage and selection operator (LASSO) for estimating the sparse oversaturated genetic model greatly reduces the computational costs of this procedure. Extensive simulations show statistical and computational efficiencies of the proposed method. We illustrate this method in a GWAS for 20 slaughtering traits and meat quality traits in beef cattle.
Gomes, James; Cashman, Neil R.; Little, Julian; Krewski, Daniel
Objective: The association between occupational exposure to lead and amyotrophic lateral sclerosis (ALS) was examined through systematic review and meta-analyses of relevant epidemiological studies and reported according to PRISMA guidelines. Methods: Relevant studies were searched in multiple bibliographic databases through September 2013; additional articles were tracked through PubMed until submission. All records were screened in DistillerSR, and the data extracted from included articles were synthesized with meta-analysis. Results: The risk of developing ALS among individuals with a history of exposure to lead was almost doubled (odds ratio, 1.81; 95% confidence interval, 1.39 to 2.36) on the basis of nine included case-control studies with specific lead exposure information, with no apparent heterogeneity across included studies (I2 = 14%). The attributable risk of ALS because of exposure to lead was estimated to be 5%. Conclusions: Previous exposure to lead may be a risk factor for ALS. PMID:25479292
Du, Qingzhang; Gong, Chenrui; Wang, Qingshi; Zhou, Daling; Yang, Haijiao; Pan, Wei; Li, Bailian; Zhang, Deqiang
Deciphering the genetic architecture underlying polygenic traits in perennial species can inform molecular marker-assisted breeding. Recent advances in high-throughput sequencing have enabled strategies that integrate linkage-linkage disequilibrium (LD) mapping in Populus. We used an integrated method of quantitative trait locus (QTL) dissection with a high-resolution linkage map and multi-gene association mapping to decipher the nature of genetic architecture (additive, dominant, and epistatic effects) of potential QTLs for growth traits in a Populus linkage population (1200 progeny) and a natural population (435 individuals). Seventeen QTLs for tree height, diameter at breast height, and stem volume mapped to 11 linkage groups (logarithm of odds (LOD) ≥ 2.5), and explained 2.7-18.5% of the phenotypic variance. After comparative mapping and transcriptome analysis, 187 expressed genes (10 046 common single nucleotide polymorphisms (SNPs)) were selected from the segmental homology regions (SHRs) of 13 QTLs. Using multi-gene association models, we observed 202 significant SNPs in 63 promising genes from 10 QTLs (P ≤ 0.0001; FDR ≤ 0.10) that exhibited reproducible associations with additive/dominant effects, and further determined 11 top-ranked genes tightly linked to the QTLs. Epistasis analysis uncovered a uniquely interconnected gene-gene network for each trait. This study opens up opportunities to uncover the causal networks of interacting genes in plants using an integrated linkage-LD mapping approach. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.
Fernandez-Villa, Julio M; Marquez, David X; Sanchez-Garrido, Natalia; Perez-Zepeda, Mario U; Gonzalez-Lara, Mariana
The aim of this article is to establish the association between beliefs about healthy habits and mortality in a group of Mexican older adults. This is an 11-year follow-up secondary analysis of the Mexican Health and Aging Study. There was a significant difference ( p healthy habits have the potential to improve health compared with those who did not. After adjustment for confounders, Cox regression models showed a hazard ratio (HR) of 0.17 (95% confidence interval [CI] [0.07, 0.38], p healthy habits. Although the mechanism is not completely clear, according to our results, believing that healthy habits can improve health was associated with lower rates of mortality. Further research should elucidate potential strategies for changing beliefs in older adults with the goal of improving their overall health.
McKay, Gareth J.; Patterson, Chris C.; Chakravarthy, Usha; Dasari, Shilpa; Klaver, Caroline C.; Vingerling, Johannes R.; Ho, Lintje; de Jong, Paulus T.V.M.; Fletcher, Astrid E.; Young, Ian S.; Seland, Johan H.; Rahu, Mati; Soubrane, Gisele; Tomazzoli, Laura; Topouzis, Fotis; Vioque, Jesus; Hingorani, Aroon D.; Sofat, Reecha; Dean, Michael; Sawitzke, Julie; Seddon, Johanna M.; Peter, Inga; Webster, Andrew R.; Moore, Anthony T.; Yates, John R.W.; Cipriani, Valentina; Fritsche, Lars G.; Weber, Bernhard H.F.; Keilhauer, Claudia N.; Lotery, Andrew J.; Ennis, Sarah; Klein, Michael L.; Francis, Peter J.; Stambolian, Dwight; Orlin, Anton; Gorin, Michael B.; Weeks, Daniel E.; Kuo, Chia-Ling; Swaroop, Anand; Othman, Mohammad; Kanda, Atsuhiro; Chen, Wei; Abecasis, Goncalo R.; Wright, Alan F.; Hayward, Caroline; Baird, Paul N.; Guymer, Robyn H.; Attia, John; Thakkinstian, Ammarin; Silvestri, Giuliana
Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status, has been reported. We present a pooled analysis (n=21,160) demonstrating associations between late AMD and APOε4 (OR=0.72 per haplotype; CI: 0.65–0.74; P=4.41×10−11) and APOε2 (OR=1.83 for homozygote carriers; CI: 1.04–3.23; P=0.04), following adjustment for age-group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR=1.54; CI: 1.38–1.72; P=2.8×10−15) and atrophic (OR=1.38; CI: 1.18–1.61; P=3.37×10−5) AMD but not early AMD (OR=0.94; CI: 0.86–1.03; P=0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyondε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology. PMID:21882290
Full Text Available This review aimed to arrange the process of a systematic review of genome-wide association studies in order to practice and apply a genome-wide meta-analysis (GWMA. The process has a series of five steps: searching and selection, extraction of related information, evaluation of validity, meta-analysis by type of genetic model, and evaluation of heterogeneity. In contrast to intervention meta-analyses, GWMA has to evaluate the Hardy–Weinberg equilibrium (HWE in the third step and conduct meta-analyses by five potential genetic models, including dominant, recessive, homozygote contrast, heterozygote contrast, and allelic contrast in the fourth step. The ‘genhwcci’ and ‘metan’ commands of STATA software evaluate the HWE and calculate a summary effect size, respectively. A meta-regression using the ‘metareg’ command of STATA should be conducted to evaluate related factors of heterogeneities.
Shim, Sungryul; Kim, Jiyoung; Jung, Wonguen; Shin, In-Soo; Bae, Jong-Myon
This review aimed to arrange the process of a systematic review of genome-wide association studies in order to practice and apply a genome-wide meta-analysis (GWMA). The process has a series of five steps: searching and selection, extraction of related information, evaluation of validity, meta-analysis by type of genetic model, and evaluation of heterogeneity. In contrast to intervention meta-analyses, GWMA has to evaluate the Hardy-Weinberg equilibrium (HWE) in the third step and conduct meta-analyses by five potential genetic models, including dominant, recessive, homozygote contrast, heterozygote contrast, and allelic contrast in the fourth step. The 'genhwcci' and 'metan' commands of STATA software evaluate the HWE and calculate a summary effect size, respectively. A meta-regression using the 'metareg' command of STATA should be conducted to evaluate related factors of heterogeneities.
Haghighatdoost, Fahimeh; Bellissimo, Nick; Totosy de Zepetnek, Julia O; Rouhani, Mohammad Hossein
Vegetarian diets contain various anti-inflammatory components. We aimed to investigate the effects of vegetarianism on inflammatory biomarkers when compared with omnivores. Systematic review and meta-analysis. Literature search was conducted in Science Direct, Proquest, MEDLINE and Google Scholar up to June 2016. Summary estimates and corresponding 95 % CI were derived via the DerSimonian and Laird method using random effects, subgroup analyses were run to find the source of heterogeneity and a fixed-effect model examined between-subgroup heterogeneity. Studies were included if they evaluated effects of any type of vegetarianism compared with omnivores on circulating levels of inflammatory biomarkers. No restriction was made in terms of language or the date of study publications. Eighteen articles were included. Pooled effect size showed no difference in high-sensitivity C-reactive protein (hs-CRP) levels in vegetarians v. omnivores (Hedges' g=-0·15; 95 % CI -0·35, 0·05), with high heterogeneity (I 2=75·6 %, Pvegetarianism showed that a minimum duration of 2 years vegetarianism was associated with lower hs-CRP levels v. omnivores (Hedges' g=-0·29; 95 % CI -0·59, 0·01), with moderate heterogeneity (I 2=68·9 %, Pvegetarianism, with low heterogeneity. Vegetarianism was associated with increased IL-6 concentrations (0·21 pg/ml; 95 % CI 0·18, 0·25), with no heterogeneity (I 2=0·0 %, P=0·60). The meta-analysis provides evidence that vegetarianism is associated with lower serum concentrations of hs-CRP when individuals follow a vegetarian diet for at least 2 years. Further research is necessary to draw appropriate conclusions regarding potential associations between vegetarianism and IL-6 levels. A vegetarian diet might be a useful approach to manage inflammaging in the long term.
Yang, Yang; Zhao, Long-Gang; Wu, Qi-Jun; Ma, Xiao; Xiang, Yong-Bing
Although in vitro and in vivo experiments have suggested that dietary fiber might have beneficial effects on health, results on the association between fiber intake and all-cause mortality in epidemiologic studies have been inconsistent. Therefore, we conducted a meta-analysis of prospective cohort studies to quantitatively assess this association. Pertinent studies were identified by searching articles in PubMed and Web of Knowledge through May 2014 and reviewing the reference lists of the retrieved articles. Study-specific risk estimates were combined using random-effects models. Seventeen prospective studies (1997-2014) that had a total of 67,260 deaths and 982,411 cohort members were included. When comparing persons with dietary fiber intakes in the top tertile with persons whose intakes were in the bottom tertile, we found a statistically significant inverse association between fiber intake and all-cause mortality, with an overall relative risk of 0.84 (95% confidence interval: 0.80, 0.87; I(2) = 41.2%). There was a 10% reduction in risk for per each 10-g/day increase in fiber intake (relative risk = 0.90; 95% confidence interval: 0.86, 0.94; I(2) = 77.2%). The combined estimate was robust across subgroup and sensitivity analyses. No publication bias was detected. A higher dietary fiber intake was associated with a reduced risk of death. These findings suggest that fiber intake may offer a potential public health benefit in reducing all-cause mortality. © The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
J. B. Alam, M. Jobair Bin Alam, M. M. Rahman, A. K. Dikshit, S. K. Khan
Full Text Available The study reports the level of traffic-induced noise pollution in Sylhet City. For this purpose noise levels have been measured at thirty-seven major locations of the city from 7 am to 11 pm during the working days. It was observed that at all the locations the level of noise remains far above the acceptable limit for all the time. The noise level on the main road near residential area, hospital area and educational area were above the recommended level (65dBA. It was found that the predictive equations are in 60-70% correlated with the measured noise level. The study suggests that vulnerable institutions like school and hospital should be located about 60m away from the roadside unless any special arrangement to alleviate sound is used.
He, Dian; Wu, Shaowen; Zhao, Haiping; Qiu, Hongyan; Fu, Yang; Li, Xingming; He, Yan
The present meta-analysis was carried out to assess the association between exposure to the level of atmospheric particulate matter 2.5 (PM2.5; fine particulate matter with aerodynamic diameter less than 2.5 μm) and type 2 diabetes mellitus or gestational diabetes mellitus (GDM). We searched the Medline, EMBASE, Cochrane and Web of Science databases to obtain articles according to the responding literature search strategies. Among a total of 279 identified articles, 55 were reviewed in depth, of which 10 articles (11 cohort studies) satisfied the inclusion criteria. Only cohort studies that disclosed the association between PM2.5 and type 2 diabetes mellitus or GDM were included in this article. A fixed-effects model was selected if P > 0.1 and I(2) diabetes mellitus (type 2 diabetes mellitus and GDM). The relative risk was used to estimate the association between PM2.5 and diabetes mellitus. The positive associations between PM2.5 and the incidence of type 2 diabetes mellitus were found in the long-term exposure period (relative risk 1.25, 95% confidence interval 1.10-1.43), which showed that with every 10-μg/m(3) increase in PM2.5, the risk of type 2 diabetes mellitus would increase by 25% in the long-term exposure. Although the significant associations were not identified between maternal exposure to PM2.5 and GDM in the first trimester, the second trimester and the entire pregnancy periods, we could conclude that maternal exposure to PM2.5 in the entire pregnancy period would be more likely to lead to developing GDM (relative risk 1.162, 95% confidence interval 0.806-1.675) than the other two periods. Long-term exposure to PM2.5 would be more likely to lead to developing type 2 diabetes mellitus, but more studies would be required to confirm the association between PM2.5 and GDM. It might be a wise to take effective measures to reduce PM2.5 exposure in vulnerable populations, especially for pregnant women. © 2017 The Authors. Journal of Diabetes
Zhang, Jian; Jiang, Hong; Sun, Min; Chen, Jianghua
Periodontal disease occurs relatively prevalently in people with chronic kidney disease (CKD), but it remains indeterminate whether periodontal disease is an independent risk factor for premature death in this population. Interventions to reduce mortality in CKD population consistently yield to unsatisfactory results and new targets are necessitated. So this meta-analysis aimed to evaluate the association between periodontal disease and mortality in the CKD population. Pubmed, Embase, Web of Science, Scopus and abstracts from recent relevant meeting were searched by two authors independently. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated for overall and subgroup meta-analyses. Statistical heterogeneity was explored by chi-square test and quantified by the I 2 statistic. Eight cohort studies comprising 5477 individuals with CKD were incorporated. The overall pooled data demonstrated that periodontal disease was associated with all-cause death in CKD population (RR, 1.254; 95% CI 1.046-1.503; P = 0.005), with a moderate heterogeneity, I 2 = 52.2%. However, no evident association was observed between periodontal disease and cardiovascular mortality (RR, 1.30, 95% CI, 0.82-2.06; P = 0.259). Besides, statistical heterogeneity was substantial (I 2 = 72.5%; P = 0.012). Associations for mortality were similar between subgroups, such as the different stages of CKD, adjustment for confounding factors. Specific to all-cause death, sensitivity and cumulative analyses both suggested that our results were robust. As for cardiovascular mortality, the association with periodontal disease needs to be further strengthened. We demonstrated that periodontal disease was associated with an increased risk of all-cause death in CKD people. Yet no adequate evidence suggested periodontal disease was also at elevated risk for cardiovascular death.
Zeng, T; Chen, L; Du, X; Lai, S J; Huang, S P; Liu, Y L; Lu, L Z
Residual feed intake (RFI) is now considered a more reasonable metric to evaluate animal feed efficiency. In this study, the correlation between RFI and other feed efficiency traits was investigated and gene expression within the hypothalamus was determined in low RFI (LRFI) and high RFI (HRFI) ducks. Further, several hypothalamic neuropeptide genes were measured using quantitative real-time PCR. The mean feed intake value was 160 g/day, whereas the egg mass laid (EML) and body weight were approximately 62.4 g/day and 1.46 kg respectively. Estimates for heritability of RFI, feed conversion ratio (FCR) and feed intake were 0.26, 0.18 and 0.23 respectively. RFI is phenotypically positively correlated with feed intake and FCR (P feed intake without significant changes in EML, whereas selection on FCR will increase EML. © 2016 Stichting International Foundation for Animal Genetics.
Xu, Shuxian; Huang, Yuli; Xiao, Jiping; Zhu, Wenjing; Wang, Lulu; Tang, Hongfeng; Hu, Yunzhao; Liu, Tiebang
Studies about work stress and the risk of coronary heart disease (CHD) have yielded inconsistent results. This meta-analysis aimed to investigate the association between job strain and the risk of CHD. We searched PubMed and Embase databases for studies reporting data on job strain and the risk of CHD. Studies were included if they reported multiple-adjusted relative risk (RR) with 95% confidence interval (CI) with respect to CHD from job strain. Fourteen prospective cohort studies comprising 232,767 participants were included. The risk of CHD was increased in high-strain (RR 1.26; 95% CI 1.12-1.41) and passive jobs (RR 1.14; 95% CI 1.02-1.29) but not in active jobs (RR 1.09; 95% CI 0.97-1.22), when compared with low-strain group. The increased risk of CHD in high-strain and passive jobs was mainly driven by studies with a follow-up duration of ≥ 10 years. Neither the low-control (RR 1.06; 95% CI 0.93-1.19) nor high-demand (RR 1.13; 95% CI 0.97-1.32) dimension was independently associated with the risk of CHD. Individuals with high-strain and passive jobs were more likely to experience a CHD event. Intervention programs incorporating individual and organizational levels are crucial for reducing job strain and the risk of CHD.
Chikkagoudar, Satish; Wang, Kai; Li, Mingyao
Gene-gene interaction in genetic association studies is computationally intensive when a large number of SNPs are involved. Most of the latest Central Processing Units (CPUs) have multiple cores, whereas Graphics Processing Units (GPUs) also have hundreds of cores and have been recently used to implement faster scientific software. However, currently there are no genetic analysis software packages that allow users to fully utilize the computing power of these multi-core devices for genetic interaction analysis for binary traits. Here we present a novel software package GENIE, which utilizes the power of multiple GPU or CPU processor cores to parallelize the interaction analysis. GENIE reads an entire genetic association study dataset into memory and partitions the dataset into fragments with non-overlapping sets of SNPs. For each fragment, GENIE analyzes: 1) the interaction of SNPs within it in parallel, and 2) the interaction between the SNPs of the current fragment and other fragments in parallel. We tested GENIE on a large-scale candidate gene study on high-density lipoprotein cholesterol. Using an NVIDIA Tesla C1060 graphics card, the GPU mode of GENIE achieves a speedup of 27 times over its single-core CPU mode run. GENIE is open-source, economical, user-friendly, and scalable. Since the computing power and memory capacity of graphics cards are increasing rapidly while their cost is going down, we anticipate that GENIE will achieve greater speedups with faster GPU cards. Documentation, source code, and precompiled binaries can be downloaded from http://www.cceb.upenn.edu/~mli/software/GENIE/.
Pereira, A C; Da Cunha, F L; Meneghim, M de C; Werner, C W
The main purpose of this study is to compare data from previous surveys to current prevalence rates of dental caries and dental fluorosis in eleven- and twelve-year-olds in a non-fluoridated Brazilian community (toothpaste and the prevalence of dental caries and dental fluorosis. The sample subjects are randomly selected schoolchildren who were examined with a dental probe and buccal mirror under natural light. The intra-examiner error was calculated, using Kappa statistics (K tau 0.85). The results showed that between 1991 and 1997 there was a 56.7 percent decrease in the prevalence of dental caries and an 80.1 percent increase in dental fluorosis. Children with dental fluorosis were 1.75 times more likely to be free of caries (OR = 1.75-CI:0.43, 6.68). Children who started using fluoride toothpaste before the age of three were 4.43 times more likely to have dental fluorosis than those who started using it after the age of three (OR = 4.43-CI:0.51, 99.61). The results of the cross-sectional surveys conducted with schoolchildren in 1991, 1995, and 1997 suggest a continuing decrease in the prevalence of dental caries and an increase in the prevalence of dental fluorosis in this nonfluoridated Brazilian town.
Ngo, Long H; Inouye, Sharon K; Jones, Richard N; Travison, Thomas G; Libermann, Towia A; Dillon, Simon T; Kuchel, George A; Vasunilashorn, Sarinnapha M; Alsop, David C; Marcantonio, Edward R
The nested case-control study (NCC) design within a prospective cohort study is used when outcome data are available for all subjects, but the exposure of interest has not been collected, and is difficult or prohibitively expensive to obtain for all subjects. A NCC analysis with good matching procedures yields estimates that are as efficient and unbiased as estimates from the full cohort study. We present methodological considerations in a matched NCC design and analysis, which include the choice of match algorithms, analysis methods to evaluate the association of exposures of interest with outcomes, and consideration of overmatching. Matched, NCC design within a longitudinal observational prospective cohort study in the setting of two academic hospitals. Study participants are patients aged over 70 years who underwent scheduled major non-cardiac surgery. The primary outcome was postoperative delirium from in-hospital interviews and medical record review. The main exposure was IL-6 concentration (pg/ml) from blood sampled at three time points before delirium occurred. We used nonparametric signed ranked test to test for the median of the paired differences. We used conditional logistic regression to model the risk of IL-6 on delirium incidence. Simulation was used to generate a sample of cohort data on which unconditional multivariable logistic regression was used, and the results were compared to those of the conditional logistic regression. Partial R-square was used to assess the level of overmatching. We found that the optimal match algorithm yielded more matched pairs than the greedy algorithm. The choice of analytic strategy-whether to consider measured cytokine levels as the predictor or outcome-- yielded inferences that have different clinical interpretations but similar levels of statistical significance. Estimation results from NCC design using conditional logistic regression, and from simulated cohort design using unconditional logistic regression, were
Khurrum, Huma; Bedaiwi, Khalid M.; AlBalahi, Naif Meshael
Background The Koebner phenomenon (KP) is a common entity observed in dermatological disorders. The reported incidence of KP in vitiligo varies widely. Although the KP is frequently observed in patients with viltiligo, the associated factors with KP has not been established yet. Objective The aim is to estimate the prevalence of KP in vitiligo patients and to investigate the associated factors with KP among vitiligo characteristics. Methods A cross-sectional observational study was conducted using 381 vitiligo patients. Demographic and clinical information was obtained via the completion of Vitiligo European Task Force (VETF) questionnaires. Patients with positive history of KP were extracted from this vitiligo database. Multivariate analysis was performed to assess associations with KP. Results The median age of cases was 24 years (range, 0.6~76). In total, 237 of the patients were male (62.2%). Vitiligo vulgaris was the most common type observed (152/381, 39.9%). Seventy-two percent (274/381) patients did not exhibit KP, whereas 28.1% (107/381) of patients exhibited this condition. Multivariable analysis showed the following to be independent factors with KP in patients with vitiligo: the progressive disease (odds ratio [OR], 1.82; 95% confidence interval [95% CI], 1.17~2.92; p=0.041), disease duration longer than 5 years (OR, 1.92; 95% CI, 1.22~2.11; p=0.003), and body surface area more than 2% (OR, 2.20; 95% CI, 1.26~3.24; pvitiligo. Further studies are needed to predict the relationship between KP and responsiveness to therapy. PMID:28566906
Mazaheri, M; Karimian, M; Behjati, M; Raygan, F; Hosseinzadeh Colagar, A
The p22phox gene encodes the main subunit of NADH/NADPH-oxidase. This enzyme is expressed in smooth muscle cells of arteries, and it produces the reactive oxygen species. On the other hand, oxidative stress plays a main role in the pathogenesis of coronary artery disease (CAD). The aim of this study is to evaluate the association between rs4673 and rs1049255 polymorphisms of p22phox gene with CAD in an Iranian population which was followed with a computational analysis approach. In a cross-sectional study, we collected blood samples of 302 Iranian Caucasian including 143 patients and 159 healthy controls. Genotype of the polymorphisms was detected through PCR-RFLP method. A computational analysis was also performed using SNAP, Polyphen-2, Chou-Fasman, RNAsnp, and miRNA SNP databases. Data of case control study demonstrated that CT genotype (R = 1.84, 95% CI = 1.13-3.00, p = 0.014) and T allele (OR = 1.53, 95% CI = 1.09-2.15, p = 0.013) of rs4673 polymorphism, have a significant association with enhanced risk of CAD. But rs1049255 analysis demonstrated the absence of such an association with CAD. Indeed, in silico data analysis demonstrated that rs4673 transition could impact on function of p22phox protein (SNAP score 56, expected accuracy 75%; Polyphen-2 score 0.99, sensitivity 0.09, specificity 0.99). Data derived from miRNA SNP database demonstrated that rs1049255 polymorphism increases the affinity of attachment between has-miR-3689a-3b with 3'-UTR of p22phox gene. Our data demonstrated that rs4673 transition may be involved in susceptibility to CAD and could be applied as a potential biomarker for this disease.
Pan, Ying; Fung, Wing-Kam
Genome-wide association studies (GWASs) in identifying the disease-associated genetic variants have been proved to be a great pioneering work. Two-stage design and analysis are often adopted in GWASs. Considering the genetic model uncertainty, many robust procedures have been proposed and applied in GWASs. However, the existing approaches mostly focused on binary traits, and few work has been done on continuous (quantitative) traits, since the statistical significance of these robust tests is difficult to calculate. In this paper, we develop a powerful F-statistic-based robust joint analysis method for quantitative traits using the combined raw data from both stages in the framework of two-staged GWASs. Explicit expressions are obtained to calculate the statistical significance and power. We show using simulations that the proposed method is substantially more robust than the F-test based on the additive model when the underlying genetic model is unknown. An example for rheumatic arthritis (RA) is used for illustration. PMID:24288575
Shega, Joseph W; Weiner, Debra K; Paice, Judith A; Bilir, S Pinar; Rockwood, Kenneth; Herr, Keela; Ersek, Mary; Emanuel, Linda; Dale, William
Noncancer pain and cognitive impairment affect many older adults and each is associated with functional disability, but their combined impact has yet to be rigorously studied. This is a cross-sectional analysis of the Canadian Study of Health and Aging. Pain was collapsed from a 5-point to a dichotomous scale (no and very mild vs moderate and greater). Cognitive status was dichotomized from the Modified Mini-Mental State Examination (0-100) to no (>77) or mild-moderate (77-50) impairment. Five Instrumental Activities of Daily Living (IADL) and seven Activities of Daily Living (ADL) were self-rated as "accomplished without any help" (0), "with some help" (1), or "completely unable to do oneself" (2) and then summed to create a composite score of 0-10 and 0-14, respectively. Multivariate linear regression analysis was conducted to determine the associations between self-reported functional status with moderate or greater pain, cognitive impairment, and the interaction of the two. A total of 5,143 (90.2%) participants were eligible, 1,813 (35.6%) reported pain at a moderate intensity or greater and 727 (14.3%) were cognitively impaired. The median IADL and ADL summary scores increased among the pain and cognition categories in the following order: no pain and cognitively intact (0.63 SD 1.24, 0.23 SD 0.80), pain and cognitively intact (1.18 SD 1.69, 0.57 SD 1.27), no pain and cognitively impaired (1.64 SD 2.22, 0.75 SD 1.57), and pain and cognitively impaired (2.27 SD 2.47, 1.35 SD 2.09), respectively. Multivariate linear regression found IADL summary scores were associated with pain, coefficient .17 (95% confidence interval [CI] 0.07-0.26), p < .01; cognitive impairment, coefficient .67 (95% CI 0.51-0.83), p < .01; and an interaction effect of pain with cognitive impairment, coefficient .24 (95% CI 0.01-0.49), p = .05. ADL summary scores were associated with pain coefficient .10 (95% CI 0.04-0.17), p < .01 and cognitive impairment, coefficient .29 (95% CI 0
C.M. O'Seaghdha (Conall); H. Wu (Hongsheng); Q. Yang (Qiong); K. Kapur (Karen); I. Guessous (Idris); P. Zuber (Patrick); A. Köttgen (Anna); C. Stoudmann (Candice); A. Teumer (Alexander); Z. Kutalik (Zoltán); M. Mangino (Massimo); A. Dehghan (Abbas); W. Zhang (Weihua); G. Eiriksdottir (Gudny); G. Li (Guo); T. Tanaka (Toshiko); L. Portas (Laura); L.M. Lopez (Lorna); C. Hayward (Caroline); K. Lohman (Kurt); K. Matsuda (Koichi); S. Padmanabhan (Sandosh); D. Firsov (Dmitri); R. Sorice; S. Ulivi (Shelia); A.C. Brockhaus (A. Catharina); M.E. Kleber (Marcus); A. Mahajan (Anubha); F.D.J. Ernst (Florian); V. Gudnason (Vilmundur); L.J. Launer (Lenore); A. Mace (Aurelien); E.A. Boerwinkle (Eric); D.E. Arking (Dan); C. Tanikawa (Chizu); Y. Nakamura (Yusuke); M.J. Brown (Morris); J.-M. Gaspoz (Jean-Michel); J.-M. Theler (Jean-Marc); D.S. Siscovick (David); B.M. Psaty (Bruce); S.M. Bergmann (Sven); P. Vollenweider (Peter); V. Vitart (Veronique); A.F. Wright (Alan); T. Zemunik (Tatijana); M. Boban (Mladen); I. Kolcic (Ivana); P. Navarro (Pau); E.M. Brown (Edward); K. Estrada Gil (Karol); J. Ding (Jinhui); T.B. Harris (Tamara); S. Bandinelli (Stefania); D.G. Hernandez (Dena); A. Singleton (Andrew); S. Girotto; D. Ruggiero; P. d' Adamo (Pio); A. Robino (Antonietta); T. Meitinger (Thomas); C. Meisinger (Christa); G. Davies (Gail); J.M. Starr (John); J.C. Chambers (John); B.O. Boehm (Bernhard); B. Winkelmann; J. Huang (Jian); D. Murgia (Daniela); S.H. Wild (Sarah); H. Campbell (Harry); A.D. Morris (Andrew); O.H. Franco (Oscar); A. Hofman (Albert); A.G. Uitterlinden (André); F. Rivadeneira Ramirez (Fernando); U. Vol̈ker (Uwe); M. Hannemann (Mario); R. Biffar (Reiner); W. Hoffmann (Wolfgang); S.-Y. Shin; P. Lescuyer (Pierre); H. Henry (Hughes); C. Schurmann (Claudia); P. Munroe (Patricia); P. Gasparini (Paolo); N. Pirastu (Nicola); M. Ciullo; C. Gieger (Christian); W. März (Winfried); L. Lind (Lars); T.D. Spector (Timothy); G.D. Smith; I. Rudan (Igor); J.F. Wilson (James); O. Polasek (Ozren); I.J. Deary (Ian); M. Pirastu (Mario); L. Ferrucci (Luigi); Y. Liu (Yongmei); B. Kestenbaum (Bryan); J.S. Kooner (Jaspal); J.C.M. Witteman (Jacqueline); M. Nauck (Matthias); W.H.L. Kao (Wen); H. Wallaschofski (Henri); O. Bonny (Olivier); C. Fox (Craig); M. Bochud (Murielle)
textabstractCalcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17
Paternoster, Lavinia; Standl, Marie; Chen, Chih-Mei; Ramasamy, Adaikalavan; Bønnelykke, Klaus; Duijts, Liesbeth; Ferreira, Manuel A; Alves, Alexessander Couto; Thyssen, Jacob P; Albrecht, Eva; Baurecht, Hansjörg; Feenstra, Bjarke; Sleiman, Patrick MA; Hysi, Pirro; Warrington, Nicole M; Curjuric, Ivan; Myhre, Ronny; Curtin, John A; Groen-Blokhuis, Maria M; Kerkhof, Marjan; Sääf, Annika; Franke, Andre; Ellinghaus, David; Fölster-Holst, Regina; Dermitzakis, Emmanouil; Montgomery, Stephen B; Prokisch, Holger; Heim, Katharina; Hartikainen, Anna-Liisa; Pouta, Anneli; Pekkanen, Juha; Blakemore, Alexandra IF; Buxton, Jessica L; Kaakinen, Marika; Duffy, David L; Madden, Pamela A; Heath, Andrew C; Montgomery, Grant W; Thompson, Philip J; Matheson, Melanie C; Le Souëf, Peter; Pourcain, Beate St; Smith, George Davey; Henderson, John; Kemp, John P; Timpson, Nicholas J; Deloukas, Panos; Ring, Susan M; Wichmann, H-Erich; Müller-Nurasyid, Martina; Novak, Natalija; Klopp, Norman; Rodríguez, Elke; McArdle, Wendy; Linneberg, Allan; Menné, Torkil; Nohr, Ellen A; Hofman, Albert; Uitterlinden, André G; van Duijn, Cornélia M; Rivadeneira, Fernando; de Jongste, Johan C; van der Valk, Ralf JP; Wjst, Matthias; Jogi, Rain; Geller, Frank; Boyd, Heather A; Murray, Jeffrey C; Kim, Cecilia; Mentch, Frank; March, Michael; Mangino, Massimo; Spector, Tim D; Bataille, Veronique; Pennell, Craig E; Holt, Patrick G; Sly, Peter; Tiesler, Carla MT; Thiering, Elisabeth; Illig, Thomas; Imboden, Medea; Nystad, Wenche; Simpson, Angela; Hottenga, Jouke-Jan; Postma, Dirkje; Koppelman, Gerard H; Smit, Henriette A; Söderhäll, Cilla; Chawes, Bo; Kreiner-Møller, Eskil; Bisgaard, Hans; Melén, Erik; Boomsma, Dorret I; Custovic, Adnan; Jacobsson, Bo; Probst-Hensch, Nicole M; Palmer, Lyle J; Glass, Daniel; Hakonarson, Hakon; Melbye, Mads; Jarvis, Deborah L; Jaddoe, Vincent WV; Gieger, Christian; Strachan, David P; Martin, Nicholas G; Jarvelin, Marjo-Riitta; Heinrich, Joachim; Evans, David M; Weidinger, Stephan
Atopic dermatitis (AD) is a common chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing AD are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 cases and 20,565 controls from 16 population-based cohorts and followed up the ten most strongly associated novel markers in a further 5,419 cases and 19,833 controls from 14 studies. Three SNPs met genome-wide significance in the discovery and replication cohorts combined: rs479844 upstream of OVOL1 (OR=0.88, p=1.1×10−13) and rs2164983 near ACTL9 (OR=1.16, p=7.1×10−9), genes which have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster on 5q31.1 (OR=1.11, p=3.8×10−8). We also replicated the FLG locus and two recently identified association signals at 11q13.5 (rs7927894, p=0.008) and 20q13.3 (rs6010620, p=0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in AD pathogenesis. PMID:22197932
Sierra Zúñiga, Marco Fidel; Castro Delgado, Oscar Eduardo; Merchán-Galvis, Angela María; Caicedo, Juan Carlos Caicedo; Calvache, Jose Andrés; Delgado-Noguera, Mario
To determine the independent contribution of prognostic factors to length of hospital stay of minor and moderate burn victims at the Hospital Universitario San José (HUSJ), Popayán, Colombia, 2000-2010. This was a retrospective cohort study of minor and moderate burn victims admitted between 2000 and 2010, at the burn unit (HUSJ). This is a further analysis of a same cohort previously published in Burns. The following variables were recorded and analyzed: age, gender, origin, depth and extent of burn, causal agent, length of hospital stay and mortality. The main outcome under study was length of stay. Survival analysis was done to explore the association of covariates and length of hospital stay and Cox regression model to adjust the effect of covariates in the outcome. During the study period 2000-2010, 842 of 921 (91.5%) patients treated at the Burn Unit of HUSJ that had complete data were included. There were 520 (61.8%) males and 322 (38.2%) females with a male to female ratio of 1.6:1. Their median age was 9 years (IQR 3-28). The median of percent total body surface area burned (TBSA) was 12% (IQR 7-21) and the most common degree of burn was 2nd degree with 58% (488 patients). There were 12 deaths (censored data) and 830 patients were discharged alive. After multivariate adjustment, significant associations with length of hospital stay remained for age group, burn degree and extension of the burn. The strongest relationship found was for burn degree (2nd degree superficial vs. 3rd degree hazard ratio=2.66 CI 95% [2.13-3.33]). In patients admitted with mild and moderate burns at HUSJ, the main predictors of length of stay were age, burn degree and extension of the burn. Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.
Abhinand, P A; Manikandan, M; Mahalakshmi, R; Ragunath, P K
Ischemic stroke is a condition characterized by reduced blood supply to part of the brain, initiating the ischemic cascade, leading to dysfunction of the brain tissue in that area. It is one of the leading causes of death and disability and is estimated to cause around 5.7 million deaths worldwide. Methyl tetra hydro-folate reductase (MTHFR) is a rate limiting enzyme in the methyl cycle which catalyzes the only biochemical reaction which produces 5, Methyl tetra hydro folate, the co-substrate for the re-methylation of homocystiene to produce methionine. MTFHR C677T is a common mutation of MTHFR and those homozygous for the MTFHR C677T produce a thermo-labile form of the protein with drastically reduced catalytic activity resulting in elevated plasma homocystiene levels - a common risk factor for cardiovascular diseases. However, the role of MTHFR C677T in ischemic stroke remains unclear. To evaluate this association, we carried out a meta-analysis of existing published studies, which included 72 studies involving 12390 cases and 16274 controls. The forest plot was made to evaluate the overall risk of the mutation in the etiology of Ischemic Stroke. The overall Odds- ratio of the study was found to be 1.319 for random effects model, revealing a ∼32% increased risk of Ischemic stroke in the presence of MTHFR C667T mutation compared to controls. Publication bias in the study was analyzed using funnel plot which revealed that only 7 studies out of the 72 contributed to publication bias. These 7 studies were excluded and Meta-analysis was repeated for 65 studies and overall odds-ratio was 1.306, which showed that there was a 30% higher risk of Ischemic stroke in the presence of MTHFR C667T.
Taylor, Luke E; Swerdfeger, Amy L; Eslick, Guy D
There has been enormous debate regarding the possibility of a link between childhood vaccinations and the subsequent development of autism. This has in recent times become a major public health issue with vaccine preventable diseases increasing in the community due to the fear of a 'link' between vaccinations and autism. We performed a meta-analysis to summarise available evidence from case-control and cohort studies on this topic (MEDLINE, PubMed, EMBASE, Google Scholar up to April, 2014). Eligible studies assessed the relationship between vaccine administration and the subsequent development of autism or autism spectrum disorders (ASD). Two reviewers extracted data on study characteristics, methods, and outcomes. Disagreement was resolved by consensus with another author. Five cohort studies involving 1,256,407 children, and five case-control studies involving 9,920 children were included in this analysis. The cohort data revealed no relationship between vaccination and autism (OR: 0.99; 95% CI: 0.92 to 1.06) or ASD (OR: 0.91; 95% CI: 0.68 to 1.20), nor was there a relationship between autism and MMR (OR: 0.84; 95% CI: 0.70 to 1.01), or thimerosal (OR: 1.00; 95% CI: 0.77 to 1.31), or mercury (Hg) (OR: 1.00; 95% CI: 0.93 to 1.07). Similarly the case-control data found no evidence for increased risk of developing autism or ASD following MMR, Hg, or thimerosal exposure when grouped by condition (OR: 0.90, 95% CI: 0.83 to 0.98; p=0.02) or grouped by exposure type (OR: 0.85, 95% CI: 0.76 to 0.95; p=0.01). Findings of this meta-analysis suggest that vaccinations are not associated with the development of autism or autism spectrum disorder. Furthermore, the components of the vaccines (thimerosal or mercury) or multiple vaccines (MMR) are not associated with the development of autism or autism spectrum disorder. Copyright © 2014 Elsevier Ltd. All rights reserved.
Kelly, Tanika N.; Takeuchi, Fumihiko; Tabara, Yasuharu; Edwards, Todd L.; Kim, Young Jin; Chen, Peng; Li, Huaixing; Wu, Ying; Yang, Chi-Fan; Zhang, Yonghong; Gu, Dongfeng; Katsuya, Tomohiro; Ohkubo, Takayoshi; Gao, Yu-Tang; Go, Min Jin; Teo, Yik Ying; Lu, Ling; Lee, Nanette R.; Chang, Li-Ching; Peng, Hao; Zhao, Qi; Nakashima, Eitaro; Kita, Yoshikuni; Shu, Xiao-Ou; Kim, Nam Hee; Tai, E Shyong; Wang, Yiqin; Adair, Linda S.; Chen, Chien-Hsiun; Zhang, Shihiu; Li, Changwei; Nabika, Toru; Umemura, Satoshi; Cai, Qiuyin; Cho, Yoon Shin; Wong, Tien Yin; Zhu, Jingwen; Wu, Jer-Yuarn; Gao, Xin; Hixson, James E.; Cai, Hui; Lee, Juyoung; Cheng, Ching-Yu; Rao, Dabeeru C.; Xiang, Yong-Bing; Cho, Myeong-Chan; Han, Bok-Ghee; Wang, Aili; Tsai, Fuu-Jen; Mohlke, Karen; Lin, Xu; Ikram, Mohammad Kamran; Lee, Jong-Young; Zheng, Wei; Tetsuro, Miki; Kato, Norihiro; He, Jiang
We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26,600 East Asian participants (stage-1) followed by replication study of up to 28,783 participants (stage-2). For novel loci, statistical significance was determined by a P<5.0×10−8 in joint analysis of stage-1 and stage-2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of trans-ethnic replication was determined by consistency in effect direction and a Bonferroni-corrected P<1.4×10−3. No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for trans-ethnic replication including rs17249754 at ATP2B1 (P=7.5×10−15), rs2681492 at ATP2B1 (P=3.4×10−7), rs11191593 at NT5C2 (1.1×10−6), rs3824755 at CYP17A1 (P=1.2×10−6), and rs13149993 at FGF5 (P=2.4×10−4). Two additional variants showed suggestive evidence of trans-ethnic replication (consistency in effect direction and P<0.05), including rs319690 at MAP4 (P=0.014) and rs1173771 at NPR3 (P=0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at ATP2B1 (P=1.2×10−5) and rs11191593 at NT5C2 (P=1.1×10−3), with suggestive evidence of replication among an additional 2 variants including rs3824755 at CYP17A1 (P=6.1×10−3) and rs2681492 at ATP2B1 (P=9.0×10−3). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mmHg for mean arterial pressure and from 0.03 to 0.21 mmHg for pulse pressure. In conclusion, we present the first evidence of trans-ethnic replication of several mean arterial and pulse pressure loci in an East Asian population. PMID:24001895
Full Text Available Background: Smoke increases the development of many diseases. Previous studies about its role in the pathogenesis of acne shows contradictory results.Methods: A questionnaire was administrated to each participant, to assess the association acne - smoke. For the systematic review, a bibliographic search on electronic databases was performed (Pubmed, Scopus and Google Scholar. Only case-control studies in English-language from 1966 to 2010 were included. All publications were analyzed by two researchers. Data regarded acneic patients in current and never smokers. Quality assessment was performed using a score for observational study.Results: Of 93 cases of the case-control study, 6 patients had severe acne, 19 moderate acne and 68 had a mild acne, according to classification of Global Alliance to improve outcomes in acne. No one of the smokers had severe acne, only one smoker had moderate acne and 11 had mild acne. Systematic review considered five population studies. First meta-analysis, with all investigations, showed a OR=2.03 (95% CI: 0.63–6.58. The sensitivity analyses include meta-analyses stratified by gender, and quality (score>6. Results for males were: OR=1.89 (95%CI:1.25-2.87; for female OR=1.84 (95%CI:0.36-9.51. The analysis using quality score reported OR=3.48, (95%CI: 1.58-7.68.Conclusions: In conclusions, smokers have higher risk to develop acne, especially males. Conclusions are not robust, because of heterogeneity definitions of smokers and acne grading.Keywords: Acne; Smoke; Tobacco; Nicotine; Cigarettes.
Ervasti, Jenni; Kivimäki, Mika; Dray-Spira, Rosemary; Head, Jenny; Goldberg, Marcel; Pentti, Jaana; Jokela, Markus; Vahtera, Jussi; Zins, Marie; Virtanen, Marianna
Among employees with diabetes, comorbidity may considerably deteriorate working capacity. We examined how socioeconomic status, lifestyle factors and job strain were related to work disability in individuals with diabetes with and without comorbidity. In this pooled analysis of individual-participant data from occupational cohorts from Finland (Finnish Public Sector Study FPS), UK (Whitehall II) and France (GAZEL), 1925 employees with diabetes were followed on average for 4 years. Participants were categorized into four groups, according to their baseline comorbidity status and subsequent work disability, as: non-comorbid diabetes with no/low work disability; comorbid diabetes with no/low work disability; non-comorbid diabetes with moderate/high work disability; and comorbid diabetes with moderate/high work disability. The risk of work disability was assessed with multinomial regression, using Group 1 (the first listed above) as the reference group. Participants with low socioeconomic status had increased odds for higher work disability, irrespective of comorbidity (OR = 3.12; 95% CI 2.25-4.33, among participants with no comorbidity, and OR = 2.61; 95% CI 1.93-3.51 among those with comorbidity). Obesity was cross-sectionally associated with comorbidity (OR = 1.95; 95% CI 1.35-2.83 for comorbidity without disability), and this association was particularly pronounced among those whom became work disabled (OR = 2.61; 95% CI 1.89-3.60 for comorbidity with disability). Job strain was associated with high/moderate work disability, only among participants with comorbidity (OR = 1.63; 95% CI 1.14-2.34). Pooled data from three cohort studies showed that low socioeconomic status, obesity, and job strain are linked to both comorbidity and increased work disability in employees with diabetes. © 2015 the Nordic Societies of Public Health.
Elks, Cathy E; Perry, John R B; Sulem, Patrick; Chasman, Daniel I; Franceschini, Nora; He, Chunyan; Lunetta, Kathryn L; Visser, Jenny A; Byrne, Enda M; Cousminer, Diana L; Gudbjartsson, Daniel F; Esko, Tõnu; Feenstra, Bjarke; Hottenga, Jouke-Jan; Koller, Daniel L; Kutalik, Zoltán; Lin, Peng; Mangino, Massimo; Marongiu, Mara; McArdle, Patrick F; Smith, Albert V; Stolk, Lisette; van Wingerden, Sophie H; Zhao, Jing Hua; Albrecht, Eva; Corre, Tanguy; Ingelsson, Erik; Hayward, Caroline; Magnusson, Patrik K E; Smith, Erin N; Ulivi, Shelia; Warrington, Nicole M; Zgaga, Lina; Alavere, Helen; Amin, Najaf; Aspelund, Thor; Bandinelli, Stefania; Barroso, Inês; Berenson, Gerald S; Bergmann, Sven; Blackburn, Hannah; Boerwinkle, Eric; Buring, Julie E; Busonero, Fabio; Campbell, Harry; Chanock, Stephen J; Chen, Wei; Cornelis, Marilyn C; Couper, David; Coviello, Andrea D; d'Adamo, Pio; de Faire, Ulf; de Geus, Eco J C; Deloukas, Panos; Döring, Angela; Smith, George Davey; Easton, Douglas F; Eiriksdottir, Gudny; Emilsson, Valur; Eriksson, Johan; Ferrucci, Luigi; Folsom, Aaron R; Foroud, Tatiana; Garcia, Melissa; Gasparini, Paolo; Geller, Frank; Gieger, Christian; Gudnason, Vilmundur; Hall, Per; Hankinson, Susan E; Ferreli, Liana; Heath, Andrew C; Hernandez, Dena G; Hofman, Albert; Hu, Frank B; Illig, Thomas; Järvelin, Marjo-Riitta; Johnson, Andrew D; Karasik, David; Khaw, Kay-Tee; Kiel, Douglas P; Kilpeläinen, Tuomas O; Kolcic, Ivana; Kraft, Peter; Launer, Lenore J; Laven, Joop S E; Li, Shengxu; Liu, Jianjun; Levy, Daniel; Martin, Nicholas G; McArdle, Wendy L; Melbye, Mads; Mooser, Vincent; Murray, Jeffrey C; Murray, Sarah S; Nalls, Michael A; Navarro, Pau; Nelis, Mari; Ness, Andrew R; Northstone, Kate; Oostra, Ben A; Peacock, Munro; Palmer, Lyle J; Palotie, Aarno; Paré, Guillaume; Parker, Alex N; Pedersen, Nancy L; Peltonen, Leena; Pennell, Craig E; Pharoah, Paul; Polasek, Ozren; Plump, Andrew S; Pouta, Anneli; Porcu, Eleonora; Rafnar, Thorunn; Rice, John P; Ring, Susan M; Rivadeneira, Fernando; Rudan, Igor; Sala, Cinzia; Salomaa, Veikko; Sanna, Serena; Schlessinger, David; Schork, Nicholas J; Scuteri, Angelo; Segrè, Ayellet V; Shuldiner, Alan R; Soranzo, Nicole; Sovio, Ulla; Srinivasan, Sathanur R; Strachan, David P; Tammesoo, Mar-Liis; Tikkanen, Emmi; Toniolo, Daniela; Tsui, Kim; Tryggvadottir, Laufey; Tyrer, Jonathon; Uda, Manuela; van Dam, Rob M; van Meurs, Joyce B J; Vollenweider, Peter; Waeber, Gerard; Wareham, Nicholas J; Waterworth, Dawn M; Weedon, Michael N; Wichmann, H Erich; Willemsen, Gonneke; Wilson, James F; Wright, Alan F; Young, Lauren; Zhai, Guangju; Zhuang, Wei Vivian; Bierut, Laura J; Boomsma, Dorret I; Boyd, Heather A; Crisponi, Laura; Demerath, Ellen W; van Duijn, Cornelia M; Econs, Michael J; Harris, Tamara B; Hunter, David J; Loos, Ruth J F; Metspalu, Andres; Montgomery, Grant W; Ridker, Paul M; Spector, Tim D; Streeten, Elizabeth A; Stefansson, Kari; Thorsteinsdottir, Unnur; Uitterlinden, André G; Widen, Elisabeth; Murabito, Joanne M; Ong, Ken K; Murray, Anna
To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
Xie, Xiaochuan; Shi, Xiaohan; Liu, Meilin
This systematic review and meta-analysis aimed to better elucidate the roles of genetic factors in Kawasaki disease (KD), and determine the potential genetic biomarkers of KD. The systematic literature search of PubMed, Medline, Embase, Web of Science and CNKI identified 164 eligible studies. The qualitative synthesis revealed that 62 genes may be correlated with the susceptibility to KD, and 47 genes may be associated with the incidence of coronary artery lesions (CALs) in KD. A total of 53 polymorphisms in 34 genes were investigated in further quantitative synthesis. Of these, 23 gene polymorphisms were found to be significantly correlated with KD susceptibility, and 10 gene polymorphisms were found to be significantly associated with the incidence of CALs in KD. In conclusion, our findings indicate that gene polymorphisms of ACE, BLK, CASP3, CD40, FCGR2A, FGβ, HLA-E, IL1A, IL6, ITPKC, LTA, MPO, PD1, SMAD3, CCL17 and TNF may affect KD susceptibility. Besides, genetic variations in BTNL2, CASP3, FCGR2A, FGF23, FGβ, GRIN3A, HLA-E, IL10, ITPKC and TGFBR2 may serve as biomarkers of CALs in KD.
Scaranelo, Anabel M; Carrillo, Maria Claudia; Fleming, Rachel; Jacks, Lindsay M; Kulkarni, Supriya R; Crystal, Pavel
To perform semiautomated quantitative analysis of the background enhancement (BE) in a cohort of patients with newly diagnosed breast cancer and to correlate it with mammographic breast density and menstrual cycle. Informed consent was waived after the research ethics board approved this study. Results of 177 consecutive preoperative breast magnetic resonance (MR) examinations performed from February to December 2009 were reviewed; 147 female patients (median age, 48 years; range, 26-86 years) were included. Ordinal values of BE and breast density were described by two independent readers by using the Breast Imaging Reporting and Data System lexicon. The BE coefficient (BEC) was calculated thus: (SI2 · 100/SI1) - 100, where SI is signal intensity, SI2 is the SI enhancement measured in the largest anteroposterior dimension in the axial plane 1 minute after the contrast agent injection, and SI1is the SI before contrast agent injection. BEC was used for the quantitative analysis of BE. Menstrual cycle status was based on the last menstrual period. The Wilcoxon rank-sum or Kruskal-Wallis test was used to compare quantitative assessment groups. Cohen weighted κ was used to evaluate agreement. Of 147 patients, 68 (46%) were premenopausal and 79 (54%) were postmenopausal. The quantitative BEC was associated with the menstrual status (BEC in premenopausal women, 31.48 ± 20.68 [standard deviation]; BEC in postmenopausal women, 25.65 ± 16.74; P = .02). The percentage of overall BE was higher when the MR imaging was performed in women in the inadequate phase of the cycle (breast density groups. Premenopausal women with breast cancer, and specifically women in the inadequate phase of the cycle, presented with higher quantitative BE than postmenopausal women. No association was found between BE and breast density.
Acikel, Cengizhan; Aydin Son, Yesim; Celik, Cemil; Gul, Husamettin
Multifactor dimensionality reduction (MDR) is a nonparametric approach that can be used to detect relevant interactions between single-nucleotide polymorphisms (SNPs). The aim of this study was to build the best genomic model based on SNP associations and to identify candidate polymorphisms that are the underlying molecular basis of the bipolar disorders. This study was performed on Whole-Genome Association Study of Bipolar Disorder (dbGaP [database of Genotypes and Phenotypes] study accession number: phs000017.v3.p1) data. After preprocessing of the genotyping data, three classification-based data mining methods (ie, random forest, naïve Bayes, and k-nearest neighbor) were performed. Additionally, as a nonparametric, model-free approach, the MDR method was used to evaluate the SNP profiles. The validity of these methods was evaluated using true classification rate, recall (sensitivity), precision (positive predictive value), and F-measure. Random forests, naïve Bayes, and k-nearest neighbors identified 16, 13, and ten candidate SNPs, respectively. Surprisingly, the top six SNPs were reported by all three methods. Random forests and k-nearest neighbors were more successful than naïve Bayes, with recall values >0.95. On the other hand, MDR generated a model with comparable predictive performance based on five SNPs. Although different SNP profiles were identified in MDR compared to the classification-based models, all models mapped SNPs to the DOCK10 gene. Three classification-based data mining approaches, random forests, naïve Bayes, and k-nearest neighbors, have prioritized similar SNP profiles as predictors of bipolar disorders, in contrast to MDR, which has found different SNPs through analysis of two-way and three-way interactions. The reduced number of associated SNPs discovered by MDR, without loss in the classification performance, would facilitate validation studies and decision support models, and would reduce the cost to develop predictive and
J.C. Bis (Joshua); M. Kavousi (Maryam); N. Franceschini (Nora); A.J. Isaacs (Aaron); G.R. Abecasis (Gonçalo); U. Schminke (Ulf); W.S. Post (Wendy S.); A.V. Smith (Albert Vernon); L.A. Cupples (Adrienne); H.S. Markus (Hugh S.); R. Schmidt (Reinhold); J.E. Huffman (Jennifer); T. Lehtimäki (Terho); J. Baumert (Jens); T. Münzel (Thomas); S.R. Heckbert (Susan); A. Dehghan (Abbas); K.E. North (Kari); B.A. Oostra (Ben); S. Bevan (Steve); E.M. Stoegerer (Eva Maria); C. Hayward (Caroline); O. Raitakari (Olli); C. Meisinger (Christa); A. Schillert (Arne); S. Sanna (Serena); H. Völzke (Henry); Y.C. Cheng (Yu Ching); B. Thorsson (Bolli); C.S. Fox (Caroline); K. Rice (Kenneth); F. Rivadeneira Ramirez (Fernando); V. Nambi (Vijay); E. Halperin (Eran); K. Petrovic (Katja); L. Peltonen (Leena Johanna); H.E. Wichmann (Heinz Erich); R.B. Schnabel (Renate); M. Dörr (Marcus); A. Parsa (Afshin); T. Aspelund (Thor); S. Demissie (Serkalem); S. Kathiresan (Sekar); M.P. Reilly (Muredach); K.D. Taylor (Kent); A.G. Uitterlinden (André); D.J. Couper (David); M. Sitzer (Matthias); M. Kähönen (Mika); T. Illig (Thomas); P.S. Wild (Philipp); M. Orrù (Marco); J. Lüdemann (Jan); A.R. Shuldiner (Alan); G. Eiriksdottir (Gudny); C.C. White (Charles); J.I. Rotter (Jerome); A. Hofman (Albert); J. Seissler (Jochen); T. Zeller (Tanja); G. Usala; F.D.J. Ernst (Florian); L.J. Launer (Lenore); R.B. D'Agostino (Ralph); D.H. O'Leary (Daniel H.); C. Ballantyne (Christie); J.P. Thiery (Joachim); A. Ziegler (Andreas); E. Lakatta (Edward); R.K. Chilukoti (Ravi Kumar); T.B. Harris (Tamara); P.A. Wolf (Philip); B.M. Psaty (Bruce); J.F. Polak (Joseph F.); X. Li (Xiaohui); W. Rathmann (Wolfgang); M. Uda (Manuela); E.A. Boerwinkle (Eric); N. Klopp (Norman); J.F. Wilson (James); J. Viikari (Jorma); W. Koenig (Wolfgang); S. Blankenberg (Stefan); A.B. Newman (Anne); J.C.M. Witteman (Jacqueline); G. Heiss (Gerardo); C.M. van Duijn (Cornelia); A. Scuteri (Angelo); G. Homuth (Georg); B.D. Mitchell (Braxton); V. Gudnason (Vilmundur); C.J. O'Donnell (Christopher)
textabstractCarotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European
Wang, Ye-Tao; Gou, Ya-Wen; Jin, Wen-Wen; Xiao, Mei; Fang, Hua-Ying
.... The purpose of this study was to summarize and examine the evidence regarding the association between alcohol intake and pancreatic cancer risk based on results from prospective cohort studies...
Wang, Ye-Tao; Gou, Ya-Wen; Jin, Wen-Wen; Xiao, Mei; Fang, Hua-Ying
Background Studies examining the association between alcohol intake and the risk of pancreatic cancer have given inconsistent results. The purpose of this study was to summarize and examine the evidence regarding the association between alcohol intake and pancreatic cancer risk based on results from prospective cohort studies. Methods We searched electronic databases consisting of PubMed, Ovid, Embase, and the Cochrane Library identifying studies published up to Aug 2015. Only prospective stu...
He, Jianbo; Meng, Shan; Zhao, Tuanjie; Xing, Guangnan; Yang, Shouping; Li, Yan; Guan, Rongzhan; Lu, Jiangjie; Wang, Yufeng; Xia, Qiuju; Yang, Bing; Gai, Junyi
The innovative RTM-GWAS procedure provides a relatively thorough detection of QTL and their multiple alleles for germplasm population characterization, gene network identification, and genomic selection strategy innovation in plant breeding. The previous genome-wide association studies (GWAS) have been concentrated on finding a handful of major quantitative trait loci (QTL), but plant breeders are interested in revealing the whole-genome QTL-allele constitution in breeding materials/germplasm (in which tremendous historical allelic variation has been accumulated) for genome-wide improvement. To match this requirement, two innovations were suggested for GWAS: first grouping tightly linked sequential SNPs into linkage disequilibrium blocks (SNPLDBs) to form markers with multi-allelic haplotypes, and second utilizing two-stage association analysis for QTL identification, where the markers were preselected by single-locus model followed by multi-locus multi-allele model stepwise regression. Our proposed GWAS procedure is characterized as a novel restricted two-stage multi-locus multi-allele GWAS (RTM-GWAS, https://github.com/njau-sri/rtm-gwas ). The Chinese soybean germplasm population (CSGP) composed of 1024 accessions with 36,952 SNPLDBs (generated from 145,558 SNPs, with reduced linkage disequilibrium decay distance) was used to demonstrate the power and efficiency of RTM-GWAS. Using the CSGP marker information, simulation studies demonstrated that RTM-GWAS achieved the highest QTL detection power and efficiency compared with the previous procedures, especially under large sample size and high trait heritability conditions. A relatively thorough detection of QTL with their multiple alleles was achieved by RTM-GWAS compared with the linear mixed model method on 100-seed weight in CSGP. A QTL-allele matrix (402 alleles of 139 QTL × 1024 accessions) was established as a compact form of the population genetic constitution. The 100-seed weight QTL-allele matrix was
Paternoster, Lavinia; Standl, Marie; Chen, Chih-Mei; Ramasamy, Adaikalavan; Bonnelykke, Klaus; Duijts, Liesbeth; Ferreira, Manuel A.; Alves, Alexessander Couto; Thyssen, Jacob P.; Albrecht, Eva; Baurecht, Hansjoerg; Feenstra, Bjarke; Sleiman, Patrick M. A.; Hysi, Pirro; Warrington, Nicole M.; Curjuric, Ivan; Myhre, Ronny; Curtin, John A.; Groen-Blokhuis, Maria M.; Kerkhof, Marjan; Saaf, Annika; Franke, Andre; Ellinghaus, David; Foelster-Holst, Regina; Dermitzakis, Emmanouil; Montgomery, Stephen B.; Prokisch, Holger; Heim, Katharina; Hartikainen, Anna-Liisa; Pouta, Anneli; Pekkanen, Juha; Blakemore, Alexandra I. F.; Buxton, Jessica L.; Kaakinen, Marika; Duffy, David L.; Madden, Pamela A.; Heath, Andrew C.; Montgomery, Grant W.; Thompson, Philip J.; Matheson, Melanie C.; Le Souef, Peter; St Pourcain, Beate; Smith, George Davey; Henderson, John; Kemp, John P.; Timpson, Nicholas J.; Deloukas, Panos; Ring, Susan M.; Wichmann, H-Erich; Mueller-Nurasyid, Martina; Novak, Natalija; Klopp, Norman; Rodriguez, Elke; McArdle, Wendy; Linneberg, Allan; Menne, Torkil; Nohr, Ellen A.; Hofman, Albert; Uitterlinden, Andre G.; van Duijin, Cornelia M.; Rivadeneira, Fernando; de Jongste, Johan C.; van der Valk, Ralf J. P.; Wjst, Matthias; Jogi, Rain; Geller, Frank; Boyd, Heather A.; Murray, Jeffrey C.; Kim, Cecilia; Mentch, Frank; March, Michael; Mangino, Massimo; Spector, Tim D.; Bataille, Veronique; Pennell, Craig E.; Holt, Patrick G.; Sly, Peter; Tiesler, Carla M. T.; Thiering, Elisabeth; Illig, Thomas; Imboden, Medea; Nystad, Wenche; Simpson, Angela; Hottenga, Jouke-Jan; Postma, Dirkje; Koppelman, Gerard H.; Smit, Henriette A.; Soderhall, Cilla; Chawes, Bo; Kreiner-Moller, Eskil; Bisgaard, Hans; Melen, Erik; Boomsma, Dorret I.; Custovic, Adnan; Jacobsson, Bo; Probst-Hensch, Nicole M.; Palmer, Lyle J.; Glass, Daniel; Hakonarson, Hakon; Melbye, Mads; Jarvis, Deborah L.; Jaddoe, Vincent W. V.; Gieger, Christian; Strachan, David P.; Martin, Nicholas G.; Jarvelin, Marjo-Riitta; Heinrich, Joachim; Evans, David M.; Weidinger, Stephan
Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16
Paternoster, Lavinia; Standl, Marie; Chen, Chih-Mei
Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 popul...
Paternoster, L.; Standl, M.; Chen, C.M.; Ramasamy, A.; Bønnelykke, K.; Duijts, L.; Ferreira, M.A.; Couto Alves, A.; Thyssen, J.P.; Albrecht, E.; Baurecht, H.; Feenstra, B.; Sleiman, P.M.A.; Hysi, P.; Warrington, N.M.; Curjuric, I.; Myhre, R.; Curtin, J.A.; Groen-Blokhuis, M.M.; Kerkhof, M.; Sääf, A.; Franke, A.; Ellinghaus, D.; Fölster-Holst, R.; Dermitzakis, E.; Montgomery, S.B.; Prokisch, H.; Heim, K.; Hartikainen, A.-L.; Pouta, A.; Pekkanen, J.; Blakemore, A.I.F.; Buxton, J.L.; Kaakinen, M.; Duffy, DL; Madden, P.A.F.; Heath, A.C.; Montgomery, G.W.; Thompson, P.J.; Matheson, M.C.; Le Souëf, P.; St Pourcain, B.; Davey Smith, G.; Henderson, J.; Kemp, J.P.; Timpson, N.J.; Deloukas, P.; Ring, S.M.; Wichmann, H.-E.; Müller-Nurasyid, M.; Novak, N.; Klopp, N.; Rodríguez, E.; McArdle, W.; Linneberg, A.; Menné, T.; Nohr, E.A.; Hofman, A.; Uitterlinden, A.G.; van Duijn, C.M.; Rivadeneira, F.; de Jongste, J.C.; van der Valk, R.J.P.; Wjst, M.; Jogi, R.; Geller, F.; Boyd, H.A.; Murray, J.C.; Kim, C.; Mentch, F.; March, M.; Mangino, M.; Spector, T.D.; Bataille, V.; Pennell, C.E.; Holt, P.G.; Sly, P.; Tiesler, C.M.T.; Hottenga, J.J.; Boomsma, D.I.; Hakonarson, H.; Melbye, M.; Ljarvis, D.; Jaddoe, V.W.V.; Gieger, C.; Strachan, D.P.; Martin, N.G.; Jarvelin, M.-R.; Heinrich, J.; Evans, D.M.; Weidinger, S.
Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16
Full Text Available BACKGROUND: Several epidemiological studies have investigated the associations of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C polymorphisms with hypertension (H or hypertension in pregnancy (HIP. However, the results were controversial. We therefore performed a comprehensive meta-analysis to provide empirical evidences on the associations. METHODOLOGIES: The English and Chinese databases were systematically searched to identify relevant studies. Odds ratios (ORs and 95% confidence intervals (CIs were calculated to evaluate the strength of the associations. Meta-regression, subgroup analysis, sensitivity analysis, cumulative meta-analysis and assessment of publication bias were performed in our study. PRINCIPAL FINDINGS: A total of 114 studies with 15411 cases and 21970 controls were included, 111 studies with 15094 cases and 21633 controls for the C677T polymorphism and 21 with 2533 cases and 2976 controls for the A1298C polymorphism. Overall, the C677T polymorphism was significantly associated with H and HIP (H & HIP: OR = 1.26, 95% CI = 1.17-1.34; H: OR = 1.36, 95% CI = 1.20-1.53; HIP: OR = 1.21, 95% CI = 1.08-1.32. Stratified analysis by ethnicity revealed a significant association among East Asians and Caucasians, but not among Latinos, Black Africans, and Indians and Sri Lankans. In the stratified analyses according to source of controls, genotyping method, sample size and study quality, significant associations were observed in all the subgroups, with the exception of population based subgroup in H studies and large sample size and "others" genotyping method subgroups in HIP studies. For the A1298C polymorphism, no significant association was observed either in overall or subgroup analysis under all genetic models. CONCLUSIONS: This meta-analysis suggests that the MTHFR C677T rather than A1298C polymorphism may be associated with H & HIP, especially among East Asians and Caucasians.
Benitez, Bruno A; Davis, Albert A; Jin, Sheng Chih; Ibanez, Laura; Ortega-Cubero, Sara; Pastor, Pau; Choi, Jiyoon; Cooper, Breanna; Perlmutter, Joel S; Cruchaga, Carlos
Most sequencing studies in Parkinson's disease (PD) have focused on either a particular gene, primarily in familial and early onset PD samples, or on screening single variants in sporadic PD cases. To date, there is no systematic study that sequences the most common PD causing genes with Mendelian inheritance [α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), PARKIN, PTEN-induced putative kinase 1 (PINK1) and DJ-1 (Daisuke-Junko-1)] and susceptibility genes [glucocerebrosidase beta acid (GBA) and microtubule-associated protein tau (MAPT)] identified through genome-wide association studies (GWAS) in a European-American case-control sample (n=815). Disease-causing variants in the SNCA, LRRK2 and PARK2 genes were found in 2% of PD patients. The LRRK2, p.G2019S mutation was found in 0.6 % of sporadic PD and 4.8 % of familial PD cases. Gene-based analysis suggests that additional variants in the LRRK2 gene also contribute to PD risk. The SNCA duplication was found in 0.8 % of familial PD patients. Novel variants were found in 0.8% of PD cases and 0.6 % of controls. Heterozygous Gaucher disease-causing mutations in the GBA gene were found in 7.1 % of PD patients. Here, we established that the GBA variant (p.T408M) is associated with PD risk and age at onset. Additionally, gene-based and single-variant analyses demostrated that GBA gene variants (p.L483P, p.R83C, p.N409S, p.H294Q and p.E365K) increase PD risk. Our data suggest that the impact of additional untested coding variants in the GBA and LRRK2 genes is higher than previously estimated. Our data also provide compelling evidence of the existence of additional untested variants in the primary Mendelian and PD GWAS genes that contribute to the genetic etiology of sporadic PD.
Gijsbers, L.; Geleijnse, J.M.; Soedamah-Muthu, S.S.
Observational studies suggest an inverse association between dairy intake and incident type 2 diabetes, but the quantity of dairy is not known. Previous meta-analyses did not take into account the type of dairy product. Therefore, we examined dose-response associations between the intake of total
Decarli, A; Parrinello, G; Cortesi, I; Lucchini, R
The "Mercury Multicentric Project" data-set was analysed with the aim to identify a group of biological variables associated with different types of Hg exposure (occupational exposure, fish dietary intake, exposure due to amalgam restorations). The distribution of socio-demographic, biological and surrogate outcome variables was rather different among the collaborating Units. Mixed linear models (MLM) were used to overcome the problems related to the heterogeneity of variances among Units. MLM are a generalization of the standard linear models, the generalization being that the data are permitted to exhibit correlation and non constant variability. MLM therefore provide with the flexibility of modelling not only the means of the dependent variable, but also their variances and co-variances as well. This allows to represent the total variability of the dependent variable as a sum of two components: the first attributable to the Units and the other one to the random error. A set of biological variables significantly associated with at least one of the Hg exposure variables or with the HgU/creatinine ratio (as surrogate variable for Hg exposure) was identified by means of MLM. This set includes beta 2-MG, sIL8, CD4+, sPRL, FT dominant, BAMT, and some variables related to neurological behaviour. An extension of this analysis will be performed with a structural equations approach in order to study the dose-response relationships among the various variables according to a hierarchical path defined on biological basis. One of the possible simplified general models including all the selected variables is described.
Full Text Available Abstract Background The incidence of fungal healthcare-associated infection (HAI has increased in a major teaching hospital in the northern part of Taiwan over the past decade, especially in the intensive care units (ICUs. The purpose of this study was to determine the factors that were responsible for the outbreak and trend in the ICU. Methods Surveillance fungal cultures were obtained from “sterile” objects, antiseptic solutions, environment of infected patients and hands of medical personnel. Risk factors for comparison included age, gender, admission service, and total length of stay in the ICU, Acute Physiology and Chronic Health Evaluation (APACHE II scores at admission to the ICU, main diagnosis on ICU admission, use of invasive devices, receipt of hemodialysis, total parenteral nutrition (TPN use, history of antibiotic therapy before HAI or during ICU stay in no HAI group, and ICU discharge status (ie, dead or alive. Univariable analysis followed by multiple logistic regression analysis was performed to identify the independent risk factors for ICU fungal HAIs and ICU mortality. Results There was a significant trend in ICU fungal HAIs from 1998 to 2009 (P Candida albicans (27.3%, Candida tropicalis (6.6%, Candida glabrata (6.6%, Candida parapsilosis (1.9%, Candida species (0.8%, and other fungi (1.9%. Candida albicans accounted for 63% of all Candida species. Yeasts were found in the environment of more heavily infected patients. The independent risk factors (P P Conclusions There was a secular trend of an increasing number of fungal HAIs in our ICU over the past decade. Patients with ICU fungal HAIs had a significantly higher mortality rate than did patients without ICU HAIs. Total parenteral nutrition was a significant risk factor for all types of ICU fungal HAIs, and its use should be monitored closely.
Jensen, Majken K; Jensen, Richard A; Mukamal, Kenneth J; Guo, Xiuqing; Yao, Jie; Sun, Qi; Cornelis, Marilyn; Liu, Yongmei; Chen, Ming-Huei; Kizer, Jorge R; Djoussé, Luc; Siscovick, David S; Psaty, Bruce M; Zmuda, Joseph M; Rotter, Jerome I; Garcia, Melissa; Harris, Tamara; Chen, Ida; Goodarzi, Mark O; Nalls, Michael A; Keller, Margaux; Arnold, Alice M; Newman, Anne B; Hoogeveen, Ron C; Rexrode, Kathryn M; Rimm, Eric B; Hu, Frank B; Ramachandran, Vasan S; Katz, Ronit; Pankow, James S; Ix, Joachim H
Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin-A concentrations by a genome-wide association study in six population-based studies. We examined the association of fetuin-A levels with ∼ 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, the strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (P AHSG locus, the top SNP was rs4917 (P =1.27 × 10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/l (∼13%) lower fetuin-A level. This variant alone explained 14% of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target. Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US.
Bond, Elizabeth G; Durbin, Laura L; Cisewski, Jodi A; Qian, Min; Guralnik, Jack M; Kasper, Judith D; Mielenz, Thelma J
Continued automobile driving is important for the wellbeing and independence of older adults. Frailty has been associated with a variety of negative health outcomes, but studies are lacking on the potential association between frailty and driving status. The present study uses data from The National Health and Aging Trends Study (NHATS) to assess if the presence of frailty is associated with being a current non-driver. NHATS is a nationally representative cohort study of Medicare beneficiaries (aged ≥65) that have been followed since 2011. We examined frailty status at baseline (Fried's frailty phenotype) and driving status over 4 years (from 2011 to 2014) excluding never drivers at baseline. Multivariable Poisson regression was used to obtain incidence rate ratios, adjusting for covariates and clustering. To account for the repeated measures in the data collection, generalized estimating equations (GEE) were employed. A significant association between baseline frailty and driving status was observed at all four time points. At T4, frail participants at baseline had an incidence rate for becoming a current non-driver 1.80 times (or an 80% increase) that of non-frail participants at baseline (adjusted 95% confidence interval (CI) 1.56-2.07). Frailty was associated with an increased rate of being a current non-driver. Based on this association, we posit that screening for and intervening on frailty may help certain older adults who are at risk for becoming a current non-driver to remain on the road longer.
Full Text Available Abstract This article investigates the application of meta-analysis on livestock candidate gene effects. The PvuII polymorphism of the ESR gene is used as an example. The association among ESR PvuII alleles with the number of piglets born alive and total born in the first (NBA1, TNB1 and later parities (NBA, TNB is reviewed by conducting a meta-analysis of 15 published studies including 9329 sows. Under a fixed effects model, litter size values were significantly lower in the "AA" genotype groups when compared with "AB" and "BB" homozygotes. Under the random effects model, the results were similar although differences between "AA" and "AB" genotype groups were not clearly significant for NBA and TNB. Nevertheless, the most noticeable result was the high and significant heterogeneity estimated among studies. This heterogeneity could be assigned to error sampling, genotype by environment interaction, linkage or epistasis, as referred to in the literature, but also to the hypothesis of population admixture/stratification. It is concluded that meta-analysis can be considered as a helpful analytical tool to synthesise and discuss livestock candidate gene effects. The main difficulty found was the insufficient information on the standard errors of the estimated genotype effects in several publications. Consequently, the convenience of publishing the standard errors or the concrete P-values instead of the test significance level should be recommended to guarantee the quality of candidate gene effect meta-analyses.
Yang, Mingyuan; Yang, Changwei; Zhai, Xiao; Zhao, Jian; Zhu, Xiaodong; Li, Ming
A retrospective study. To determine primary contributors to sagittal balance and establish a predictive equation of sagittal balance in normal asymptomatic subjects. Sagittal balance has been verified to be associated with health-related quality of life. Although many studies have been performed to explore factors contributing to sagittal balance in various disease states, no study has been conducted in normal asymptomatic subjects in East China. Medical records of 340 asymptomatic healthy volunteers were reviewed from January 2014 to August 2015, including 311 for exploring the risk factors and predictive equation, and 29 for validation. Demographic and radiological parameters were evaluated. Correlation analysis between spinopelvic parameters was pursued. Regression analyses were performed to establish predictive radiographic parameters for sagittal balance. Paired t test was conducted to test the regression equation. There was a very good correlation between T1 sagittal angle and maxTK, maxLL and SS, SS and PI, and PT and PI; a moderate correlation between maxTK and maxLL, and maxLL and PI; a weak correlation between T1 sagittal angle and age, age and maxTK, age and SS, age and PT, age and SVA, T1 sagittal angel and SVA, SVA and PT, and SVA and PI; and very weak correlation between T1 sagittal angle and maxLL, maxLL and PT, SVA and LL, and PT and SS. Age, T1 sagittal angle, maxLL, PT, and PI were primary contributors to sagittal balance, which could be predicted by the regression equation: SVA = 0.294 × age + 0.367 × T1 sagittal angle - 1.149 × maxLL-0.704 × PT + 1.378 × PI - 34.164. No significant difference was found between actual SVA and predicted SVA using our equation (P = 0.307). Age, T1 sagittal angle, maxLL, PT, and PI were primary contributors to maintaining sagittal balance in normal asymptomatic subjects, and sagittal balance could be predicted by calculation using the equation derived in this study. 2.
Conall M O'Seaghdha
Full Text Available Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12, rs10491003 upstream of GATA3 (P = 4.8E-09 and rs7481584 in CARS (P = 1.2E-10 implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11, also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10 are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
Amaral, André F S; Patel, Jaymini; Gnatiuc, Louisa; Jones, Meinir; Burney, Peter G J
Low lung function, measured using spirometry, has been associated with mortality from cardiovascular disease, but whether this is explained by airflow obstruction or restriction is a question that remains unanswered. To assess the association of total lung capacity (TLC), forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) with several cardio-metabolic and inflammatory markers. In the follow up of the Burden of Lung Disease (BOLD) study in London, acceptable post-bronchodilator spirometric, pulse rate, pulse wave velocity and blood pressure data were obtained from 108 participants. Blood samples for measurement of cardio-metabolic and inflammatory markers were also collected from these participants. Association of lung function and volume with the different biomarkers was examined in multivariable linear regression models adjusted for potential confounders. Following adjustment for age, sex, height, and ethnicity, TLC (adjusted coefficient = -1.53; 95% CI: -2.57, -0.49) and FVC (adjusted coefficient = -2.66; 95% CI: -4.98, -0.34) were inversely associated with pulse wave velocity, and further adjustment for smoking status, pack-years and body mass index (BMI) did not materially change these results. FEV1 was inversely associated with systolic blood pressure, and adjustment for smoking status, pack-years and BMI made this association stronger (adjusted coefficient = -9.47; 95% CI: -15.62, -3.32). The inverse association of pulse wave velocity, which is a marker of cardiovascular disease, with TLC suggests that the association of the former with low FVC is independent of airflow obstruction. The association between FEV1 with systolic blood pressure after adjustment for FVC suggests an association with airflow obstruction rather than with restricted spirometry. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
Zhang, Di; Zhao, Linhai; Li, Biao; He, Zongxiao; Wang, Gao T; Liu, Dajiang J; Leal, Suzanne M
Massively parallel sequencing technologies provide great opportunities for discovering rare susceptibility variants involved in complex disease etiology via large-scale imputation and exome and whole-genome sequence-based association studies. Due to modest effect sizes, large sample sizes of tens to hundreds of thousands of individuals are required for adequately powered studies. Current analytical tools are obsolete when it comes to handling these large datasets. To facilitate the analysis of large-scale sequence-based studies, we developed SEQSpark which implements parallel processing based on Spark to increase the speed and efficiency of performing data quality control, annotation, and association analysis. To demonstrate the versatility and speed of SEQSpark, we analyzed whole-genome sequence data from the UK10K, testing for associations with waist-to-hip ratios. The analysis, which was completed in 1.5 hr, included loading data, annotation, principal component analysis, and single variant and rare variant aggregate association analysis of >9 million variants. For rare variant aggregate analysis, an exome-wide significant association (p analysis of a quantitative trait using several rare variant aggregate association methods. Additionally, the performance of SEQSpark was compared to Variant Association Tools and PLINK/SEQ. SEQSpark was always faster and in some situations computation was reduced to a hundredth of the time. SEQSpark will empower large sequence-based epidemiological studies to quickly elucidate genetic variation involved in the etiology of complex traits. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Zuo, Ting; Fan, Xin-sheng; Tian, Shuo; Jiang, Chen-xue; Chen, Fei
To explore the current application and features of Aconite prescriptions with incompatible herbs in grade A class three hospitals in east China and central China through a clinical study and comparative analysis. Clinical prescriptions containing Aconite with incompatible herbs were collected. Association rules were utilized to analyze the compatible features of these herbs. This analysis found that the frequently used incompatible herba; pairs are Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma, with the support rate of 44.45%, occupying nearly half of the surveyed prescriptions; Pinelliae Rhizoma is the most frequently used herb in the two areas, with support rate up to 76.24%. Among the top 10 herbal pairs in the support rate, except for Aconiti Lateralis Radix Praeparata and Pinelliae Rhizoma, the top 10 herbs in Central China were mostly for warming the middle jiao and tonifying qi, such as Zingiberis Rhizoma, Atractylodis Macrocephalae Rhizoma and Codonopsis Radix; Whereas those in east China were mostly for activating and nourishing blood, such as Angelicae Sinensis Radix, Chuanxiong Rhizoma, and Salviae Miltiorrhizae Radix et Rhizoma. Among the top 10 herbal pairs in the support rate, except for Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma, the core herbal pairs applied in central China were mainly for resolving phlegm and warming the middle jiao, such as Pinelliae Rhizoma-Glycyrrhizae Radix et Rhizoma, Pinelliae Rhizoma-Zingiberis Rhizoma; Whereas those in east China were principally for activating blood and tonifying qi, like Atractylodis Macrocephalae Rhizoma and Pinelliae Rhizoma, Angelicae Sinensis Radix and Pinelliae Rhizoma. Among the core herbal groups in the two areas, the most frequently used herbal groups in the two areas are Aconiti Lateralis Radix Praeparata, Glycyrrhizae Radix et Rhizoma and Pinelliae Rhizoma with the support rate of 59.73%, accounting for the highest proportion among all of herbal groups. There are the combined
Sampson, Joshua N; Wheeler, William A; Yeager, Meredith; Panagiotou, Orestis; Wang, Zhaoming; Berndt, Sonja I; Lan, Qing; Abnet, Christian C; Amundadottir, Laufey T; Figueroa, Jonine D; Landi, Maria Teresa; Mirabello, Lisa; Savage, Sharon A; Taylor, Philip R; De Vivo, Immaculata; McGlynn, Katherine A; Purdue, Mark P; Rajaraman, Preetha; Adami, Hans-Olov; Ahlbom, Anders; Albanes, Demetrius; Amary, Maria Fernanda; An, She-Juan; Andersson, Ulrika; Andriole, Gerald; Andrulis, Irene L; Angelucci, Emanuele; Ansell, Stephen M; Arici, Cecilia; Armstrong, Bruce K; Arslan, Alan A; Austin, Melissa A; Baris, Dalsu; Barkauskas, Donald A; Bassig, Bryan A; Becker, Nikolaus; Benavente, Yolanda; Benhamou, Simone; Berg, Christine; Van Den Berg, David; Bernstein, Leslie; Bertrand, Kimberly A; Birmann, Brenda M; Black, Amanda; Boeing, Heiner; Boffetta, Paolo; Boutron-Ruault, Marie-Christine; Bracci, Paige M; Brinton, Louise; Brooks-Wilson, Angela R; Bueno-de-Mesquita, H Bas; Burdett, Laurie; Buring, Julie; Butler, Mary Ann; Cai, Qiuyin; Cancel-Tassin, Geraldine; Canzian, Federico; Carrato, Alfredo; Carreon, Tania; Carta, Angela; Chan, John K C; Chang, Ellen T; Chang, Gee-Chen; Chang, I-Shou; Chang, Jiang; Chang-Claude, Jenny; Chen, Chien-Jen; Chen, Chih-Yi; Chen, Chu; Chen, Chung-Hsing; Chen, Constance; Chen, Hongyan; Chen, Kexin; Chen, Kuan-Yu; Chen, Kun-Chieh; Chen, Ying; Chen, Ying-Hsiang; Chen, Yi-Song; Chen, Yuh-Min; Chien, Li-Hsin; Chirlaque, María-Dolores; Choi, Jin Eun; Choi, Yi Young; Chow, Wong-Ho; Chung, Charles C; Clavel, Jacqueline; Clavel-Chapelon, Françoise; Cocco, Pierluigi; Colt, Joanne S; Comperat, Eva; Conde, Lucia; Connors, Joseph M; Conti, David; Cortessis, Victoria K; Cotterchio, Michelle; Cozen, Wendy; Crouch, Simon; Crous-Bou, Marta; Cussenot, Olivier; Davis, Faith G; Ding, Ti; Diver, W Ryan; Dorronsoro, Miren; Dossus, Laure; Duell, Eric J; Ennas, Maria Grazia; Erickson, Ralph L; Feychting, Maria; Flanagan, Adrienne M; Foretova, Lenka; Fraumeni, Joseph F; Freedman, Neal D; Beane Freeman, Laura E; Fuchs, Charles; Gago-Dominguez, Manuela; Gallinger, Steven; Gao, Yu-Tang; Gapstur, Susan M; Garcia-Closas, Montserrat; García-Closas, Reina; Gascoyne, Randy D; Gastier-Foster, Julie; Gaudet, Mia M; Gaziano, J Michael; Giffen, Carol; Giles, Graham G; Giovannucci, Edward; Glimelius, Bengt; Goggins, Michael; Gokgoz, Nalan; Goldstein, Alisa M; Gorlick, Richard; Gross, Myron; Grubb, Robert; Gu, Jian; Guan, Peng; Gunter, Marc; Guo, Huan; Habermann, Thomas M; Haiman, Christopher A; Halai, Dina; Hallmans, Goran; Hassan, Manal; Hattinger, Claudia; He, Qincheng; He, Xingzhou; Helzlsouer, Kathy; Henderson, Brian; Henriksson, Roger; Hjalgrim, Henrik; Hoffman-Bolton, Judith; Hohensee, Chancellor; Holford, Theodore R; Holly, Elizabeth A; Hong, Yun-Chul; Hoover, Robert N; Horn-Ross, Pamela L; Hosain, G M Monawar; Hosgood, H Dean; Hsiao, Chin-Fu; Hu, Nan; Hu, Wei; Hu, Zhibin; Huang, Ming-Shyan; Huerta, Jose-Maria; Hung, Jen-Yu; Hutchinson, Amy; Inskip, Peter D; Jackson, Rebecca D; Jacobs, Eric J; Jenab, Mazda; Jeon, Hyo-Sung; Ji, Bu-Tian; Jin, Guangfu; Jin, Li; Johansen, Christoffer; Johnson, Alison; Jung, Yoo Jin; Kaaks, Rudolph; Kamineni, Aruna; Kane, Eleanor; Kang, Chang Hyun; Karagas, Margaret R; Kelly, Rachel S; Khaw, Kay-Tee; Kim, Christopher; Kim, Hee Nam; Kim, Jin Hee; Kim, Jun Suk; Kim, Yeul Hong; Kim, Young Tae; Kim, Young-Chul; Kitahara, Cari M; Klein, Alison P; Klein, Robert J; Kogevinas, Manolis; Kohno, Takashi; Kolonel, Laurence N; Kooperberg, Charles; Kricker, Anne; Krogh, Vittorio; Kunitoh, Hideo; Kurtz, Robert C; Kweon, Sun-Seog; LaCroix, Andrea; Lawrence, Charles; Lecanda, Fernando; Lee, Victor Ho Fun; Li, Donghui; Li, Haixin; Li, Jihua; Li, Yao-Jen; Li, Yuqing; Liao, Linda M; Liebow, Mark; Lightfoot, Tracy; Lim, Wei-Yen; Lin, Chien-Chung; Lin, Dongxin; Lindstrom, Sara; Linet, Martha S; Link, Brian K; Liu, Chenwei; Liu, Jianjun; Liu, Li; Ljungberg, Börje; Lloreta, Josep; Di Lollo, Simonetta; Lu, Daru; Lund, Eiluv; Malats, Nuria; Mannisto, Satu; Le Marchand, Loic; Marina, Neyssa; Masala, Giovanna; Mastrangelo, Giuseppe; Matsuo, Keitaro; Maynadie, Marc; McKay, James; McKean-Cowdin, Roberta; Melbye, Mads; Melin, Beatrice S; Michaud, Dominique S; Mitsudomi, Tetsuya; Monnereau, Alain; Montalvan, Rebecca; Moore, Lee E; Mortensen, Lotte Maxild; Nieters, Alexandra; North, Kari E; Novak, Anne J; Oberg, Ann L; Offit, Kenneth; Oh, In-Jae; Olson, Sara H; Palli, Domenico; Pao, William; Park, In Kyu; Park, Jae Yong; Park, Kyong Hwa; Patiño-Garcia, Ana; Pavanello, Sofia; Peeters, Petra H M; Perng, Reury-Perng; Peters, Ulrike; Petersen, Gloria M; Picci, Piero; Pike, Malcolm C; Porru, Stefano; Prescott, Jennifer; Prokunina-Olsson, Ludmila; Qian, Biyun; Qiao, You-Lin; Rais, Marco; Riboli, Elio; Riby, Jacques; Risch, Harvey A; Rizzato, Cosmeri; Rodabough, Rebecca; Roman, Eve; Roupret, Morgan; Ruder, Avima M; Sanjose, Silvia de; Scelo, Ghislaine; Schned, Alan; Schumacher, Fredrick; Schwartz, Kendra; Schwenn, Molly; Scotlandi, Katia; Seow, Adeline; Serra, Consol; Serra, Massimo; Sesso, Howard D; Setiawan, Veronica Wendy; Severi, Gianluca; Severson, Richard K; Shanafelt, Tait D; Shen, Hongbing; Shen, Wei; Shin, Min-Ho; Shiraishi, Kouya; Shu, Xiao-Ou; Siddiq, Afshan; Sierrasesúmaga, Luis; Sihoe, Alan Dart Loon; Skibola, Christine F; Smith, Alex; Smith, Martyn T; Southey, Melissa C; Spinelli, John J; Staines, Anthony; Stampfer, Meir; Stern, Marianna C; Stevens, Victoria L; Stolzenberg-Solomon, Rachael S; Su, Jian; Su, Wu-Chou; Sund, Malin; Sung, Jae Sook; Sung, Sook Whan; Tan, Wen; Tang, Wei; Tardón, Adonina; Thomas, David; Thompson, Carrie A; Tinker, Lesley F; Tirabosco, Roberto; Tjønneland, Anne; Travis, Ruth C; Trichopoulos, Dimitrios; Tsai, Fang-Yu; Tsai, Ying-Huang; Tucker, Margaret; Turner, Jenny; Vajdic, Claire M; Vermeulen, Roel C H; Villano, Danylo J; Vineis, Paolo; Virtamo, Jarmo; Visvanathan, Kala; Wactawski-Wende, Jean; Wang, Chaoyu; Wang, Chih-Liang; Wang, Jiu-Cun; Wang, Junwen; Wei, Fusheng; Weiderpass, Elisabete; Weiner, George J; Weinstein, Stephanie; Wentzensen, Nicolas; White, Emily; Witzig, Thomas E; Wolpin, Brian M; Wong, Maria Pik; Wu, Chen; Wu, Guoping; Wu, Junjie; Wu, Tangchun; Wu, Wei; Wu, Xifeng; Wu, Yi-Long; Wunder, Jay S; Xiang, Yong-Bing; Xu, Jun; Xu, Ping; Yang, Pan-Chyr; Yang, Tsung-Ying; Ye, Yuanqing; Yin, Zhihua; Yokota, Jun; Yoon, Ho-Il; Yu, Chong-Jen; Yu, Herbert; Yu, Kai; Yuan, Jian-Min; Zelenetz, Andrew; Zeleniuch-Jacquotte, Anne; Zhang, Xu-Chao; Zhang, Yawei; Zhao, Xueying; Zhao, Zhenhong; Zheng, Hong; Zheng, Tongzhang; Zheng, Wei; Zhou, Baosen; Zhu, Meng; Zucca, Mariagrazia; Boca, Simina M; Cerhan, James R; Ferri, Giovanni M; Hartge, Patricia; Hsiung, Chao Agnes; Magnani, Corrado; Miligi, Lucia; Morton, Lindsay M; Smedby, Karin E; Teras, Lauren R; Vijai, Joseph; Wang, Sophia S; Brennan, Paul; Caporaso, Neil E; Hunter, David J; Kraft, Peter; Rothman, Nathaniel; Silverman, Debra T; Slager, Susan L; Chanock, Stephen J; Chatterjee, Nilanjan
Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Our results provide important insights into
Abete, Itziar; Romaguera, Dora; Vieira, Ana Rita; Lopez de Munain, Adolfo; Norat, Teresa
An association between processed and red meat consumption and total mortality has been reported by epidemiological studies; however, there are many controversial reports regarding the association between meat consumption and CVD and IHD mortality. The present meta-analysis was carried out to summarise the evidence from prospective cohort studies on the association between consumption of meat (total, red, white and processed) and all-cause, CVD and IHD mortality. Cohort studies were identified by searching the PubMed and ISI Web of Knowledge databases. Risk estimates for the highest v. the lowest consumption category and dose-response meta-analysis were calculated using a random-effects model. Heterogeneity among the studies was also evaluated. A total of thirteen cohort studies were identified (1 674 272 individuals). Subjects in the highest category of processed meat consumption had 22 and 18 % higher risk of mortality from any cause and CVD, respectively. Red meat consumption was found to be associated with a 16 % higher risk of CVD mortality, while no association was found for total and white meat consumption. In the dose-response meta-analysis, an increase of 50 g/d in processed meat intake was found to be positively associated with all-cause and CVD mortality, while an increase of 100 g/d in red meat intake was found to be positively associated with CVD mortality. No significant associations were observed between consumption of any type of meat and IHD mortality. The results of the present meta-analysis indicate that processed meat consumption could increase the risk of mortality from any cause and CVD, while red meat consumption is positively but weakly associated with CVD mortality. These results should be interpreted with caution due to the high heterogeneity observed in most of the analyses as well as the possibility of residual confounding.
Ge, Beihai; Guo, Xiaomei
There is uncertainty about the relationship between sleep duration and stroke risk. We aimed to clarify the relationship between sleep duration and risk of stroke by using epidemiological evidence. We searched MEDLINE and EMBASE to identify all studies that might be looking at the association between sleep duration and stroke, including both cohort and cross-sectional studies. Pooled hazard ratios (HRs) and odds ratios (ORs) were calculated through a random-effects model. Our study included a total of 12 cohort studies and 6 cross-sectional studies. Pooled results from the cohort studies showed that short sleep duration was associated with a higher risk for stroke [HR, 1.13; 95% confidence interval (CI) 1.02-1.25], and that long sleep duration also increases the risk of having a stroke (HR, 1.40; 95% CI, 1.16-1.64). Results from cross-sectional studies confirmed the relationship between stroke and inappropriate sleep duration, either too little sleep or too much. For short sleep duration, the OR was 1.71 (1.39-2.02); for long sleep duration, the OR was 2.12 (1.51-2.73). Both short and long sleep durations have a significant association with higher risk of stroke. © 2014 World Stroke Organization.
Full Text Available Apolipoprotein A5 (APOA5 is associated with plasma triglyceride (TG levels, a risk factor for coronary heart disease (CHD. This study explored the association between CHD and the APOA5 rs662799 polymorphism.We collected 1,521 samples (783 CHD patients and 738 controls for this case-control study. Meta-analysis was performed using Review Manager Software and Stata Software.Significant differences were observed between CHD cases and controls at the level of both genotype (χ2 = 8.964, df = 2, P = 0.011 and allele (χ2 = 9.180, df = 1, P = 0.002, OR = 1.275, 95% CI = 1.089-1.492. A breakdown analysis by gender showed a significant association of APOA5 rs662799 with CHD in males (χ2 = 7.770, df = 1, P = 0.005; OR = 1.331, 95% CI = 1.088-1.628. An additional meta-analysis using 21378 cases and 28428 controls established that rs662799 is significantly associated with CHD (P < 0.00001.Both our case-control study and meta-analysis confirm a significant association between APOA5 rs662799 and CHD. In addition, our results suggest a male-specific association between the APOA5 rs662799 polymorphism and CHD.
Zillikens, M Carola; Demissie, Serkalem; Hsu, Yi-Hsiang
Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorpt...
Paternoster, Lavinia; Standl, Marie; Chen, Chih-Mei
population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream...
Zillikens, M.C.; Demissie, Serkalem; Hsu, Yi Hsiang; Yerges-Armstrong, Laura M.; Chou, Wen Chi; Stolk, Lisette; Livshits, Gregory; Broer, Linda; Johnson, Toby; Koller, Daniel L.; Kutalik, Zoltán; Luan, J.A.; Malkin, Ida; Ried, Janina S.; Smith, Albert V.; Thorleifsson, Gudmar; Vandenput, Liesbeth; Hua Zhao, Jing; Zhang, Weihua; Aghdassi, Ali; Åkesson, Kristina; Amin, Najaf; Baier, Leslie J.; Barroso, Inês; Bennett, David A.; Bertram, Lars; Biffar, Rainer; Bochud, Murielle; Boehnke, Michael; Borecki, Ingrid B.; Buchman, Aron S.; Byberg, Liisa; Campbell, Harry; Campos Obanda, Natalia; Cauley, Jane A.; Cawthon, Peggy M.; Cederberg, Henna; Chen, Zhao; Cho, Nam H.; Jin Choi, Hyung; Claussnitzer, Melina; Collins, Francis; Cummings, Steven R.; Jager, De Philip L.; Demuth, Ilja; Dhonukshe-Rutten, Rosalie A.M.; DIatchenko, Luda; Eiriksdottir, Gudny; Enneman, Anke W.; Erdos, Mike; Eriksson, Johan G.; Eriksson, Joel; Estrada, Karol; Evans, Daniel S.; Feitosa, Mary F.; Fu, Mao; Garcia, Melissa; Gieger, Christian; Girke, Thomas; Glazer, Nicole L.; Grallert, Harald; Grewal, Jagvir; Han, Bok Ghee; Hanson, Robert L.; Hayward, Caroline; Hofman, Albert; Hoffman, Eric P.; Homuth, Georg; Hsueh, Wen Chi; Hubal, Monica J.; Hubbard, Alan; Huffman, Kim M.; Husted, Lise B.; Illig, Thomas; Ingelsson, Erik; Ittermann, Till; Jansson, John Olov; Jordan, Joanne M.; Jula, Antti; Karlsson, Magnus; Khaw, Kay Tee; Kilpelaïnen, Tuomas O.; Klopp, Norman; Kloth, Jacqueline S.L.; Koistinen, Heikki A.; Kraus, William E.; Kritchevsky, Stephen; Kuulasmaa, Teemu; Kuusisto, Johanna; Laakso, Markku; Lahti, Jari; Lang, Thomas; Langdahl, Bente L.; Launer, Lenore J.; Lee, Jong Young; Lerch, Markus M.; Lewis, Joshua R.; Lind, Lars; Lindgren, Cecilia M.; Liu, Yongmei; Liu, Tian; Liu, Youfang; Ljunggren, Östen; Lorentzon, Mattias; Luben, Robert N.; Maixner, William; McGuigan, Fiona E.; Medina-Gomez, Carolina; Meitinger, Thomas; Melhus, Håkan; Mellström, Dan; Melov, Simon; Michaëlsson, Karl; Mitchell, Braxton D.; Morris, Andrew P.; Mosekilde, Leif; Newman, Anne; Nielson, Carrie M.; O'Connell, Jeffrey R.; Oostra, Ben A.; Orwoll, Eric S.; Palotie, Aarno; Parker, Stephan; Peacock, Munro; Perola, Markus; Peters, Annette; Polasek, Ozren; Prince, Richard L.; Raïkkönen, Katri; Ralston, Stuart H.; Ripatti, Samuli; Robbins, John A.; Rotter, Jerome I.; Rudan, Igor; Salomaa, Veikko; Satterfield, Suzanne; Schadt, Eric E.; Schipf, Sabine; Scott, Laura; Sehmi, Joban; Shen, Jian; Soo Shin, Chan; Sigurdsson, Gunnar; Smith, Shad; Soranzo, Nicole; Stančáková, Alena; Steinhagen-Thiessen, Elisabeth; Streeten, Elizabeth A.; Styrkarsdottir, Unnur; Swart, Karin M.A.; Tan, Sian Tsung; Tarnopolsky, Mark A.; Thompson, Patricia; Thomson, Cynthia A.; Thorsteinsdottir, Unnur; Tikkanen, Emmi; Tranah, Gregory J.; Tuomilehto, Jaakko; Schoor, van Natasja M.; Verma, Arjun; Vollenweider, Peter; Völzke, Henry; Wactawski-Wende, Jean; Walker, Mark; Weedon, Michael N.; Welch, Ryan; Wichman, H.E.; Widen, Elisabeth; Williams, Frances M.K.; Wilson, James F.; Wright, Nicole C.; Xie, Weijia; Yu, Lei; Zhou, Yanhua; Chambers, John C.; Döring, Angela; Duijn, Van Cornelia M.; Econs, Michael J.; Gudnason, Vilmundur; Kooner, Jaspal S.; Psaty, Bruce M.; Spector, Timothy D.; Stefansson, Kari; Rivadeneira, Fernando; Uitterlinden, André G.; Wareham, Nicholas J.; Ossowski, Vicky; Waterworth, Dawn M.; Loos, Ruth J.F.; Karasik, David; Harris, Tamara B.; Ohlsson, Claes; Kiel, Douglas P.
Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray
Reiling, Erwin; van Vliet-Ostaptchouk, Jana V.; van't Riet, Esther; van Haeften, Timon W.; Arp, Pascal A.; Hansen, Torben; Kremer, Dennis; Groenewoud, Marlous J.; van Hove, Els C.; Romijn, Johannes A.; Smit, Jan W. A.; Nijpels, Giel; Heine, Robert J.; Uitterlinden, Andre G.; Pedersen, Oluf; Slagboom, P. Eline; Maassen, Johannes A.; Hofker, Marten H.; 't Hart, Leen M.; Dekker, Jacqueline M.
Mitochondria play an important role in many processes, like glucose metabolism, fatty acid oxidation and ATP synthesis. In this study, we aimed to identify association of common polymorphisms in nuclear-encoded genes involved in mitochondrial protein synthesis and biogenesis with type II diabetes
Reiling, Erwin; van Vliet-Ostaptchouk, Jana V; van 't Riet, Esther
Mitochondria play an important role in many processes, like glucose metabolism, fatty acid oxidation and ATP synthesis. In this study, we aimed to identify association of common polymorphisms in nuclear-encoded genes involved in mitochondrial protein synthesis and biogenesis with type II diabetes...
Sampson, JN; Wheeler, WA; Yeager, M.; Panagiotou, O.; Wang, Z; Berndt, SI; Lan, Q; Abnet, CC; Amundadottir, LT; Figueroa, JD; Landi, Mt; Mirabello, L.; Savage, SA; TAYLOR, PR; De Vivo, I
Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common SNPs for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49,492 cancer cases and 34,131 controls. We apply novel mixed model methodology (GCTA) to this GWAS data...
Duarte, Darlene Ana Souza
A large number of quantitative trait loci (QTLs) for meat quality and carcass traits has been identified in several studies, but the genetic architecture remains poorly understood. Thus, a methodology that allows study genes and pathways that affect these traits would offers many advantages and increase the knowledge of physiological mechanisms. With this purpose, a methodology named Association Weight Matrix (AWM) was used to investigate the genetic basis of these traits and generate gene ne...
Full Text Available BACKGROUND: Common genetic polymorphisms on chromosome 5p15.33, including rs401681 in cleft lip and palate transmembrane 1-like gene (CLPTM1L, have been implicated in susceptibility to lung cancer through genome-wide association studies (GWAS; however, subsequent replication studies yielded controversial results. METHODOLOGY AND FINDINGS: A hospital-based case-control study in a Chinese population was conducted to replicate the association, and then a meta-analysis combining our non-overlapping new data and previously published data was performed to clearly discern the real effect of lung cancer susceptibility. In our study with 611 cases and 1062 controls, the minor allele T carrier (TT plus CT group conferred an OR of 0.801 (95% CI = 0.654-0.981 under the dominant model. The meta-analysis comprising 9111 cases and 11424 controls further confirmed the significant association in the dominant model (OR = 0.842, 95% CI = 0.795-0.891. By stratified analysis, we revealed that ethnicity and study design might constitute the source of between-study heterogeneity. Besides, the sensitivity and cumulative analyses indicated the high stability of the results. CONCLUSION: The results from our case-control study and meta-analysis provide convincing evidence that rs401681 is significantly associated with lung cancer risk.
Full Text Available Based on the data mining research, the data mining based on genetic algorithm method, the genetic algorithm is briefly introduced, while the genetic algorithm based on two important theories and theoretical templates principle implicit parallelism is also discussed. Focuses on the application of genetic algorithms for association rule mining method based on association rule mining, this paper proposes a genetic algorithm fitness function structure, data encoding, such as the title of the improvement program, in particular through the early issues study, proposed the improved adaptive Pc, Pm algorithm is applied to the genetic algorithm, thereby improving efficiency of the algorithm. Finally, a genetic algorithm based association rule mining algorithm, and be applied in sea water samples database in data mining and prove its effective.
Full Text Available Human papillomavirus (HPV causes tumors primarily Cervical cancer. Recently, inconsistent reports came up in Breast cancer (BC too. In India, despite treatment 70,218 BC patients die each year. So, we explored the association of HPV, if any, with BC prognosis in Indian pre-therapeutic (PT and Neo-adjuvant chemotherapy (NACT patients with subsequent analysis of HPV profile.HPV prevalence was checked and analysis of physical status, copy number, genome variation, promoter methylation and expression (mRNA and protein of the prevalent subtype was done.High prevalence of HPV was observed in both PT (64.0% and NACT (71.0% cases with significant association with younger (20-45 yrs PT patients. Interestingly, HPV infection was significantly increased from adjacent normal breast (9.5%, 2/21, fibro adenomas (30%, 3/10 to tumors (64.8%, 203/313 samples. In both PT and NACT cases, HPV16 was the most prevalent subtype (69.0% followed by HPV18 and HPV33. Survival analysis illustrated hrHPV infected PT patients had worst prognosis. So, detailed analysis of HPV16 profile was done which showed Europian-G350 as the most frequent HPV16 variant along with high rate of integration. Moreover, low copy number and hyper-methylation of P97 early promoter were concordant with low HPV16 E6 and E7 mRNA and protein expression. Notably, four novel variations (KT020838, KT020840, KT020841 and KT020839 in the LCR region and two (KT020836 and KT020837 in the E6 region were identified for the first time along with two novel E6^E7*I (KU199314 and E6^E7*II (KU199315 fusion transcript variants.Thus, significant association of hrHPV with prognosis of Indian BC patients led to additional investigation of HPV16 profile. Outcomes indicated a plausible role of HPV in Indian BC patients.
Lee, So Yeon; Lee, Yong Joo; Yang, Jung-Hwa; Kim, Chul-Min; Choi, Whan-Seok
A frequent manifestation of advanced cancer patients is malnutrition, which is correlated with poor prognosis and high mortality. Bioelectrical impedance analysis (BIA) is an easy-to-use and non-invasive technique to evaluate changes in body composition and nutritional status. We investigated BIA-derived phase angle as a prognostic indicator for survival in advanced cancer patients. Twenty-eight patients treated at the hospice center of Seoul St. Mary's Hospital underwent BIA measurements from January, 2013 to May, 2013. We also evaluated palliative prognostic index (PPI) and palliative performance scale to compare with the prognostic value of phase angle. Cox's proportional hazard models were constructed to evaluate the prognostic effect of phase angle. The Kaplan Meier method was used to calculate survival. Using univariate Cox analysis, phase angle (hazard ratio [HR], 0.61/per degree increase; 95% confidence interval [CI], 0.42 to 0.89; P = 0.010), PPI (HR, 1.21; 95% CI, 1.00 to 1.47; P = 0.048) were found to be significantly associated with survival. Adjusting age, PPI, body mass index, phase angle significantly showed association with survival in multivariate analysis (HR, 0.64/per degree increase; 95% CI, 0.42 to 0.95; P = 0.028). Survival time of patients with phase angle ≥ 4.4° was longer than patients with phase angle < 4.4° (log rank, 6.208; P-value = 0.013). Our data suggest BIA-derived phase angle may serve as an independent prognostic indicator in advanced cancer patients.
Full Text Available BACKGROUND: Lung cancer is the most commonly diagnosed cancer and leading cause of cancer mortality in the world. A single nucleotide polymorphism (SNP, rs402710, located in 5p15.33, was firstly identified to be associated with the lung cancer risk in a genome-wide association study. However, some following replication studies yielded inconsistent results. METHODOLOGY AND FINDINGS: A case-control study of 611 cases and 1062 controls in a Chinese population was conducted, and then a meta-analysis integrating the current and previously published studies with a total 31811 cases and 36333 controls was performed to explore the real effect of rs402710 on lung cancer susceptibility. Significant associations between the SNP rs402710 and lung cancer risk were observed in both case-control study and meta-analysis, with ORs equal to 0.77 (95%CI = 0.63-0.95 and 0.83 (95%CI = 0.81-0.86 in dominant model, respectively. By stratified analysis of our case-control study, the associations were also observed in never smoker group and non-small cell lung cancer(NSCLC group with ORs equal to 0.71 (95%CI = 0.53-0.95 and 0.69 (95%CI = 0.55-0.87, which was remarkable that larger effect of the minor allele T was seen in the two groups than that in overall lung cancer. Besides, the sensitive and cumulative analysis indicated the robust stability of the current results of meta-analysis. CONCLUSION: The results from our replication study and the meta-analysis provided firm evidence that rs402710 T allele significantly contributed to decreased lung cancer risk, and the case-control study implied that the variant may yield stronger effect on NSCLC and never smokers. However, the mechanism underlying the polymorphism conferring susceptibility to lung cancer is warranted to clarify in the follow-up studies.
Yang, Boyi; Fan, Shujun; Zhi, Xueyuan; Li, Yongfang; Liu, Yuyan; Wang, Da; He, Miao; Hou, Yongyong; Zheng, Quanmei; Sun, Guifan
Background Several epidemiological studies have investigated the associations of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with hypertension (H) or hypertension in pregnancy (HIP). However, the results were controversial. We therefore performed a comprehensive meta-analysis to provide empirical evidences on the associations. Methodologies The English and Chinese databases were systematically searched to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Meta-regression, subgroup analysis, sensitivity analysis, cumulative meta-analysis and assessment of publication bias were performed in our study. Principal Findings A total of 114 studies with 15411 cases and 21970 controls were included, 111 studies with 15094 cases and 21633 controls for the C677T polymorphism and 21 with 2533 cases and 2976 controls for the A1298C polymorphism. Overall, the C677T polymorphism was significantly associated with H and HIP (H & HIP: OR = 1.26, 95% CI = 1.17–1.34; H: OR = 1.36, 95% CI = 1.20–1.53; HIP: OR = 1.21, 95% CI = 1.08–1.32). Stratified analysis by ethnicity revealed a significant association among East Asians and Caucasians, but not among Latinos, Black Africans, and Indians and Sri Lankans. In the stratified analyses according to source of controls, genotyping method, sample size and study quality, significant associations were observed in all the subgroups, with the exception of population based subgroup in H studies and large sample size and “others” genotyping method subgroups in HIP studies. For the A1298C polymorphism, no significant association was observed either in overall or subgroup analysis under all genetic models. Conclusions This meta-analysis suggests that the MTHFR C677T rather than A1298C polymorphism may be associated with H & HIP, especially among East Asians and Caucasians. PMID:24505291
Pounis, George; Bonaccio, Marialaura; Di Castelnuovo, Augusto; Costanzo, Simona; de Curtis, Amalia; Persichillo, Mariarosaria; Sieri, Sabina; Donati, Maria Benedetta; Cerletti, Chiara; de Gaetano, Giovanni; Iacoviello, Licia
The association of polyphenol content of human diet with low-grade inflammation is not yet fully understood. It was the objective of this study to evaluate the association of flavonoid and lignan intake with frequently used and easily applicable in clinical practice low-grade inflammation biomarkers, in a novel holistic approach. A total of 5,948 women and 5,965 men (aged ≥ 35 years) were analysed from the Moli-sani cohort, randomly recruited from the general population. The EPIC-FFQ was used for dietary assessment. Flavonol, flavone, flavanone, flavanol, anthocyanin, isoflavone and lignan intakes were calculated using Eurofir eBASIS and the polyphenol antioxidant content (PAC)-score was constructed to assess the total content of diet in these nutrients. CRP levels, WBC and PLT count and granulocyte to lymphocyte ratio were conceived as low-grade inflammation biomarkers. INFLA-score was constructed summarizing synergistic effects of these biomarkers. The INFLA-score was negatively associated with PAC-score in different levels of adjustment, in both genders (for all β-coefinflammation status (i.e. higher quartile of INFLA-score) in men and women (odds ratio [ORs] 0.92 to 0.95, pinflammation biomarkers in a large population based study. For the first time low-grade inflammation was evaluated in a holistic way through INFLA-score and was associated with polyphenol content of diet.
Chen, Yi-Hau; Chatterjee, Nilanjan; Carroll, Raymond J
Genetic epidemiologic studies often involve investigation of the association of a disease with a genomic region in terms of the underlying haplotypes, that is the combination of alleles at multiple loci along homologous chromosomes. In this article, we consider the problem of estimating haplotype-environment interactions from case-control studies when some of the environmental exposures themselves may be influenced by genetic susceptibility. We specify the distribution of the diplotypes (haplotype pair) given environmental exposures for the underlying population based on a novel semiparametric model that allows haplotypes to be potentially related with environmental exposures, while allowing the marginal distribution of the diplotypes to maintain certain population genetics constraints such as Hardy-Weinberg equilibrium. The marginal distribution of the environmental exposures is allowed to remain completely nonparametric. We develop a semiparametric estimating equation methodology and related asymptotic theory for estimation of the disease odds ratios associated with the haplotypes, environmental exposures, and their interactions, parameters that characterize haplotype-environment associations and the marginal haplotype frequencies. The problem of phase ambiguity of genotype data is handled using a suitable expectation-maximization algorithm. We study the finite-sample performance of the proposed methodology using simulated data. An application of the methodology is illustrated using a case-control study of colorectal adenoma, designed to investigate how the smoking-related risk of colorectal adenoma can be modified by "NAT2," a smoking-metabolism gene that may potentially influence susceptibility to smoking itself.
Reilly, Dermot; Hao, Ke; Jensen, Majken K; Girman, Cynthia J; Rimm, Eric B
With the advance of genome-wide association studies and newly identified SNP (single-nucleotide polymorphism) associations with complex disease, important discoveries have emerged focusing not only on individual genes but on disease-associated pathways and gene sets. The authors used prospective myocardial infarction case-control studies nested in the Nurses' Health and Health Professionals Follow-Up Studies to investigate genetic variants associated with myocardial infarction or LDL, HDL, triglycerides, adiponectin and apolipoprotein B (apoB). Using these case-control studies to illustrate an integrative systems biology approach, the authors applied SNP set enrichment analysis to identify gene sets where expression SNPs representing genes from these sets show enrichment in their association with endpoints of interest. The authors also explored an aggregate score approach. While power limited one's ability to detect significance for association of individual loci with myocardial infarction, the authors found significance for loci associated with LDL, HDL, apoB and triglycerides, replicating previous observations. Applying SNP set enrichment analysis and risk score methods, the authors also found significance for three gene sets and for aggregate scores associated with myocardial infarction as well as for loci-related to cardiovascular risk factors, supporting the use of these methods in practice.
Lurie, Galina; Wilkens, Lynne R; Thompson, Pamela J
The association of invasive ovarian carcinoma risk with the functional polymorphism rs2228570 (aka rs10735810; FokI polymorphism) in the vitamin D receptor (VDR) gene was examined in 1820 white non-Hispanic cases and 3479 controls in a pooled analysis of five population-based case-control studies...... analysis provides further evidence that the VDR rs2228570 polymorphism might influence ovarian cancer susceptibility....
Bind, Marie-Abele; Lepeule, Johanna; Zanobetti, Antonella; Gasparrini, Antonio; Baccarelli, Andrea; Coull, Brent A; Tarantini, Letizia; Vokonas, Pantel S; Koutrakis, Petros; Schwartz, Joel
The mechanisms by which air pollution has multiple systemic effects in humans are not fully elucidated, but appear to include inflammation and thrombosis. This study examines whether concentrations of ozone and components of fine particle mass are associated with changes in methylation on tissue factor (F3), interferon gamma (IFN-γ), interleukin 6 (IL-6), toll-like receptor 2 (TLR-2), and intercellular adhesion molecule 1 (ICAM-1). We investigated associations between air pollution exposure and gene-specific methylation in 777 elderly men participating in the Normative Aging Study (1999-2009). We repeatedly measured methylation at multiple CpG sites within each gene's promoter region and calculated the mean of the position-specific measurements. We examined intermediate-term associations between primary and secondary air pollutants and mean methylation and methylation at each position with distributed-lag models. Increase in air pollutants concentrations was significantly associated with F3, ICAM-1, and TLR-2 hypomethylation, and IFN-γ and IL-6 hypermethylation. An interquartile range increase in black carbon concentration averaged over the four weeks prior to assessment was associated with a 12% reduction in F3 methylation (95% CI: -17% to -6%). For some genes, the change in methylation was observed only at specific locations within the promoter region. DNA methylation may reflect biological impact of air pollution. We found some significant mediated effects of black carbon on fibrinogen through a decrease in F3 methylation, and of sulfate and ozone on ICAM-1 protein through a decrease in ICAM-1 methylation.
Carty, Cara L.; Keene, Keith L.; Cheng, Yu-Ching; Meschia, James F.; Chen, Wei-Min; Nalls, Mike; Bis, Joshua C.; Kittner, Steven J.; Rich, Stephen S.; Tajuddin, Salman; Zonderman, Alan B.; Evans, Michele K.; Langefeld, Carl D.; Gottesman, Rebecca; Mosley, Thomas H.; Shahar, Eyal; Woo, Daniel; Yaffe, Kristine; Liu, YongMei; Sale, Michèle M.; Dichgans, Martin; Malik, Rainer; Longstreth, WT; Mitchell, Braxton D.; Psaty, Bruce M.; Kooperberg, Charles; Reiner, Alexander; Worrall, Bradford B.; Fornage, Myriam
Background and Purpose The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African-Americans despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population genome-wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations. Methods Using METAL, we conducted meta-analyses of GWAS in 14,746 African-Americans (1,365 ischemic and 1,592 total stroke cases) from COMPASS, and tested SNPs with P<10−6 for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations. Results The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613, P=3.9×10−8) in African-Americans. Nominal associations (P<10−6) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/ mRNA pre-splicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS. Conclusions We identified a novel SNP associated with total stroke in African-Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African-Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations. PMID:26089329
Siddiq, Afshan; Couch, Fergus J.; Chen, Gary K.; Lindström, Sara; Eccles, Diana; Millikan, Robert C.; Michailidou, Kyriaki; Stram, Daniel O.; Beckmann, Lars; Rhie, Suhn Kyong; Ambrosone, Christine B.; Aittomäki, Kristiina; Amiano, Pilar; Apicella, Carmel; Baglietto, Laura; Bandera, Elisa V.; Beckmann, Matthias W.; Berg, Christine D.; Bernstein, Leslie; Blomqvist, Carl; Brauch, Hiltrud; Brinton, Louise; Bui, Quang M.; Buring, Julie E.; Buys, Saundra S.; Campa, Daniele; Carpenter, Jane E.; Chasman, Daniel I.; Chang-Claude, Jenny; Chen, Constance; Clavel-Chapelon, Françoise; Cox, Angela; Cross, Simon S.; Czene, Kamila; Deming, Sandra L.; Diasio, Robert B.; Diver, W. Ryan; Dunning, Alison M.; Durcan, Lorraine; Ekici, Arif B.; Fasching, Peter A.; Feigelson, Heather Spencer; Fejerman, Laura; Figueroa, Jonine D.; Fletcher, Olivia; Flesch-Janys, Dieter; Gaudet, Mia M.; Gerty, Susan M.; Rodriguez-Gil, Jorge L.; Giles, Graham G.; van Gils, Carla H.; Godwin, Andrew K.; Graham, Nikki; Greco, Dario; Hall, Per; Hankinson, Susan E.; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Hoover, Robert N.; Hopper, John L.; Hu, Jennifer J.; Huntsman, Scott; Ingles, Sue A.; Irwanto, Astrid; Isaacs, Claudine; Jacobs, Kevin B.; John, Esther M.; Justenhoven, Christina; Kaaks, Rudolf; Kolonel, Laurence N.; Coetzee, Gerhard A.; Lathrop, Mark; Le Marchand, Loic; Lee, Adam M.; Lee, I.-Min; Lesnick, Timothy; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Martin, Nicholas G.; McLean, Catriona A.; Meijers-Heijboer, Hanne; Meindl, Alfons; Miron, Penelope; Monroe, Kristine R.; Montgomery, Grant W.; Müller-Myhsok, Bertram; Nickels, Stefan; Nyante, Sarah J.; Olswold, Curtis; Overvad, Kim; Palli, Domenico; Park, Daniel J.; Palmer, Julie R.; Pathak, Harsh; Peto, Julian; Pharoah, Paul; Rahman, Nazneen; Rivadeneira, Fernando; Schmidt, Daniel F.; Schmutzler, Rita K.; Slager, Susan; Southey, Melissa C.; Stevens, Kristen N.; Sinn, Hans-Peter; Press, Michael F.; Ross, Eric; Riboli, Elio; Ridker, Paul M.; Schumacher, Fredrick R.; Severi, Gianluca; dos Santos Silva, Isabel; Stone, Jennifer; Sund, Malin; Tapper, William J.; Thun, Michael J.; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Waisfisz, Quinten; Wang, Xianshu; Wang, Zhaoming; Weaver, Joellen; Schulz-Wendtland, Rüdiger; Wilkens, Lynne R.; van den Berg, David; Zheng, Wei; Ziegler, Regina G.; Ziv, Elad; Nevanlinna, Heli; Easton, Douglas F.; Hunter, David J.; Henderson, Brian E.; Chanock, Stephen J.; Garcia-Closas, Montserrat; Kraft, Peter; Haiman, Christopher A.; Vachon, Celine M.
Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of
Verhoeven, Virginie J. M.; Hysi, Pirro G.; Saw, Seang-Mei; Vitart, Veronique; Mirshahi, Alireza; Guggenheim, Jeremy A.; Cotch, Mary Frances; Yamashiro, Kenji; Baird, Paul N.; Mackey, David A.; Wojciechowski, Robert; Ikram, M. Kamran; Hewitt, Alex W.; Duggal, Priya; Janmahasatian, Sarayut; Khor, Chiea-Chuen; Fan, Qiao; Zhou, Xin; Young, Terri L.; Tai, E.-Shyong; Goh, Liang-Kee; Li, Yi-Ju; Aung, Tin; Vithana, Eranga; teo, Yik-Ying; Tay, Wanting; Sim, Xueling; Rudan, Igor; Hayward, Caroline; Wright, Alan F.; Polasek, Ozren; Campbell, Harry; Wilson, James F.; Fleck, Brian W.; Nakata, Isao; Yoshimura, Nagahisa; Yamada, Ryo; Matsuda, Fumihiko; Ohno-Matsui, Kyoko; Nag, Abhishek; McMahon, George; St Pourcain, Beate; Lu, Yi; Rahi, Jugnoo S.; Cumberland, Phillippa M.; Bhattacharya, Shomi; Simpson, Claire L.; Atwood, Larry D.; Li, Xiaohui; Raffel, Leslie J.; Murgia, Federico; Portas, Laura; Despriet, Dominiek D. G.; van Koolwijk, Leonieke M. E.; Wolfram, Christian; Lackner, Karl J.; Tönjes, Anke; Mägi, Reedik; Lehtimäki, Terho; Kähönen, Mika; Esko, Tõnu; Metspalu, Andres; Rantanen, Taina; Pärssinen, Olavi; Klein, Barbara E.; Meitinger, Thomas; Spector, Timothy D.; Oostra, Ben A.; Smith, Albert V.; de Jong, Paulus T. V. M.; Hofman, Albert; Amin, Najaf; Karssen, Lennart C.; Rivadeneira, Fernando; Vingerling, Johannes R.; Eiríksdóttir, Guðný; Gudnason, Vilmundur; Döring, Angela; Bettecken, Thomas; Uitterlinden, André G.; Williams, Cathy; Zeller, Tanja; Castagné, Raphaële; Oexle, Konrad; van Duijn, Cornelia M.; Iyengar, Sudha K.; Mitchell, Paul; Wang, Jie Jin; Höhn, René; Pfeiffer, Norbert; Bailey-Wilson, Joan E.; Stambolian, Dwight; Wong, Tien-Yin; Hammond, Christopher J.; Klaver, Caroline C. W.
Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis
Jafari Nedooshan, Jamal; Kargar, Saeed; Neamatzadeh, Hossein; Haghighi, Fatemeh; Dehghani Mohammad Abadi, Reihaneh; Seddighi, Niloofar
Background: Previously published data on any association of the fat mass and obesity-associated (FTO) gene with breast cancer risk remain inconclusive. Therefore, we conducted the present meta-analysis of links between breast cancer and the FTO rs9939609 polymorphism. Methods: We have conducted a systematic review of the English literature by searching PubMed, Google Scholar and ISI Web of Knowledge databases for studies on associations between the FTO rs9939609 polymorphism and breast cancer risk. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association using fixed- or random-effects model. Results: We included five studies with 1134 cases and 1453 controls. Overall, no significant association between the FTO rs9939609 polymorphism and risk of breast cancer was found. On subgroup analysis by ethnicity, there was still no significant association detected. Conclusions: To our knowledge, this is the first meta-analysis of the FTO rs9939609 polymorphism and risk of breast cancer. However, the present meta-analysis suggested that only there might be a significant association of the CXCL12 rs1801157 polymorphisms with breast cancer risk. Creative Commons Attribution License
Szulc, Pawel; Boutroy, Stéphanie; Vilayphiou, Nicolas; Chaitou, Ali; Delmas, Pierre D; Chapurlat, Roland
Areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry (DXA) identifies 20% of men who will sustain fragility fractures. Thus we need better fracture predictors in men. We assessed the association between the low-trauma prevalent fractures and bone microarchitecture assessed at the distal radius and tibia by high-resolution peripheral quantitative computed tomography (HR-pQCT) in 920 men aged 50 years of older. Ninety-eight men had vertebral fractures identified on the vertebral fracture assessment software of the Hologic Discovery A device using the semiquantitative criteria, whereas 100 men reported low-trauma peripheral fractures. Men with vertebral fractures had poor bone microarchitecture. However, in the men with vertebral fractures, only cortical volumetric density (D.cort) and cortical thickness (C.Th) remained significantly lower at both the radius and tibia after adjustment for aBMD of ultradistal radius and hip, respectively. Low D.cort and C.Th were associated with higher prevalence of vertebral fractures regardless of aBMD. Severe vertebral fractures also were associated with poor trabecular microarchitecture regardless of aBMD. Men with peripheral fractures had poor bone microarchitecture. However, after adjustment for aBMD, all microarchitectural parameters became nonsignificant. In 15 men with multiple peripheral fractures, trabecular spacing and distribution remained increased after adjustment for aBMD. Thus, in men, vertebral fractures and their severity are associated with impaired cortical bone, even after adjustment for aBMD. The association between peripheral fractures and bone microarchitecture was weaker and nonsignificant after adjustment for aBMD. Thus bone microarchitecture may be a determinant of bone fragility in men, which should be investigated in prospective studies. Copyright © 2011 American Society for Bone and Mineral Research.
Turner, Adam W.; Martinuk, Amy; Silva, Anada
growth factor-β pathway signaling. Here, we seek to identify ≥1 causal coronary artery disease–associated single nucleotide polymorphisms at the SMAD3 locus and characterize mechanisms whereby the risk allele(s) contribute to coronary artery disease risk. APPROACH AND RESULTS—: By genetic and epigenetic......OBJECTIVE—: A recent genome-wide association study meta-analysis identified an intronic single nucleotide polymorphism in SMAD3, rs56062135C>T, the minor allele (T) which associates with protection from coronary artery disease. Relevant to atherosclerosis, SMAD3 is a key contributor to transforming...
Fan, Qiao; Wojciechowski, Robert; Kamran Ikram, M; Cheng, Ching-Yu; Chen, Peng; Zhou, Xin; Pan, Chen-Wei; Khor, Chiea-Chuen; Tai, E-Shyong; Aung, Tin; Wong, Tien-Yin; Teo, Yik-Ying; Saw, Seang-Mei
Refractive error is a complex ocular trait governed by both genetic and environmental factors and possibly their interplay. Thus far, data on the interaction between genetic variants and environmental risk factors for refractive errors are largely lacking. By using findings from recent genome-wide association studies, we investigated whether the main environmental factor, education, modifies the effect of 40 single nucleotide polymorphisms on refractive error among 8461 adults from five studies including ethnic Chinese, Malay and Indian residents of Singapore. Three genetic loci SHISA6-DNAH9, GJD2 and ZMAT4-SFRP1 exhibited a strong association with myopic refractive error in individuals with higher secondary or university education (SHISA6-DNAH9: rs2969180 A allele, β = -0.33 D, P = 3.6 × 10(-6); GJD2: rs524952 A allele, β = -0.31 D, P = 1.68 × 10(-5); ZMAT4-SFRP1: rs2137277 A allele, β = -0.47 D, P = 1.68 × 10(-4)), whereas the association at these loci was non-significant or of borderline significance in those with lower secondary education or below (P for interaction: 3.82 × 10(-3)-4.78 × 10(-4)). The evidence for interaction was strengthened when combining the genetic effects of these three loci (P for interaction = 4.40 × 10(-8)), and significant interactions with education were also observed for axial length and myopia. Our study shows that low level of education may attenuate the effect of risk alleles on myopia. These findings further underline the role of gene-environment interactions in the pathophysiology of myopia.
Nappo, A; González-Gil, E M; Ahrens, W; Bammann, K; Michels, N; Moreno, L A; Kourides, Y; Iacoviello, L; Mårild, S; Fraterman, A; Molnàr, D; Veidebaum, T; Siani, A; Russo, P
Adipokines may play a role in the pathogenesis of the metabolic syndrome (MetS) in children. We aimed to evaluate the association of leptin, adiponectin, and its ratio (L/A ratio) with the metabolic syndrome (MetS) in a subsample of the IDEFICS (Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS) cohort. Leptin, adiponectin and MetS parameters were measured in a subsample of 1253 children (3-9.9 years) participating to the IDEFICS study, grouped as: Non-OW (underweight/normal weight) and OW/Ob (overweight/obese). MetS was defined using the sex- and age-specific cut-offs based on the distribution of MetS components in the IDEFICS cohort. The prevalence of the MetS among OW/Ob was 24.8% and 27.1% in boys and girls respectively, whereas ≤2% among Non-OW. OW/Ob had significantly higher leptin and L/A ratio as compared to Non-OW. Significantly higher leptin was found in OW/Ob with MetS as compared with OW/Ob without MetS. Significantly lower adiponectin was observed only in OW/Ob girls as compared to Non-OW. A 1SD increase in leptin and L/A ratio z-scores or a 1SD decrease in adiponectin z-score were significantly associated with higher risk of MetS. After adjustment for BMI or body fat mass (BFM) the association remained significant only for leptin. We showed that in European children, higher leptin concentration is associated with MetS, even after adjusting for BMI or BFM, confirming an early role of leptin in MetS, while the association of adiponectin with MetS seems be mediated by body fat in this age range. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.
van der Kooi, Anne-Lotte L F; Snijder, Marieke B; Peters, Ron J G; van Valkengoed, Irene G M
We investigated whether ethnic differences in handgrip strength, a marker of poor muscle strength and quality, is a potential cause of ethnic disparities in type 2 diabetes mellitus. We included 2086 Dutch, 2216 South Asian Surinamese, 2084 African Surinamese, 1786 Ghanaian, 2223 Turkish and 2199 Moroccan origin participants from the HELIUS study. We analyzed ethnic differences in handgrip strength, and its association with type 2 diabetes mellitus using logistic regression analyses adjusted for socio-demographic factors, body composition and lifestyle factors. Additionally, we investigated whether handgrip strength explained the ethnic differences in type 2 diabetes mellitus. We found that handgrip strength differed significantly across ethnic groups. After full adjustment, we found an inverse association with type 2 diabetes mellitus (OR 0.95; 95% CI 0.92-0.97) that did not differ substantially between ethnic groups, men and among women, and lean and overweight individuals. The association was not affected by the measure used to define type 2 diabetes mellitus, but was attenuated by exclusion of people with known diabetes. The ethnic differences in type 2 diabetes mellitus were not explained by handgrip strength (e.g. the OR for the South Asian Surinamese vs. Dutch changed from 5.03; 3.69-6.68 to 4.87; 3.57-6.65). In conclusion, we found large ethnic differences in handgrip strength and a consistent association of low handgrip strength with prevalent type 2 diabetes mellitus. This suggests that handgrip strength may be investigated as a target for intervention or a marker to identify people at risk of type 2 diabetes mellitus.
Mägi, Reedik; Suleimanov, Yury V; Clarke, Geraldine M; Kaakinen, Marika; Fischer, Krista; Prokopenko, Inga; Morris, Andrew P
Genome-wide association studies (GWAS) of single nucleotide polymorphisms (SNPs) have been successful in identifying loci contributing genetic effects to a wide range of complex human diseases and quantitative traits. The traditional approach to GWAS analysis is to consider each phenotype separately, despite the fact that many diseases and quantitative traits are correlated with each other, and often measured in the same sample of individuals. Multivariate analyses of correlated phenotypes have been demonstrated, by simulation, to increase power to detect association with SNPs, and thus may enable improved detection of novel loci contributing to diseases and quantitative traits. We have developed the SCOPA software to enable GWAS analysis of multiple correlated phenotypes. The software implements "reverse regression" methodology, which treats the genotype of an individual at a SNP as the outcome and the phenotypes as predictors in a general linear model. SCOPA can be applied to quantitative traits and categorical phenotypes, and can accommodate imputed genotypes under a dosage model. The accompanying META-SCOPA software enables meta-analysis of association summary statistics from SCOPA across GWAS. Application of SCOPA to two GWAS of high-and low-density lipoprotein cholesterol, triglycerides and body mass index, and subsequent meta-analysis with META-SCOPA, highlighted stronger association signals than univariate phenotype analysis at established lipid and obesity loci. The META-SCOPA meta-analysis also revealed a novel signal of association at genome-wide significance for triglycerides mapping to GPC5 (lead SNP rs71427535, p = 1.1x10-8), which has not been reported in previous large-scale GWAS of lipid traits. The SCOPA and META-SCOPA software enable discovery and dissection of multiple phenotype association signals through implementation of a powerful reverse regression approach.
Wangdee, C; Leegwater, P A J; Heuven, H C M; van Steenbeek, F G; Techakumphu, M; Hazewinkel, H A W
The genetics of patellar luxation (PL) were investigated in Pomeranian dogs presented at the Small Animal Hospital, Faculty of Veterinary Science, Chulalongkorn University. A cohort of 339 Pomeranian dogs, part of a four-generation pedigree of 842 Pomeranians, was screened for PL from 2006 to 2013. PL was present in 77% of the screened dogs, with 84% having bilateral and 16% unilateral luxation. Medial PL was more common (95%) than lateral PL (2%) or bidirectional PL (3%). The risk of PL was similar in male and female dogs (female:male relative risk 1.11, 95% CI 0.98-1.25). The heritability of PL in the screened population was 0.44±0.04 using a threshold model. A genome-wide association study of PL (48 cases and 48 controls) using a high-density SNP array indicated the possible involvement of 15 chromosomal regions, of which CFA05 and CFA32 remained associated in a larger study involving an additional 128 cases and 7 controls. Candidate genes in these regions may be involved in the pathogenesis of PL in Pomeranian dogs. Copyright © 2016 Elsevier Ltd. All rights reserved.
Full Text Available The objective of this study was to spatially analyze total trihalomethanes (TTHMs and health risk associated with TTHMs in drinking water of different densely populated towns of Karachi city. Lifetime cancer risk and hazard index of THMs through oral ingestion and dermal absorption were calculated and mapped using kriging as an interpolation method to evaluate the carcinogenic and noncarcinogenic risk to human health in the study area. Lifetime cancer risk value due to the oral ingestion of TTHMs in different towns of the city was exceeded from 1.0×10−6, showing that residents of these towns were expected to be at higher cancer risk. The hazard index for different towns was found to be lower than unity, indicating that no adverse health effects are expected as a result of exposure to THMs.
Li, Weilong; Baumbach, Jan; Christiansen, Lene
Background Identical twin pairs discordant for a disease have been widely used in epigenome-wide association studies (EWAS) of complex diseases because the underlying genetic background is cancelled out. Although the twin design is deemed to have enriched power as compared with ordinary case......-control design, its statistical power has not been well investigated. Methods We perform a computer simulation study on the power of the disease discordant twin design assuming that both genetic and environmental factors contribute to the liability of a disease phenotype. Power is assessed under different levels...... with moderate effect and for diseases with heritability>0.3. The power advantage in discordant twin design becomes more obvious with increasing heritability. For diseases with no genetic background, the twin design is slightly underpowered, while for high heritability (0.5), high intrapair methylation...
Full Text Available BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR is an important enzyme of folate and methionine metabolism, making it crucial for DNA synthesis and methylation. The objective of this study was to analyze MTHFR gene 677C>T polymorphism in infertile male individuals from North India, followed by a meta-analysis on our data and published studies. METHODOLOGY/PRINCIPAL FINDINGS: We undertook genotyping on a total of 837 individuals including well characterized infertile (N = 522 and confirmed fertile (N = 315 individuals. The SNP was typed by direct DNA sequencing. Chi square test was done for statistical analysis. Published studies were searched using appropriate keywords. Source of data collection for meta-analysis included 'Pubmed', 'Ovid' and 'Google Scholar'. Those studies analyzing 677C>T polymorphism in male infertility and presenting all relevant data were included in meta-analysis. The genotype data for infertile subjects and fertile controls was extracted from each study. Chi square test was done to obtain odds ratio (OR and p-value. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2. The frequency of mutant (T allele (p = 0.0025 and genotypes (CT+TT (p = 0.0187 was significantly higher in infertile individuals in comparison to fertile controls in our case-control study. The overall summary estimate (OR for allele and genotype meta-analysis were 1.304 (p = 0.000, 1.310 (p = 0.000, respectively, establishing significant association of 677C>T polymorphism with male infertility. CONCLUSIONS/SIGNIFICANCE: 677C>T substitution associated strongly with male infertility in Indian population. Allele and genotype meta-analysis also supported its strong correlation with male infertility, thus establishing it as a risk factor.
Full Text Available Aims. Genetic association studies have reported the E23K variant of KCNJ11 gene to be associated with Type 2 diabetes. In Arab populations, only four studies have investigated the role of this variant. We aimed to replicate and validate the association between the E23K variant and Type 2 diabetes in Tunisian and Arab populations. Methods. We have performed a case-control association study including 250 Tunisian patients with Type 2 diabetes and 267 controls. Allelic association has also been evaluated by 2 meta-analyses including all population-based studies among Tunisians and Arabs (2 and 5 populations, resp.. Results. A significant association between the E23K variant and Type 2 diabetes was found (OR = 1.6, 95% CI = 1.14–2.27, and P=0.007. Furthermore, our meta-analysis has confirmed the significant role of the E23K variant in susceptibility of Type 2 diabetes in Tunisian and Arab populations (OR = 1.29, 95% CI = 1.15–1.46, and P<10-3 and OR = 1.33, 95% CI = 1.13–1.56, and P=0.001, resp.. Conclusion. Both case-control and meta-analyses results revealed the significant association between the E23K variant of KCNJ11 and Type 2 diabetes among Tunisians and Arabs.
Full Text Available OBJECTIVE: Cyclooxygenase-2 (COX-2 is an inducible enzyme converting arachidonic acid to prostaglandins and playing important roles in inflammatory diseases as well as tumor development. Previous studies investigating the association between COX-2 polymorphisms and colorectal cancer (CRC risk reported conflicting results. We performed a meta-analysis of all available studies to explore this association. METHODS: All studies published up to October 2013 on the association between COX-2 polymorphisms and CRC risk were identified by searching electronic databases PubMed, EMBASE, and Cochrane library. The association between COX-2 polymorphisms and CRC risk was assessed by odds ratios (ORs together with their 95% confidence intervals (CIs. RESULTS: Ten studies with 6,774 cases and 9,772 controls were included for -1195A>G polymorphism, 13 studies including 6,807 cases and 10,052 controls were available for -765G>C polymorphism, and 8 studies containing 5,121 cases and 7,487 controls were included for 8473T>C polymorphism. With respect to -765G>C polymorphism, we did not find a significant association with CRC risk when all eligible studies were pooled into the meta-analysis. However, in subgroup analyses by ethnicity and cancer location, with a Bonferroni corrected alpha of 0.05/2, statistical significant increased CRC risk was found in the Asian populations (dominant model CC+CG vs. GG: OR = 1.399, 95%CI: 1.113-1.760, P = 0.004 and rectum cancer patients (CC vs. GG: OR = 2.270, 95%CI: 1.295-3.980, P = 0.004; Recessive model CC vs. CG+GG: OR = 2.269, 95%CI: 1.297-3.970, P = 0.004. In subgroup analysis according to source of control, no significant association was detected. With respect to -1195A>G and 8473T>C polymorphisms, no significant association with CRC risk was demonstrated in the overall and subgroup analyses. CONCLUSIONS: The present meta-analysis suggests that the COX-2 -765G>C polymorphism may be a risk factor for
Moradi, Sajjad; Shab-Bidar, Sakineh; Alizadeh, Shahab; Djafarian, Kurosh
Increasing evidence has suggested an association between sleep duration and osteoporosis risk, although the results of previous studies have been inconsistent. To our knowledge, this is the first meta-analysis of the literature and quantitative estimates of the association between sleep duration and risk of osteoporosis in population-based studies of middle aged and elderly women. Pertinent studies were identified by searching PubMed and EMBASE databases up to February 2016. Five out of six included studies were cross-sectional and one was a prospective cohort study. They included 72,326 participants from three different countries. We extracted 31,625 individuals in these studies for our meta-analysis. A pooled odds ratio analysis in women between 40 to 86years indicated that there is an inverse relationship between sleep duration and osteoporosis (overall OR =1.07 95% CI: 1.00-1.15). The negative association of long sleep duration (8h or more per day) with osteoporosis risk was observed in middle aged and elderly women (OR =1.22, 95% CI: 1.06-1.38) but not in women with short sleep duration (7h or less per day) (OR =0.98, 95% CI: 0.90-1.05). This meta-analysis suggests that long sleep duration (8h or more per day) may be associated with a higher risk of osteoporosis in middle-aged and elderly. Further prospective cohort studies with longer follow-up periods, valid instruments for measurement of sleep duration and dynamic sleep quality are warranted to support the possible relationship between sleep duration and osteoporosis risk in women. Copyright © 2017 Elsevier Inc. All rights reserved.
Zhang, Yin; Xie, Yan-Ming; Chen, Cen; Zhang, Chang; Zhuang, Yan
Fufang Kushen injection is used in real world clinical situations to treat different types of malignant tumors. The present study aimed to analyze the association rules of Fufang Kushen injection in combination with other traditional Chinese medicine(TCM) or modern medications in treating malignant tumors based on the electrical medical records extracted from real-world hospital information system. This real world retrospective analysis was based on the clinicians' prescriptions regarding to such treatment by combined TCM and modern medications. Hospital information system data from 22 hospitals, including electrical medical records of 44 588 patients with malignant tumors and Fufang Kushen injection were included in this study, providing useful reference for the development of clinical treatment ideas, and providing reference for clinical rational use of Fufang Kushen injection. High correlation and causal relations were not present in this study, so further exploration and analysis were still needed for the conclusion. Copyright© by the Chinese Pharmaceutical Association.
Praestegaard, C.; Jensen, A.; Jensen, S.M.; Nielsen, T.S.; Webb, P.M.; Nagle, C.M.; Defazio, A.; Hogdall, E.; Rossing, M.A.; Doherty, J.A.; Wicklund, K.G.; Goodman, M.T.; Modugno, F.; Moysich, K.; Ness, R.B.; Edwards, R.; Matsuo, K.; Hosono, S.; Goode, E.L.; Winham, S.J.; Fridley, B.L.; Cramer, D.W; Terry, K.L.; Schildkraut, J.M.; Berchuck, A.; Bandera, E.V.; Paddock, L.E.; Massuger, L.F.A.G.; Wentzensen, N.; Pharoah, P.; Song, H.; Whittemore, A.; McGuire, V.; Sieh, W.; Rothstein, J.; Anton-Culver, H.; Ziogas, A.; Menon, U.; Gayther, S.A.; Ramus, S.J.; Gentry-Maharaj, A.; Wu, A.H.; Pearce, C.L.; Pike, M.; Lee, A.W.; Sutphen, R.; Chang-Claude, J.; Risch, H.A.; Kjaer, S.K.
Cigarette smoking is associated with an increased risk of developing mucinous ovarian tumors but whether it is associated with ovarian cancer survival overall or for the different histotypes is unestablished. Furthermore, it is unknown whether the association between cigarette smoking and survival
Moutsianas, Loukas; Morris, Andrew P
Genome-wide association studies have been successful in identifying common variants that impact complex human traits and diseases. However, despite this success, the joint effects of these variants explain only a small proportion of the genetic variance in these phenotypes, leading to speculation that rare genetic variation might account for much of the 'missing heritability'. Consequently, there has been an exciting period of research and development into the methodology for the analysis of rare genetic variants, typically by considering their joint effects on complex traits within the same functional unit or genomic region. In this review, we describe a general framework for modelling the joint effects of rare genetic variants on complex traits in association studies of unrelated individuals. We summarise a range of widely used association tests that have been developed from this model and provide an overview of the relative performance of these approaches from published simulation studies. © The Author 2014. Published by Oxford University Press.
Iris M Heid
Full Text Available The INSIG2 rs7566605 polymorphism was identified for obesity (BMI> or =30 kg/m(2 in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345, including general population (GP studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP, and obesity studies (OB. We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213 combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR of 1.05 (p-value = 0.27. The I(2 measure of 41% (p-value = 0.015 indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I(2 measure of 11% (p-value = 0.33 and an OR of 1.10 (p-value = 0.015. Regarding the five hypotheses, our data showed (a some difference between GP and HP studies (p-value = 0.012 and (b an association in extreme comparisons (BMI> or =32.5, 35.0, 37.5, 40.0 kg/m(2 versus BMI<25 kg/m(2 yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003, which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002. We did not find evidence for differential ORs (c among studies with higher than average obesity prevalence compared to lower, (d among studies with BMI assessment after the year 2000 compared to those before, or (e among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889 or children (n = 3243 yielded ORs of 1.01 (p-value = 0.94 or 1.15 (p-value = 0.22, respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may
Rusconi, Anna Carlotta; Valeriani, Giuseppe; Carlone, Cristiano; Raimondo, Pasquale; Quartini, Adele; Coccanari de' Fornari, Maria Antonietta; Biondi, Massimo
Internet Addiction Disorder (IAD) is an emerging psychiatric disorder, assimilable to impulse control problems and related to maladaptive use of new networks and social and virtual technologies. Our study aims to analyze the presence of IAD among adolescents and to study the correlation with social interaction anxiousness. We investigated also the possibility that the Social Network (SN) represent a source of risk for the development of IAD. The test group was composed of 250 subjects, aged between 14 and 18 years. They were administered: Young's IAT; IAS (Interaction Anxiousness Scale), AAS (Audience Anxiousness Scale) and SISST (Social Interaction Self-Statement Test) to analyze the dimension of social interaction anxiousness. We found a rate of 2% of the IAD. The SN are the most common use of the Net in our sample, but not the most clicked sites by subjects with IAD. It should be noted, finally, a correlation between social interaction anxiety and IAD, but not a significant difference in scores of social anxiousness scales based on the SN use/non-use. The use of SN intended as single variable doesn't correlate with increased risk for IAD, or for increased social interaction anxiousness. However, if associated with prolonged use of the net for 5-6 hours or more, or concomitant use of chat rooms and/or net gambling, we find a more significant risk of psychopathology. The data presented require further investigations, in order to guide new pathogenetic models and appropriate intervention strategies.
Chaix, Basile; Bean, Kathy; Daniel, Mark; Zenk, Shannon N; Kestens, Yan; Charreire, Hélène; Leal, Cinira; Thomas, Frédérique; Karusisi, Noëlla; Weber, Christiane; Oppert, Jean-Michel; Simon, Chantal; Merlo, Juan; Pannier, Bruno
Previous research on the influence of the food environment on weight status has often used impersonal measures of the food environment defined for residential neighborhoods, which ignore whether people actually use the food outlets near their residence. To assess whether supermarkets are relevant contexts for interventions, the present study explored between-residential neighborhood and between-supermarket variations in body mass index (BMI) and waist circumference (WC), and investigated associations between brands and characteristics of supermarkets and BMI or WC, after adjustment for individual and residential neighborhood characteristics. Participants in the RECORD Cohort Study (Paris Region, France, 2007-2008) were surveyed on the supermarket (brand and exact location) where they conducted their food shopping. Overall, 7 131 participants shopped in 1 097 different supermarkets. Cross-classified multilevel linear models were estimated for BMI and WC. Just 11.4% of participants shopped for food primarily within their residential neighborhood. After accounting for participants' residential neighborhood, people shopping in the same supermarket had a more comparable BMI and WC than participants shopping in different supermarkets. After adjustment for individual and residential neighborhood characteristics, participants shopping in specific supermarket brands, in hard discount supermarkets (especially if they had a low education), and in supermarkets whose catchment area comprised low educated residents had a higher BMI/WC. A public health strategy to reduce excess weight may be to intervene on specific supermarkets to change food purchasing behavior, as supermarkets are where dietary preferences are materialized into definite purchased foods.
Full Text Available Previous research on the influence of the food environment on weight status has often used impersonal measures of the food environment defined for residential neighborhoods, which ignore whether people actually use the food outlets near their residence. To assess whether supermarkets are relevant contexts for interventions, the present study explored between-residential neighborhood and between-supermarket variations in body mass index (BMI and waist circumference (WC, and investigated associations between brands and characteristics of supermarkets and BMI or WC, after adjustment for individual and residential neighborhood characteristics.Participants in the RECORD Cohort Study (Paris Region, France, 2007-2008 were surveyed on the supermarket (brand and exact location where they conducted their food shopping. Overall, 7 131 participants shopped in 1 097 different supermarkets. Cross-classified multilevel linear models were estimated for BMI and WC.Just 11.4% of participants shopped for food primarily within their residential neighborhood. After accounting for participants' residential neighborhood, people shopping in the same supermarket had a more comparable BMI and WC than participants shopping in different supermarkets. After adjustment for individual and residential neighborhood characteristics, participants shopping in specific supermarket brands, in hard discount supermarkets (especially if they had a low education, and in supermarkets whose catchment area comprised low educated residents had a higher BMI/WC.A public health strategy to reduce excess weight may be to intervene on specific supermarkets to change food purchasing behavior, as supermarkets are where dietary preferences are materialized into definite purchased foods.
Full Text Available Understanding the spatial point pattern of human settlements and their geographical associations are important for understanding the drivers of land use and land cover change and the relationship between environmental and ecological processes on one hand and cultures and lifestyles on the other. In this study, a Geographic Information System (GIS approach, Ripley’s K function and Monte Carlo simulation were used to investigate human settlement point patterns. Remotely sensed tools and regression models were employed to identify the effects of geographical determinants on settlement locations in the Wen-Tai region of eastern coastal China. Results indicated that human settlements displayed regular-random-cluster patterns from small to big scale. Most settlements located on the coastal plain presented either regular or random patterns, while those in hilly areas exhibited a clustered pattern. Moreover, clustered settlements were preferentially located at higher elevations with steeper slopes and south facing aspects than random or regular settlements. Regression showed that influences of topographic factors (elevation, slope and aspect on settlement locations were stronger across hilly regions. This study demonstrated a new approach to analyzing the spatial patterns of human settlements from a wide geographical prospective. We argue that the spatial point patterns of settlements, in addition to the characteristics of human settlements, such as area, density and shape, should be taken into consideration in the future, and land planners and decision makers should pay more attention to city planning and management. Conceptual and methodological bridges linking settlement patterns to regional and site-specific geographical characteristics will be a key to human settlement studies and planning.
Turner, Adam W.; Martinuk, Amy; Silva, Anada
OBJECTIVE—: A recent genome-wide association study meta-analysis identified an intronic single nucleotide polymorphism in SMAD3, rs56062135C>T, the minor allele (T) which associates with protection from coronary artery disease. Relevant to atherosclerosis, SMAD3 is a key contributor to transforming....... The common allele (C) preserves an activator protein (AP)-1 site and enhancer function, whereas the protective (T) allele disrupts the AP-1 site and significantly reduces enhancer activity (PT single nucleotide polymorphism represents a novel functional cis-acting element at the SMAD3 locus. The protective...
Siddiq, A.; Couch, F.J. (Fergus J.); Chen, G. K.; Lindstrom, S.; Eccles, D.; Millikan, R. C.; Michailidou, K. (Kyriaki); Stram, D O; Beckmann, L; Rhie, S. K.; Ambrosone, C. B. (Christine B.); Aittomaki, K.; Amiano, P.; Apicella, C.; Baglietto, L
Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls o...
He, Qiao; Zhang, Peng; Li, Guangxiao; Dai, Huixu; Shi, Jingpu
Background Insomnia symptoms have been suggested to be associated with the risk of cardio-cerebral events. However, the results of previous studies have been inconsistent. Therefore, we conducted a meta-analysis to examine whether there were associations between cardio-cerebral vascular events and insomnia symptoms, including difficulty initiating sleep, difficulty maintaining sleep, early-morning awakening or non-restorative sleep. Design A meta-analysis of prospective cohort studies. Methods PubMed, Web of science and the Cochrane Library were searched without language restriction. Prospective cohort studies of adults with at least a 2-year follow-up duration were included. Random effect models were used in order to pool the results for each insomnia symptom. Subgroup and sensitivity analyses were conducted in order to assess potential heterogeneity, and funnel plots and Egger's tests were used in order to assess publication bias. Results Fifteen studies (23 cohorts) were included. Positive associations were observed between difficulty initiating sleep, difficulty maintaining sleep and non-restorative sleep with risk of cardio-cerebral vascular events. The pooled relative risks and 95% confidence intervals were 1.27 (1.15-1.40), 1.11 (1.04-1.19) and 1.18 (1.05-1.33), respectively. However, less evidence existed to support the conclusions about the association between early-morning awakening and cardio-cerebral vascular events. Conclusion Our meta-analysis demonstrated that insomnia symptoms of difficulty initiating sleep, difficulty maintaining sleep and non-restorative sleep were associated with an increased risk of future cardio-cerebral vascular events.
Li, Fa-Mei; Liu, Lin; Pang, Li-Nan; Shen, Min; Lu, Hong-Wen; Zhang, Xiao-Hong; Chu, Xun; Song, Zhen-Ju
The etiology of the Graves' disease (GD) is largely unknown. However, genetic factors are believed to play a major role. A recent genome-wide association study in a Han Chinese sample collection revealed two new Graves' disease (GD) risk loci within chromosome band 4p14 and 6q27. In this study, we aimed to investigate these associations with Weifang Han Chinese population of Shandong province and perform a meta-analysis of associations with GD. A case-control study was conducted to investigate association of variation within 4p14 and 6q27 to GD susceptibility in Weifang Han Chinese population of Shandong province. SNP rs6832151 at chromosome 4p14 and SNP rs9355610 at chromosome 6q27 was selected for genotyping in 2,382 GD patients and 3,092 unrelated controls. SNP genotyping was performed using TaqMan Real-time PCR technique assays on ABI7900 platform. A meta-analysis was performed with the data obtained in the current sample-set and those available from prior studies. Association analysis revealed both rs6832151 located in 4p14 (odds ratio (OR) = 1.27, P Allelic = 1.48 × 10-9) and rs9355610 located in 6q27 (OR = 1.10, P Allelic = 1.04 × 10-2) was associated with GD susceptibility. By model of inheritance analysis, we found the recessive model should be preferred (P Recessive = 2.75 × 10-11) for rs6832151. The dominant model should be preferred (P Dominant = 7.15 × 10-3) for rs9355610, whereas analysis of recessive model showed no significant association (P Recessive = 0.13). Meta-analysis with the data of 10,781 cases and 16,304 controls obtained from present sample-set and those available from prior studies confirmed association of rs6832151 at 4p14 with GD susceptibility using a fixed model (OR = 1.27, 95% CI: 1.22 to 1.32; I2 = 0%). Meta-analysis with the data of 11,306 cases and 12,756 controls confirmed association of rs9355610 at 6q27 with GD susceptibility using a fixed model (OR = 1.18, 95
Full Text Available Abstract Background The association between MHTFR Ala222Val polymorphism and breast cancer (BC risk are inconclusive. To derive a more precise estimation of the relationship, a systematic review and meta-analysis was performed. Methods A comprehensive search was conducted through researching MEDLINE, EMBASE, PubMed, Web of Science, Chinese Biomedical Literature database (CBM and China National Knowledge Infrastructure (CNKI databases before August 2012. Crude odds ratios (ORs with 95% confidence intervals (CIs were calculated to estimate the strength of the association. Results A total of 51 studies including 20,907 cases and 23,905 controls were involved in this meta-analysis. Overall, significant associations were found between MTHFR Ala222Val polymorphism and BC risk when all studies pooled into the meta-analysis (Ala/Ala vs Val/Val: OR=0.870, 95%CI=0.789–0.958,P=0.005; Ala/Val vs Val/Val: OR=0.895, 95%CI=0.821–0.976, P=0.012; dominant model: OR=0.882, 95%CI=0.808–0.963, P=0.005; and recessive model: OR = 0.944, 95%CI=0.898–0.993, P=0.026; Ala allele vs Val allele: OR = 0.935, 95%CI=0.887–0.986, P=0.013. In the subgroup analysis by ethnicity, the same results were found in Asian populations, while no significant associations were found for all comparison models in other Ethnicity populations. Conclusion In conclusion, our meta-analysis provides the evidence that MTHFR Ala222Val gene polymorphisms contributed to the breast cancer development. Virtual slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1966146911851976
Vlachopoulos, Charalambos V; Terentes-Printzios, Dimitrios G; Aznaouridis, Konstantinos A; Pietri, Panagiota G; Stefanadis, Christodoulos I
Streptococcus pneumoniae is the most common cause of community-acquired pneumonia (CAP) and CAP-related mortality in adults. Pneumococcal vaccination (PV) could protect subjects from cardiovascular events by reducing pneumonia severity or even preventing it. We sought to determine the ability of PV to protect from the risk of cardiovascular events. A comprehensive search of electronic databases was conducted up to March 2014. Cohort studies that reported relative risk (RR) estimates with 95% confidence intervals (CI) were included. Eleven studies were included (332,267 participants, mean follow-up 20.1 months). The pooled RRs for cardiovascular events and cardiovascular mortality were 0.86 (95% CI: 0.76-0.97) and 0.92 (95% CI: 0.86-0.98; fixed-effects), respectively, for subjects with PV versus without PV. Protective ability was more prominent in high cardiovascular risk populations and with older age. The protective role of PV was attenuated after 1 year (RR: 0.72; 95% CI: 0.59-0.88 vs RR: 1.03; 95% CI: 0.93-1.14; p = 0.002, for follow-up >1 year vs ≤1 year, respectively). It also increased as the presence of cardiovascular and pulmonary disease increased. Regarding myocardial infarction (MI) and cerebrovascular events, the protective role of PV was statistically significant only in the elderly (RR: 0.90; 95% CI: 0.817-0.999; fixed-effects and RR: 0.86; 95% CI: 0.75-0.99, respectively). PV is associated with decreased risk of cardiovascular events and mortality. This protective effect increases at older age and in high cardiovascular risk subjects and decreases as the time elapses from PV. PV decreases the risk of MI and cerebrovascular events in the elderly. © The European Society of Cardiology 2014.
Bazerbachi, F; Haffar, S; Szarka, L A; Wang, Z; Prokop, L J; Murad, M H; Camilleri, M
Colonic pseudo-obstruction (CPO) is characterized by colonic distention in the absence of mechanical obstruction or toxic megacolon. Concomitant secretory diarrhea (SD) with hypokalemia (SD-CPO) due to gastrointestinal (GI) loss requires further characterization. To perform a systematic review of SD-CPO, report a case study, and compare SD-CPO with classical CPO (C-CPO). We performed a search of MEDLINE, EMBASE, Cochrane, and Scopus for reports based on a priori criteria for CPO, SD and GI loss of potassium. An additional case at Mayo Clinic was included. Nine publications met inclusion criteria, with a total of 14 cases. Six studies had high, three moderate, and our case high methodological quality. Median age was 74 years (66-97), with 2:1 male/female ratio. Kidney disease was present in 6/14 patients. Diarrhea was described as profuse, watery, or viscous in 10 patients. Median serum, stool, and urine potassium concentrations (mmol/L) were 2.4 (range: 1.9-3.1), 137 (100-180), and 17 (8-40), respectively. Maximal diameter of colon and cecum (median) were 10.2 cm and 10.5 cm, respectively. Conservative therapy alone was effective in five out of 14 patients. Median potassium supplementation was 124 mEq/d (40-300). Colonic decompression was effective in three out of six patients; one had a total colectomy; three out of 14 had died. The main differences between SD-CPO and C-CPO were lower responses to treatments: conservative measures (35.7% vs 73.6%, P=.01), neostigmine (17% vs 89.2%, PCPO is a rare phenotype associated with increased fecal potassium and is more difficult to treat than C-CPO. © 2017 John Wiley & Sons Ltd.
Ben, Qiwen; Zhong, Jie; Liu, Jun; Wang, Lifu; Sun, Yunwei; Yv, Lifen; Yuan, Yaozong
There have been contradictory results about the association of fruits and vegetables intake with colorectal adenoma (CRA) risk, the precursor lesion of colorectal cancer. Herein, we have conducted a meta-analysis of the published observational studies to have a clear understanding about this association.Eligible studies up to November 30, 2014, were identified and retrieved by searching MEDLINE and EMBASE databases along with the manual review of the reference list of the retrieved studies. The quality of the included studies was evaluated using Newcastle-Ottawa Quality Assessment Scale, and random-effects model was used to calculate summary relative risk (SRR) and corresponding 95% confidence interval (CI).A total of 22 studies involving 11,696 CRA subjects were part of this meta-analysis. The SRR for the highest versus the lowest intake of vegetables alone was 0.91 (95% CI: 0.80-1.02, Pheterogeneity = 0.025), whereas for vegetables and fruits combined, it was 0.82 (95% CI: 0.75-0.91, Pheterogeneity = 0.369), and for fruits alone, it was 0.79 (95% CI: 0.71-0.88, Pheterogeneity = 0.111). In addition, linear dose-response analysis also showed similar results, for example, for per 100 g/d increment of fruits, the SRR was 0.94 (95% CI: 0.92-0.97) and for vegetables it was 0.98 (95% CI: 0.96-1.01). Nonlinear association was only observed for vegetables (Pnonlinearity = 0.024), but not for fruits (Pnonlinearity = 0.583).Thus, this meta-analysis suggested that fruits consumption have a significant protective effect on CRA risk, but not vegetables. Moreover, we recommend additional studies with prospective designs that use validated questionnaires and control for important confounders to further validate the overall results.
C. Rodriguez-Fontenla (Cristina); M. Calaza (Manuel); E. Evangelou (Evangelos); A.M. Valdes (Ana Maria); N.K. Arden (Nigel); F.J. Blanco; A.J. Carr (Andrew Jonathan); K. Chapman (Kay); P. Deloukas (Panagiotis); M. Doherty (Michael); T. Esko (Tõnu); C.M. Garcés Aletá (Carlos); J.J. Gomez-Reino Carnota (Juan); H.T. Helgadottir (Hafdis); A. Hofman (Albert); I. Jonsdottir (Ingileif); J.M. Kerkhof (Hanneke); M. Kloppenburg (Margreet); A. McCaskie (Andrew); E.E. Ntzani (Evangelia); W.E.R. Ollier (William); N. Oreiro (Natividad); K. Panoutsopoulou (Kalliope); S.H. Ralston (Stuart); Y.F.M. Ramos (Yolande); J.A. Riancho (José); F. Rivadeneira Ramirez (Fernando); P.E. Slagboom (Eline); U. Styrkarsdottir (Unnur); U. Thorsteinsdottir (Unnur); G. Thorleifsson (Gudmar); A. Tsezou (Aspasia); A.G. Uitterlinden (André); G.A. Wallis (Gillian); J.M. Wilkinson (Mark); G. Zhai (Guangju); Y. Zhu (Yanyan); D. Felson; J.P.A. Ioannidis (John); J. Loughlin (John); A. Metspalu (Andres); I. Meulenbelt (Ingrid); J-A. Zwart (John-Anker); J.B.J. van Meurs (Joyce); E. Zeggini (Eleftheria); T.D. Spector (Timothy); A. Gonzalez (Antonio)
textabstractObjective To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA. Methods A total of 199 candidate genes for association with OA were identified using Human Genome
Chai, Fan; Liang, Yan; Chen, Li; Zhang, Fan; Jiang, Jun
Studies have shown that gene and environmental factors, such as BRCA1/2 mutations, ionized radiation, and chemical carcinogens, are related with breast cancer. X-ray repair cross-complementing group 3 (XRCC3) is involved in homologous repair of double DNA breaks. It was reported that Thr241Met single-nucleotide polymorphism (SNP) in XRCC3 is associated with increased risk of breast cancer. However, the finding remains controversial. The current meta-analysis aims to determine whether XRCC3 Thr241Met polymorphism is associated with increased risk of breast cancer. We performed a meta-analysis of association between XRCC3 T241M polymorphism and the risk of breast cancer. Crude odds ratios (ORs) together with 95% confidence intervals (CIs) were used to assess the strength of association in dominant, recessive, and homozygote models. We included 23 studies consisting of 13513 cases and 14100 controls in our study. For meta-analysis on the entire database, association of the SNP and breast cancer risk was observed in recessive (OR=1.10, 95% CI: 1.03-1.18, p=0.005) and homozygote (OR=1.09, 95% CI: 1.01-1.18, p=0.023) models. For the analysis on the Asian population subgroup, association of the SNP and breast cancer risk was also observed in recessive (OR=1.615, 95% CI: 1.17-2.228, p=0.004) and homozygote (OR=1.609, 95% CI: 1.154-2.241, p=0.005) models. For the evaluation of the patients without family history of breast cancer, association of the SNP and breast cancer risk was observed in dominant (OR=1.364, 95% CI: 1.096-1.698, p=0.005), recessive (OR=1.336, 95% CI: 0.999-1.788, p=0.051) and homozygote (OR=1.492, 95% CI: 1.085-2.051, p=0.014) models. We can conclude that XRCC3 Thr241Met polymorphism might be associated with breast cancer risk, especially in Asian populations and in patients without family history of breast cancer.
Wang, Weijing; Wu, Yili; Zhang, Dongfeng
The association of dairy products consumption with risk of obesity remains controversial. Therefore, we reviewed and quantitatively synthesized the evidence from observational studies with a meta-analysis. A literature search was performed in relevant databases. Random-effects model was used to pool odds ratios with 95% confidence intervals. Dose-response relationship was assessed by restricted cubic spline model. Seventeen studies for total dairy products and 16 studies for milk with risk of obesity were eligible. The pooled odds ratios (95% confidence intervals) of obesity for the highest versus lowest category of total dairy products consumption were 0.54 (0.38-0.77) in children, 0.75 (0.69-0.81) in adults, and 0.74 (0.68-0.80) for both. Evidence of a nonlinear relationship was found (Pfor nonlinearity = .009). Milk consumption was also associated with risk of obesity [0.81 (0.75-0.88)] both in children [0.87 (0.80-0.95)] and in adults [0.77 (0.68-0.87)], and a linear relationship (Pfor nonlinearity = .598) suggested that risk of obesity decreased by 16% [0.84 (0.77-0.92)] for every 200 g/d increment of milk consumption. This meta-analysis indicates that dairy products consumption may be associated with a decreased risk of obesity. This association may be of public health significance. Copyright Â© 2016 Elsevier Inc. All rights reserved.
Full Text Available BACKGROUND: Three non-synonymous single nucleotide polymorphisms (Q223R, K109R and K656N of the leptin receptor gene (LEPR have been tested for association with obesity-related outcomes in multiple studies, showing inconclusive results. We performed a systematic review and meta-analysis on the association of the three LEPR variants with BMI. In addition, we analysed 15 SNPs within the LEPR gene in the CoLaus study, assessing the interaction of the variants with sex. METHODOLOGY/PRINCIPAL FINDINGS: We searched electronic databases, including population-based studies that investigated the association between LEPR variants Q223R, K109R and K656N and obesity- related phenotypes in healthy, unrelated subjects. We furthermore performed meta-analyses of the genotype and allele frequencies in case-control studies. Results were stratified by SNP and by potential effect modifiers. CoLaus data were analysed by logistic and linear regressions and tested for interaction with sex. The meta-analysis of published data did not show an overall association between any of the tested LEPR variants and overweight. However, the choice of a BMI cut-off value to distinguish cases from controls was crucial to explain heterogeneity in Q223R. Differences in allele frequencies across ethnic groups are compatible with natural selection of derived alleles in Q223R and K109R and of the ancient allele in K656N in Asians. In CoLaus, the rs10128072, rs3790438 and rs3790437 variants showed interaction with sex for their association with overweight, waist circumference and fat mass in linear regressions. CONCLUSIONS: Our systematic review and analysis of primary data from the CoLaus study did not show an overall association between LEPR SNPs and overweight. Most studies were underpowered to detect small effect sizes. A potential effect modification by sex, population stratification, as well as the role of natural selection should be addressed in future genetic association studies.
Lee, Seunggeun; Fuchsberger, Christian; Kim, Sehee; Scott, Laura
For aggregation tests of genes or regions, the set of included variants often have small total minor allele counts (MACs), and this is particularly true when the most deleterious sets of variants are considered. When MAC is low, commonly used asymptotic tests are not well calibrated for binary phenotypes and can have conservative or anti-conservative results and potential power loss. Empirical p-values obtained via resampling methods are computationally costly for highly significant p-values and the results can be conservative due to the discrete nature of resampling tests. Based on the observation that only the individuals containing minor alleles contribute to the score statistics, we develop an efficient resampling method for single and multiple variant score-based tests that can adjust for covariates. Our method can improve computational efficiency >1000-fold over conventional resampling for low MAC variant sets. We ameliorate the conservativeness of results through the use of mid-p-values. Using the estimated minimum achievable p-value for each test, we calibrate QQ plots and provide an effective number of tests. In analysis of a case-control study with deep exome sequence, we demonstrate that our methods are both well calibrated and also reduce computation time significantly compared with resampling methods. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: email@example.com.
Full Text Available Thoroughbred, a relatively recent horse breed, is best known for its use in horse racing. Although myostatin (MSTN variants have been reported to be highly associated with horse racing performance, the trait is more likely to be polygenic in nature. The purpose of this study was to identify genetic variants strongly associated with racing performance by using estimated breeding value (EBV for race time as a phenotype. We conducted a two-stage genome-wide association study to search for genetic variants associated with the EBV. In the first stage of genome-wide association study, a relatively large number of markers (~54,000 single-nucleotide polymorphisms, SNPs were evaluated in a small number of samples (240 horses. In the second stage, a relatively small number of markers identified to have large effects (170 SNPs were evaluated in a much larger number of samples (1,156 horses. We also validated the SNPs related to MSTN known to have large effects on racing performance and found significant associations in the stage two analysis, but not in stage one. We identified 28 significant SNPs related to 17 genes. Among these, six genes have a function related to myogenesis and five genes are involved in muscle maintenance. To our knowledge, these genes are newly reported for the genetic association with racing performance of Thoroughbreds. It complements a recent horse genome-wide association studies of racing performance that identified other SNPs and genes as the most significant variants. These results will help to expand our knowledge of the polygenic nature of racing performance in Thoroughbreds.
Shin, Dong-Hyun; Lee, Jin Woo; Park, Jong-Eun; Choi, Ik-Young; Oh, Hee-Seok; Kim, Hyeon Jeong; Kim, Heebal
Thoroughbred, a relatively recent horse breed, is best known for its use in horse racing. Although myostatin (MSTN) variants have been reported to be highly associated with horse racing performance, the trait is more likely to be polygenic in nature. The purpose of this study was to identify genetic variants strongly associated with racing performance by using estimated breeding value (EBV) for race time as a phenotype. We conducted a two-stage genome-wide association study to search for genetic variants associated with the EBV. In the first stage of genome-wide association study, a relatively large number of markers (~54,000 single-nucleotide polymorphisms, SNPs) were evaluated in a small number of samples (240 horses). In the second stage, a relatively small number of markers identified to have large effects (170 SNPs) were evaluated in a much larger number of samples (1,156 horses). We also validated the SNPs related to MSTN known to have large effects on racing performance and found significant associations in the stage two analysis, but not in stage one. We identified 28 significant SNPs related to 17 genes. Among these, six genes have a function related to myogenesis and five genes are involved in muscle maintenance. To our knowledge, these genes are newly reported for the genetic association with racing performance of Thoroughbreds. It complements a recent horse genome-wide association studies of racing performance that identified other SNPs and genes as the most significant variants. These results will help to expand our knowledge of the polygenic nature of racing performance in Thoroughbreds.
Hoffman, Aaron E; Zheng, Tongzhang; Stevens, Richard G; Ba, Yue; Zhang, Yawei; Leaderer, Derek; Yi, Chunhui; Holford, Theodore R; Zhu, Yong
Circadian genes have the potential to influence a variety of cancer-related biological pathways, including immunoregulation, which may influence susceptibility to non-Hodgkin's lymphoma (NHL). However, few studies have examined the role of circadian genes in lymphomagenesis. The current study examined Cryptochrome 2 (CRY2), a core circadian gene and transcriptional repressor, as a potential circadian biomarker for NHL. We first performed genetic association analyses of tagging single nucleotide polymorphisms (SNP) in CRY2 and NHL risk using DNA samples from a population-based case-control study (n = 455 cases and 527 controls). Three SNPs were found to be significantly associated with risk of NHL when combining all subtypes [dbSNP IDs, odds ratios (ORs), and 95% confidence intervals: rs11038689, OR, 2.34 (1.28-4.27), P = 0.006; rs7123390, OR, 2.40 (1.39-4.13), P = 0.002; and rs1401417, OR, 2.97 (1.57-5.63, P = 0.001)]. Each of these associations remained significant when restricting the analysis to B-cell cases and when further restricting to follicular lymphomas. An analysis of CRY2 diplotypes confirmed these significant findings. To further determine the functional effect of CRY2, we silenced the gene in vitro and performed a whole genome expression microarray. A pathway-based analysis showed that genes significantly altered by CRY2 knockdown formed networks associated with immune response and hematologic system development. In addition, these genes were predicted to have significant effects on several disease processes, including cancer (B-H P = 3.75E(-9)) and hematologic disease (B-H P = 8.01E(-8)). In conclusion, both genetic association and functional analyses suggest that the circadian gene CRY2 may play an important role in NHL development.
Deviations from Hardy-Weinberg equilibrium (HWE) in control subjects may bias the estimates of genetic effects in genetic association studies (GAS) and meta-analysis. A large empirical evaluation was carried out to evaluate the impact of HWE deviation and explore the effect of variance adjustment for the allele-based odds ratio in 833 individual GAS and 72 meta-analyses. In individual GAS, the variance adjustment for any deviation from HWE resulted in stronger associations, and 10 GAS (1%) became significant (P < 0.05). One hundred sixteen GAS (14%) showed significant deviation from HWE (P (HWE) < 0.05); however, only 37 GAS (4%) had more than 90% power to detect significant deviation from HWE at the 5% level. In meta-analyses, adjustment for any deviation from HWE improved the significance in 53 meta-analyses (74%). Then, a formal statistical significance (P < 0.05) was revealed for one previously negative meta-analyses whereas one meta-analysis lost its significance. Between-study heterogeneity was enhanced in 50 meta-analyses (69%). None of the meta-analyses lost the significance of heterogeneity (P ( Q ) < 0.10) whereas in one meta-analysis, the non significant heterogeneity became significant. Sensitivity analysis for studies not conforming to HWE (P (HWE) < 0.05) was applied to 45 meta-analyses (69%). Then, the significance of association was increased in 26 the meta-analyses (58%) and one meta-analysis became significant (P < 0.05) whereas seven meta-analyses (16%) were no longer significant. Adjustment for HWE deviation could be an effective strategy for dealing with HWE violations in GAS and meta-analyses.
Melsen, W.G.; Rovers, M.M.; Groenwold, R.H.; Bergmans, D.C.; Camus, C.; Bauer, T.T.; Hanisch, E.W.; Klarin, B.; Koeman, M.; Krueger, W.A.; Lacherade, J.C.; Lorente, L.; Memish, Z.A.; Morrow, L.E.; Nardi, G.; Nieuwenhoven, C.A. van; O'Keefe, G.E.; Nakos, G.; Scannapieco, F.A.; Seguin, P.; Staudinger, T.; Topeli, A.; Ferrer, M.; Bonten, M.J.
BACKGROUND: Estimating attributable mortality of ventilator-associated pneumonia has been hampered by confounding factors, small sample sizes, and the difficulty of doing relevant subgroup analyses. We estimated the attributable mortality using the individual original patient data of published
Ushigome, Emi; Fukui, Michiaki; Hamaguchi, Masahide; Tanaka, Toru; Atsuta, Haruhiko; Ohnishi, Masayoshi; Tsunoda, Sei; Yamazaki, Masahiro; Hasegawa, Goji; Nakamura, Naoto
Epidemiological studies have shown that elevated heart rate (HR) is associated with an increased risk of diabetic nephropathy, as well as cardiovascular events and mortality, in patients with type 2 diabetes mellitus. Recently, the advantages of the self-measurement of blood pressure (BP) at home have been recognized. The aim of this study was to investigate the relationship between home-measured HR and albuminuria in patients with type 2 diabetes mellitus. We designed a cross-sectional multicenter analysis of 1245 patients with type 2 diabetes mellitus. We investigated the relationship between the logarithm of urinary albumin excretion (log UAE) and home-measured HR or other factors that may be related to nephropathy using univariate and multivariate analyses. Multivariate linear regression analysis indicated that age, duration of diabetes mellitus, morning HR (β=0.131, Palcohol, use of angiotensin II receptor blockers and use of beta-blockers were independently associated with the log UAE. Multivariate logistic regression analysis indicated that the odds ratio (95% confidence interval) associated with 1 beat per min and 1 mm Hg increases in the morning HR and morning systolic BP for albuminuria were 1.024 ((1.008-1.040), P=0.004) and 1.039 ((1.029-1.048), Pdiabetes mellitus.
Marcelo A. Kauffman
Full Text Available We performed an association study in a population of patients with Mesial Temporal Lobe Epilepsy (TLE with Hippocampal Sclerosis (MTEHS together with a systematic revision of the literature to investigate the role of transcriptionally less active polymorphic alleles of Prodynorphin (PDYN gene in this pathology. We included 102 patients with a diagnosis of MTEHS and 86 healthy controls. The positive antecedent of family history for epileptic events defined a TLE subgroup with familial predisposition for epileptic disorders. The PDYN promoter polymorphism was genotyped by means of a PCR assay. For meta-analysis, we identified case-control association studies between TLE and PDYN by searching PUBMED. The pooled OR was estimated using a fixed effects model under dominant and co-dominant heredity models. No differences in genotypic and allelic frequencies were found between cases and controls (p = 0.61 in our population, neither in the whole cohort nor in the analysis limited to TLE with familial predisposition (p = 0.71. The Meta-Analysis included 591 TLE patients and 1117 healthy controls. We found an association between L allele (p = 0.003; OR = 1.40; IC 95 = 1.12–1.74 and a modestly higher risk to develop TLE in the group of patients with familial predisposition. Therefore, functional allelic variants in the PDYN promoter might modify the risk to develop TLE in subjects with familial predisposition.
R.N. Lemaitre (Rozenn); T. Tanaka (Toshiko); W. Tang (Weihong); A. Manichaikul (Ani); M. Foy (Millennia); E.K. Kabagambe (Edmond); J.A. Nettleton (Jennifer ); I.B. King (Irena); L.-C. Weng; S. Bhattacharya (Sayanti); S. Bandinelli (Stefania); J.C. Bis (Joshua); S.S. Rich (Stephen); D.R. Jacobs (David); A. Cherubini (Antonio); B. McKnight (Barbara); S. Liang (Shuang); X. Gu (Xiangjun); K.M. Rice (Kenneth); C.C. Laurie (Cathy); T. Lumley (Thomas); B.L. Browning (Brian); B.M. Psaty (Bruce); Y.D.I. Chen (Yii-Der Ida); Y. Friedlander (Yechiel); L. Djousse (Luc); J.H.Y. Wu (Jason); D.S. Siscovick (David); A.G. Uitterlinden (André); L. Ferrucci (Luigi); M. Fornage (Myriam); M.Y. Tsai (Michael); D. Mozaffarian (Dariush); L.M. Steffen (Lyn); D.K. Arnett (Donna)
textabstractLong-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide
Bakolis, Ioannis; Burney, Peter; Hooper, Richard
Dietary patterns derived empirically using principal components analysis (PCA) are widely employed for investigating diet-disease relationships. In the present study, we investigated whether PCA performed better at identifying such associations than an analysis of each food on a FFQ separately, referred to here as an exhaustive single food analysis (ESFA). Data on diet and disease were simulated using real FFQ data and by assuming a number of food intakes in combination that were associated with the risk of disease. In each simulation, ESFA and PCA were employed to identify the combinations of foods that are associated with the risk of disease using logistic regression, allowing for multiple testing and adjusting for energy intake. ESFA was also separately adjusted for principal components of diet, foods that were significant in the unadjusted ESFA and propensity scores. For each method, we investigated the power with which an association between diet and disease could be identified, and the power and false discovery rate (FDR) for identifying the specific combination of food intakes. In some scenarios, ESFA had greater power to detect a diet-disease association than PCA. ESFA also typically had a greater power and a lower FDR for identifying the combinations of food intakes that are associated with the risk of disease. The FDR of both methods increased with increasing sample size, but when ESFA was adjusted for foods that were significant in the unadjusted ESFA, FDR were controlled at the desired level. These results question the widespread use of PCA in nutritional epidemiology. The adjusted ESFA identifies the combinations of foods that are causally linked to the risk of disease with low FDR and surprisingly good power.
Thelma Beatriz, González-Castro; Isela, Juárez-Rojop; Alma, Genis; María Lilia, López-Narváez; Carlos Alfonso, Tovilla-Zárate
Suicide is an important public health problem and one of the most common causes of death throughout the world. Suicidal behaviour is complex, and its causes are multifactorial. Case-control studies have reported an association between an alteration of the serotonin system and suicidal behaviour. Recently, it has been suggested that the 5-HTRC2 serotonin receptor gene is involved in the pathogenesis of suicidal behaviour. To evaluate the role of the 5-HTR2C gene in suicidal behaviour, we will perform a systematic review and a meta-analysis of worldwide reports that have investigated the association between the serotonin system and suicidal behaviour. This analysis will be reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Studies deemed fit for inclusion in the systematic review will be scored for methodological quality using the Newcastle-Ottawa Assessment Scale (NOS). The inclusion criteria will be to present independent data, to be case-control studies and to be published in journal peer reviews. To generate more accurate analyses, we will grade the reports using the GRADES scale procedures. This study will describe the association between the HTR2C gene and suicidal behaviour. The results will be reported in a peer-reviewed publication and in scientific presentations in Mexico and throughout the world. PROSPERO CRD42014009213. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Namazi, Nazli; Larijani, Bagher; Azadbakht, Leila
The association between a low-carbohydrate diet (LCD) score and the risk of diabetes mellitus (DM) is contradictory. This study is a systemic review of cohort studies that have focused on the association between the LCD score and DM. We searched PubMed/Medline, Scopus, Embase, ISI Web of Science, and Google Scholar for papers published through January 2017 with no language restrictions. Cohort studies that reported relative risks (RRs) with 95% confidence intervals (CI) for DM were included. Finally, 4 studies were considered for our meta-analysis. The total number of participants ranged from 479 to 85 059. Among 4 cohort studies, 8 081 cases with DM were observed over follow-up durations ranging from 3.6 to 20 years. A marginal significant association was observed between the highest LCD score and the risk of DM (RR=1.17; 95% CI: 0.9, 1.51). Moreover, the RRs for studies with energy adjustments showed a significant association (RR: 1.32; 95% CI: 1.17, 1.49; I2: 0%). Based on our findings, study qualities score of less or equal to 7 had a significant influence on the pooled effect size (RR=1.31, 95%CI: 1.15, 1.49; I2: 0%), whereas the overall RR in the studies with quality score more than 7 was 1.09 (95% CI: 0.73, 1.63). In conclusion, we have found that the highest LCD score was marginally associated with the risk of DM. However, more prospective cohort studies are needed to clarify the effects of the LCD score on the risk of DM. © Georg Thieme Verlag KG Stuttgart · New York.
Katkam, S K; Rajasekhar, L; Kumaraswami, K; Kutala, V K
Cytokines play a direct role in disease pathogenesis of systemic lupus erythematosus (SLE). Elevated levels of serum IL-6 are well documented with the disease activity and anti-dsDNA antibodies in SLE. The 5' promoter region of the IL-6 gene has been shown to play a significant role in the regulation of gene expression. In view of this, the current study aimed to investigate the possible association of 5' promoter polymorphisms G-597A (rs1800797), G-572C (rs1800796) and G-174C (rs1800795) with the risk of SLE. Analysis of 468 subjects (202 SLE patients and 266 controls) showed a significant association of the -174 G/C variant with the SLE risk in both dominant and recessive model (odds ratio (OR) 3.20, 95% confidence interval (CI) 1.18-8.69, P = 0.020 and OR 2.02, 95% CI 1.35-3.02, P = 0.0005), respectively. The 'G allele of the -174 loci (OR 1.97, 95% CI 1.39-2.78, P = 0.00012) has shown significant distribution between the cases and controls. The haplotype analysis revealed that AGG haplotype carriers are more frequent in cases than controls and found a significant positive association (OR 1.394, 95% CI 1.07-7.12, P = 0.028) with SLE. In addition, we also undertook a meta-analysis on 13 study groups for -174 G/C, comprising a total of 1585 cases and 1690 controls. The pooled OR also suggested a significant association of -174 G/C with SLE (OR 1.36, 95% CI 1.22-1.53, P SLE disease and pathogenesis. Meta-analysis has also suggested the overall correlation between -174 G/C polymorphism and SLE risk.
Moskvina, Valentina; Harold, Denise; Russo, GianCarlo; Vedernikov, Alexey; Sharma, Manu; Saad, Mohamed; Holmans, Peter; Bras, Jose M; Bettella, Francesco; Keller, Margaux F; Nicolaou, Nayia; Simón-Sánchez, Javier; Gibbs, J Raphael; Schulte, Claudia; Durr, Alexandra; Guerreiro, Rita; Hernandez, Dena; Brice, Alexis; Stefánsson, Hreinn; Majamaa, Kari; Gasser, Thomas; Heutink, Peter; Wood, Nick; Martinez, Maria; Singleton, Andrew B; Nalls, Michael A; Hardy, John; Owen, Michael J; O'Donovan, Michael C; Williams, Julie; Morris, Huw R; Williams, Nigel M
Despite Alzheimer disease (AD) and Parkinson disease (PD) being clinically distinct entities, there is a possibility of a pathological overlap, with some genome-wide association (GWA) studies suggesting that the 2 diseases represent a biological continuum. The application of GWA studies to idiopathic forms of AD and PD have identified a number of loci that contain genetic variants that increase the risk of these disorders. To assess the genetic overlap between PD and AD by testing for the presence of potentially pleiotropic loci in 2 recent GWA studies of PD and AD. Combined GWA analysis. Data sets from the United Kingdom, Germany, France, and the United States. Thousands of patients with AD or PD and their controls. Meta-analysis of GWA studies of AD and PD. To identify evidence for potentially pleiotropic alleles that increased the risk for both PD and AD, we performed a combined PD-AD meta-analysis and compared the results with those obtained in the primary GWA studies.We also tested for a net effect of potentially polygenic alleles that were shared by both disorders by performing a polygenic score analysis. Finally, we also performed a gene-based association analysis that was aimed at detecting genes that harbor multiple disease-causing single-nucleotide polymorphisms, some of which confer a risk of PD and some a risk of AD. Detailed interrogation of the single-nucleotide polymorphism, polygenic, and gene-based analyses resulted in no significant evidence that supported the presence of loci that increase the risk of both PD and AD. Our findings therefore imply that loci that increase the risk of both PD and AD are not widespread and that the pathological overlap could instead be “downstream” of the primary susceptibility genes that increase the risk of each disease.
van Oort, Pouline M P; Nijsen, Tamara; Weda, Hans; Knobel, Hugo; Dark, Paul; Felton, Timothy; Rattray, Nicholas J W; Lawal, Oluwasola; Ahmed, Waqar; Portsmouth, Craig; Sterk, Peter J; Schultz, Marcus J; Zakharkina, Tetyana; Artigas, Antonio; Povoa, Pedro; Martin-Loeches, Ignacio; Fowler, Stephen J; Bos, Lieuwe D J
The diagnosis of ventilator-associated pneumonia (VAP) remains time-consuming and costly, the clinical tools lack specificity and a bedside test to exclude infection in suspected patients is unavailable. Breath contains hundreds to thousands of volatile organic compounds (VOCs) that result from host and microbial metabolism as well as the environment. The present study aims to use breath VOC analysis to develop a model that can discriminate between patients who have positive cultures and who have negative cultures with a high sensitivity. The Molecular Analysis of Exhaled Breath as Diagnostic Test for Ventilator-Associated Pneumonia (BreathDx) study is a multicentre observational study. Breath and bronchial lavage samples will be collected from 100 and 53 intubated and ventilated patients suspected of VAP. Breath will be analysed using Thermal Desorption - Gas Chromatography - Mass Spectrometry (TD-GC-MS). The primary endpoint is the accuracy of cross-validated prediction for positive respiratory cultures in patients that are suspected of VAP, with a sensitivity of at least 99% (high negative predictive value). To our knowledge, BreathDx is the first study powered to investigate whether molecular analysis of breath can be used to classify suspected VAP patients with and without positive microbiological cultures with 99% sensitivity. UKCRN ID number 19086, registered May 2015; as well as registration at www.trialregister.nl under the acronym 'BreathDx' with trial ID number NTR 6114 (retrospectively registered on 28 October 2016).
Simmons, Sarah M; Hicks, Anne; Caird, Jeff K
A systematic review and meta-analysis of naturalistic driving studies involving estimates of safety-critical event risk associated with handheld device use while driving is described. Fifty-seven studies identified from targeted databases, journals and websites were reviewed in depth, and six were ultimately included. These six studies, published between 2006 and 2014, encompass seven sets of naturalistic driver data and describe original research that utilized naturalistic methods to assess the effects of distracting behaviors. Four studies involved non-commercial drivers of light vehicles and two studies involved commercial drivers of trucks and buses. Odds ratios quantifying safety-critical event (SCE) risk associated with talking, dialing, locating or answering, and texting or browsing were extracted. Stratified meta-analysis of pooled odds ratios was used to estimate SCE risk by distraction type; meta-regression was used to test for sources of heterogeneity. The results indicate that tasks that require drivers to take their eyes off the road, such as dialing, locating a phone and texting, increase SCE risk to a greater extent than tasks that do not require eyes off the road such as talking. Although talking on a handheld device did not increase SCE risk, further research is required to determine whether it indirectly influences SCE risk (e.g., by encouraging other cell phone activities). In addition, a number of study biases and quality issues of naturalistic driving studies are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.
Thyssen, Jacob Pontoppidan; Johansen, Jeanne Duus; Carlsen, Berit Christina
in uninvolved skin. So far five relatively small patient-based case-control studies have rejected a possible association between psoriasis and the two most prevalent filaggrin null mutations, 2282del4 and R501X. Objectives To reinvestigate a possible association between psoriasis and filaggrin null mutation...... status by using cross-sectional general population questionnaire data. Also, to perform a meta-analysis including published studies that investigated the relation between filaggrin gene mutations R501X and 2282del4, respectively, and psoriasis vulgaris. Methods Between June 2006 and May 2008, a cross......-sectional study was performed in the general population in Copenhagen. A random sample of 7931 subjects aged 18-69 years was invited to participate in a general health examination including a questionnaire and 3471 (43.7%) participated. A total of 3335 (96.1%) individuals were filaggrin genotyped for the 2282del4...
Full Text Available Xiang Ao,1,* Ying Liu,1,* Xiao-Yan Bai,1 Xinjian Qu,2 Zhaowei Xu,1 Gaolei Hu,1 Min Chen,1 Huijian Wu1,21Laboratory of Molecular Medicine & Pharmacy, School of Life Science and Biotechnology, Dalian University of Technology, Dalian, 2Laboratory of Molecular Medicine & Pharmacy, School of Life Science and Medicine, Dalian University of Technology, Panjin, Liaoning, People’s Republic of China*These authors have contributed equally to this workBackground: EHBP1 rs721048(A was first identified as a prostate cancer (PCa risk in Caucasians by genome-wide association study, but subsequent replication studies involving Caucasian and other ethnicities did not produce consistent results. The aim of this study was to obtain a more definite association between rs721048(A and PCa risk.Methods: We comprehensively searched several databases updated to September 2014, including PubMed, Web of Science, EBSCO, and Google Scholar. Two authors independently screened and reviewed the eligibility of each study. The quality of the included studies was assessed by the Newcastle–Ottawa scale. The association of rs721048(A and PCa risk was assessed by pooling odds ratios (ORs with 95% confidence intervals (CIs.Results: A total of 17 studies, including 48,135 cases and 102,543 controls, published between 2008 and 2014 were included in the meta-analysis. Overall, the pooled analysis demonstrated that rs721048(A was significantly associated with the risk of PCa under the allele model (OR=1.14, 95% CI=1.11–1.17, P=0.000. Subgroup analysis based on ethnicity revealed a significant association between rs721048(A and PCa in Caucasian (OR=1.14, 95% CI=1.11–1.16, P=0.000, African descent (OR=1.11, 95% CI=1.01–1.23, P=0.025, and Asian (OR=1.35, 95% CI=1.12–1.64, P=0.002.Conclusion: Our results provided strong evidence that rs721048(A could be a risk factor for PCa.Keywords: EHBP1, rs721048, meta-analysis, prostate cancer
Full Text Available Many observational studies have found that exposure to dental X-rays is associated with the risk of development of meningioma. However, these findings are inconsistent. We conducted a meta-analysis to assess the relationship between exposure to dental X-rays and the risk of development of meningioma.The PubMed and EMBASE databases were searched to identify eligible studies. Summary odds ratio (OR estimates and 95% confidence intervals (95% CIs were used to compute the risk of meningioma development according to heterogeneity. Subgroup and sensitivity analyses were performed to further explore the potential heterogeneity. Finally, publication bias was assessed.Seven case-control studies involving 6,174 patients and 19,459 controls were included in the meta-analysis. Neither exposure to dental X-rays nor performance of full-mouth panorex X-rays was associated with an increased risk of development of meningioma (overall: OR, 0.97; 95% CI, 0.70-1.32; dental X-rays: OR, 1.05; 95% CI, 0.89-1.25; panorex X-rays: OR, 1.01; 95% CI, 0.76-1.34. However, exposure to bitewing X-rays was associated with a slightly increased risk of development of meningioma (OR, 1.73; 95% CI, 1.28-2.34. Similar results were obtained in the subgroup and sensitivity analyses. Little evidence of publication bias was observed.Based on the currently limited data, there is no association between exposure to dental X-rays and the risk of development of meningioma. However, these results should be cautiously interpreted because of the heterogeneity among studies. Additional large, high-quality clinical trials are needed to evaluate the association between exposure to dental X-rays and the risk of development of meningioma.
Kapoor, Manav; Wang, Jen-Chyong; Wetherill, Leah; Le, Nhung; Bertelsen, Sarah; Hinrichs, Anthony L; Budde, John; Agrawal, Arpana; Bucholz, Kathleen; Dick, Danielle; Harari, Oscar; Hesselbrock, Victor; Kramer, John; Nurnberger, John I; Rice, John; Saccone, Nancy; Schuckit, Marc; Tischfield, Jay; Porjesz, Bernice; Edenberg, Howard J; Bierut, Laura; Foroud, Tatiana; Goate, Alison
Maximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (> 50%) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (N=2322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case-control sample (N=2593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (p = 2.1×10−6) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (p = 7.1×10−7), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the LMO1 (p = 7.2×10−7) and PLCL1 genes (p = 4.1×10−6) with increased maxdrinks. A variant in AUTS2 and variants in INADL, C15orf32 and HIP1 that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (p≤10−4) far more showed the same direction of effect in the other dataset than would be expected by chance (p = 2×10−3, 3×10−6), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance. PMID:23743675
Kapoor, Manav; Wang, Jen-Chyong; Wetherill, Leah; Le, Nhung; Bertelsen, Sarah; Hinrichs, Anthony L; Budde, John; Agrawal, Arpana; Bucholz, Kathleen; Dick, Danielle; Harari, Oscar; Hesselbrock, Victor; Kramer, John; Nurnberger, John I; Rice, John; Saccone, Nancy; Schuckit, Marc; Tischfield, Jay; Porjesz, Bernice; Edenberg, Howard J; Bierut, Laura; Foroud, Tatiana; Goate, Alison
Maximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (>50 %) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (N = 2,322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case-control sample (N = 2,593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (p = 2.1 × 10(-6)) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (p = 7.1 × 10(-7)), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the LMO1 (p = 7.2 × 10(-7)) and PLCL1 genes (p = 4.1 × 10(-6)) with maxdrinks. A variant in AUTS2 and variants in INADL, C15orf32 and HIP1 that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (p ≤ 10(-4)) far more showed the same direction of effect in the other dataset than would be expected by chance (p = 2 × 10(-3), 3 × 10(-6)), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance.
Glasser, Stephen P; Wadley, Virginia; Judd, Suzanne; Kana, Bhumika; Prince, Valerie; Jenny, Nancy; Kissela, Brett; Safford, Monika; Prineas, Ronald; Howard, George
Statin use and type have been variably associated with impaired or improved cognitive performance. To assess the association of statin use and type (lipophilic vs hydrophilic) and cognitive impairment. Cross-sectional analysis of 24 595 participants (7191 statin users and 17 404 nonusers) age > or = 45 years, from a population-based national cohort study (Reasons for Geographic And Racial Differences in Stroke) enrolled between January 2003 and October 2008, with oversampling from the southeastern Stroke Belt and African Americans. Statin use and type were documented in participants' homes by a trained health professional. Cognitive performance was assessed with a prior validated instrument of global cognitive status (Six-Item Screener). Cognitive impairment was defined as a score of cognitive impairment and statin use was observed (8.6% of users vs 7.7% of nonusers had cognitive impairment, P = 0.014); but, after adjusting for variables known to be associated with cognition (age, gender, race, income, education level, and cardiovascular disease), the association was attenuated (odds ratio [OR]: 0.98, confidence interval [CI]: 0.87-1.10). No association was observed between statin type (lipophilic vs hydrophilic) and cognition (OR: 1.03, CI: 0.86-1.24), and there were no regional differences in cognitive impairment in statin users (8% in the Stroke Belt and 7.9% in other regions, P = 0.63). Statin use and type were marginally associated with cognitive impairment. After adjusting for known variables that affect cognition, no association was observed. No regional differences were observed. This large study found no evidence to support an association between statins and cognitive performance. Copyright 2010 Wiley Periodicals, Inc.
Khankhanian, Pouya; Cozen, Wendy; Himmelstein, Daniel S.; Madireddy, Lohith; Din, Lennox; van den Berg, Anke; Matsushita, Takuya; Glaser, Sally L.; More, Jayaji M.; Smedby, Karin E.; Baranzini, Sergio E.; Mack, Thomas M.; Lizee, Antoine; de Sanjose, Silvia; Gourraud, Pierre-Antoine; Nieters, Alexandra; Hauser, Stephen L.; Cocco, Pierluigi; Maynadie, Marc; Foretova, Lenka; Staines, Anthony; Delahaye-Sourdeix, Manon; Li, Dalin; Bhatia, Smita; Melbye, Mads; Onel, Kenan; Jarrett, Ruth; McKay, James D.; Oksenberg, Jorge R.; Hjalgrim, Henrik
Background: Based on epidemiological commonalities, multiple sclerosis (MS) and Hodgkin lymphoma (HL), two clinically distinct conditions, have long been suspected to be aetiologically related. MS and HL occur in roughly the same age groups, both are associated with Epstein-Barr virus infection and
López-Isac, Elena; Martín, Jose-Ezequiel; Assassi, Shervin; Simeón, Carmen P; Carreira, Patricia; Ortego-Centeno, Norberto; Freire, Mayka; Beltrán, Emma; Narváez, Javier; Alegre-Sancho, Juan J; Fernández-Gutiérrez, Benjamín; Balsa, Alejandro; Ortiz, Ana M; González-Gay, Miguel A; Beretta, Lorenzo; Santaniello, Alessandro; Bellocchi, Chiara; Lunardi, Claudio; Moroncini, Gianluca; Gabrielli, Armando; Witte, Torsten; Hunzelmann, Nicolas; Distler, Jörg HW; Riekemasten, Gabriella; van der Helm-van Mil, Annete H; de Vries-Bouwstra, Jeska; Magro-Checa, Cesar; Voskuyl, Alexandre E; Vonk, Madelon C; Molberg, Øyvind; Merriman, Tony; Hesselstrand, Roger; Nordin, Annika; Padyukov, Leonid; Herrick, Ariane; Eyre, Steve; Koeleman, Bobby PC; Denton, Christopher P; Fonseca, Carmen; Radstake, Timothy RDJ; Worthington, Jane; Mayes, Maureen D; Martín, Javier
Objectives Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that share clinical and immunological characteristics. To date, several shared SSc-RA loci have been identified independently. In this study, we aimed to systematically search for new common SSc-RA loci through an inter-disease meta-GWAS strategy. Methods We performed a meta-analysis combining GWAS datasets of SSc and RA using a strategy that allowed identification of loci with both same-direction and opposing-direction allelic effects. The top single-nucleotide polymorphisms (SNPs) were followed-up in independent SSc and RA case-control cohorts. This allowed us to increase the sample size to a total of 8,830 SSc patients, 16,870 RA patients and 43,393 controls. Results The cross-disease meta-analysis of the GWAS datasets identified several loci with nominal association signals (P-value < 5 × 10-6), which also showed evidence of association in the disease-specific GWAS scan. These loci included several genomic regions not previously reported as shared loci, besides risk factors associated with both diseases in previous studies. The follow-up of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these two diseases (Pcombined = 3.29 × 10-12). In addition, the analysis of the biological relevance of the known SSc-RA shared loci pointed to the type I interferon and the interleukin 12 signaling pathways as the main common etiopathogenic factors. Conclusions Our study has identified a novel shared locus, IRF4, for SSc and RA and highlighted the usefulness of cross-disease GWAS meta-analysis in the identification of common risk loci. PMID:27111665
Thyssen, J P; Johansen, J D; Carlsen, B C; Linneberg, A; Meldgaard, M; Szecsi, P B; Stender, S; Menné, T
Psoriasis vulgaris could be associated with the filaggrin null genotype since certain known susceptibility loci for psoriasis are shared with susceptibility loci for atopic dermatitis. Furthermore, filaggrin expression is lowered in psoriatic skin lesions but normally expressed in uninvolved skin. So far five relatively small patient-based case-control studies have rejected a possible association between psoriasis and the two most prevalent filaggrin null mutations, 2282del4 and R501X. To reinvestigate a possible association between psoriasis and filaggrin null mutation status by using cross-sectional general population questionnaire data. Also, to perform a meta-analysis including published studies that investigated the relation between filaggrin gene mutations R501X and 2282del4, respectively, and psoriasis vulgaris. Between June 2006 and May 2008, a cross-sectional study was performed in the general population in Copenhagen. A random sample of 7931 subjects aged 18-69 years was invited to participate in a general health examination including a questionnaire and 3471 (43.7%) participated. A total of 3335 (96.1%) individuals were filaggrin genotyped for the 2282del4 and R501X mutations. A meta-analysis was undertaken to investigate the relation between filaggrin gene mutations and psoriasis vulgaris. The prevalence of self-reported psoriasis was 6.7% among the 3240 respondents. The prevalence of the R501X and 2282del4 filaggrin null genotypes was 9.3% in subjects who reported psoriasis and 8.0% in subjects who did not report psoriasis (OR = 1.28; 95% CI = 0.74-1.89; P = 0.78). The meta-analysis found no association between the filaggrin null genotypes R501X and 2282del4 and psoriasis (OR = 1.04; 95% CI = 0.81-1.35). Psoriasis was not associated with the R501X and 2282del4 filaggrin null genotypes in a general population study and in a meta-analysis on published studies. © 2011 The Authors. Journal of the European Academy
Zhernakova, Alexandra; Stahl, Eli A; Trynka, Gosia; Raychaudhuri, Soumya; Festen, Eleanora A; Franke, Lude; Westra, Harm-Jan; Fehrmann, Rudolf S N; Kurreeman, Fina A S; Thomson, Brian; Gupta, Namrata; Romanos, Jihane; McManus, Ross; Ryan, Anthony W; Turner, Graham; Brouwer, Elisabeth; Posthumus, Marcel D; Remmers, Elaine F; Tucci, Francesca; Toes, Rene; Grandone, Elvira; Mazzilli, Maria Cristina; Rybak, Anna; Cukrowska, Bozena; Coenen, Marieke J H; Radstake, Timothy R D J; van Riel, Piet L C M; Li, Yonghong; de Bakker, Paul I W; Gregersen, Peter K; Worthington, Jane; Siminovitch, Katherine A; Klareskog, Lars; Huizinga, Tom W J; Wijmenga, Cisca; Plenge, Robert M
Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated Pshared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.
Toma, Claudio; Hervás, Amaia; Torrico, Bàrbara; Balmaña, Noemí; Salgado, Marta; Maristany, Marta; Vilella, Elisabet; Martínez-Leal, Rafael; Planelles, Ma Inmaculada; Cuscó, Ivon; del Campo, Miguel; Pérez-Jurado, Luis A; Caballero-Andaluz, Rafaela; de Diego-Otero, Yolanda; Pérez-Costillas, Lucía; Ramos-Quiroga, Josep A; Ribasés, Marta; Bayés, Mònica; Cormand, Bru
Impairment of language abilities is a common feature in autistic individuals. Heterozygous mutations in the Forkhead Box P2 (FOXP2) gene lead to a severe spoken language disorder. Recently, several studies have pinpointed the involvement of common variants of the Contactin-Associated Protein-Like 2 (CNTNAP2) gene, whose transcription is regulated by the product of FOXP2, in several disorders characterized by language impairments such as autism, specific language impairment (SLI), and selective mutism (SM). In the present study, common variants of the FOXP2 and the CNTNAP2 genes were analyzed through a case-control association study in 322 Spanish autistic patients and 524 controls. The results of this study suggest that common variants of FOXP2 are unlikely to contribute to autism susceptibility, in agreement with previous findings. Furthermore, we failed to replicate in our sample a previous association finding of two single nucleotide polymorphisms (rs2710102 and rs7794745) in the CNTNAP2 gene with autism. No evidence for the association of these genes with language traits was observed in our analysis.
Radua, Joaquim; Del Pozo, Natalia Ojeda; Gómez, José; Guillen-Grima, Francisco; Ortuño, Felipe
We hypothesize that time perception and executive functions are interrelated and share neuroanatomical basis, and that fluctuations in levels of cognitive effort play a role in mediating that relation. The main goal of this study was to identify brain structures activated both by increases in cognitive activity and during time perception tasks. We performed a multimodal meta-analysis to identify common brain regions in the findings of (a) an SDM meta-analysis of neuroimaging studies assessing the brain response to increasing levels of cognitive difficulty, and (b) an ALE meta-analysis on neuroimaging of time perception (Ortuño, Guillén-Grima, López-García, Gómez, & Pla, 2011. Schizophr. Res., 125(2-3), 129-35). Consistent with results of previous, separate meta-analyses, the current study supports the hypothesis that there exists a group of brain regions engaged both in time perception tasks and during tasks requiring cognitive effort. Thus, brain regions associated with working memory and executive functions were found to be engaged during time estimation tasks, and regions associated with time perception were found to be engaged by an increase in the difficulty of non-temporal tasks. The implication is that temporal perception and cognitive processes demanding cognitive control become interlinked when there is an increase in the level of cognitive effort demanded. Copyright © 2014 Elsevier Ltd. All rights reserved.
Full Text Available Results of the association of folate metabolism and carcinogenesis are conflicting. We performed a meta-analysis to examine the effect of the interaction of serum concentration of homocysteine (Hcy, folate, and vitamin B12 and 5,10-methylenetetrahydrofolate reductase (MTHFR polymorphism on risk of cancer overall.Two reviewers independently searched for all published studies of Hcy and cancer in PubMed, EMBASE-MEDLINE and Chinese databases. Pooled results were reported as odds ratios (ORs and mean differences and presented with 95% confidence intervals (95% CIs and 2-sided probability values.We identified 83 eligible studies of 15,046 cases and 20,712 controls. High level of Hcy but low level of folate was associated with risk of cancer overall, with little effect by type of cancer or ethnicity. Vitamin B12 level was inversely associated with only urinary-system and gastrointestinal carcinomas and for Asian and Middle Eastern patients. As well, MTHFR C677T, A1298C and G1793A polymorphisms were related to elevated serum level of Hcy, and folate and vitamin B12 deficiency. However, only MTHFR C677T homogeneity/wild-type (TT/CC polymorphism was positively associated with overall risk of cancer.Elevated serum Hcy level and folate deficiency are associated with increased overall risk of cancer.
Zillikens, M. C.; Demissie, Serkalem; Hsu, Yi Hsiang; Laura M Yerges-Armstrong; Chou, Wen?Chi; Stolk, Lisette; Livshits, Gregory; Broer, Linda; Johnson, Toby; Koller, Daniel L.; Kutalik, Zoltán; Luan, J.A.; Malkin, Ida; Ried, Janina S.; Smith, Albert V.
We acknowledge the essential role of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium in development and support of this manuscript. CHARGE members include the Netherland’s Rotterdam Study (RS), Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), the NHLBI’s Atherosclerosis Risk in Communities (ARIC) Study, and Iceland’s Age, Gene/Environment Susceptibility (AGES) Reykjavik Study. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykja...
Full Text Available Ai-Min Gong,1,2,* Xin-Yuan Li,2,* Yi-Qiang Xie,1 Zhan-Dong Jia,3 Yuan-Xin Li,4 Yong-Yan Zou,5 Chang-Qing Xu,2,* Zhen-Yu Wang2,* 1Department of Internal Medicine of Traditional Chinese Medicine, Hainan Medical University, Hainan, 2Department of Pathophysiology, Harbin Medical University, Harbin, 3Department of Nephrology, Ningbo Tradition Chinese Medicine Hospital affiliated to Zhejiang Chinese Medical University, Ningbo, 4The Fifth Department of Acupuncture, 5Department of Nephrology, Jining Tradition Chinese Medicine Hospital, Jining, People’s Republic of China *These authors contributed equally to this work Purpose: The association between CD14 -159C/T polymorphism and the susceptibility to gastric cancer (GC has been reported. However, the results were inconclusive. In the present study, a case–control study and a meta-analysis were performed to assess the possible association between -159C/T in the CD14 gene and GC risk. Patients and methods: Relevant studies were searched in several databases including PubMed, Web of Science, EMBASE, Chinese National Knowledge Infrastructure database, and Wanfang database (last search was performed on December 30, 2015. In addition, a case–control study involving 164 GC cases and 169 controls was also performed in the analysis. Statistical analysis was performed by the software Revman5.3.Results: A total of ten published studies and the present case–control study involving 2,844 GC and 3,983 controls were included for the meta-analysis. The analysis result indicated that the T allele of CD14 -159C/T polymorphism did not confer risk for GC (in our study: [P=0.93]; in the meta-analysis: T vs 2N odds ratio =1.28 and 95% confidence interval (CI =0.95–1.24, [P=0.24]. However, we found a significant association in the recessive model (in our study: TT vs TC+CC [P=0.04]; in the meta-analysis: TT vs TC+CC odds ratio =1.12 and 95% CI =1.01–1.26, [P=0.04]. Furthermore, a subgroup analysis by ethnicity
Content analysis of 1,000 job ads in marketing, management, finance, and human resource management showed that ads were significantly more likely to ask for specific personal skills relevant to the job category. A survey of 170 companies that placed the ads indicated their motives for stipulating personal skills; two-thirds conducted formal job…
Ji, Yinwen; Song, Fei; Xu, Bo; Zhu, Yining; Lu, Chuncheng; Xia, Yankai
Studies of the associations between maternal exposure to particulate matter (PM) and risk of adverse effects on fetal growth are inconsistent and inconclusive. This question can be well answered by carefully designed birth cohort studies; however, so far the evidence from such studies has not come to the same conclusion. We sought to evaluate the association between maternal exposures to PM and low birthweight (LBW) enrolling 14 studies from 11 centers, and to explore the influence of trimester and exposure assessment methods on between-center heterogeneity in this association. Data were derived from PubMed, Embase, Google Scholar, CNKI, and WanFang database, references from relevant articles, and results from published studies until March 2017. Using a random-effects meta-analysis, we combined the coefficient and odds ratios (OR) of individual studies conducted among 14 birth cohort studies. Random-effect meta-analysis results suggested that a 17% and 6% increase in risk of LBW was relevant to a 10 mg/m(3) rise in PM2.5 and PM10 exposure concentrations at the 3rd trimester (pooled odds ratios (OR), 1.17 and 1.06; 95% confidence interval (CI), 0.94-1.46 and 0.97-1.15, respectively), but the null value was included in our 95% CI. Our results showed that exposure to PM2.5 and PM10 during pregnancy has a positive relevance to LBW based on birth cohort studies. However, neither reached formal statistical significance. Negative impacts on outcomes of birth is implied by maternal exposure to PM. Further mechanistic researches are needed to explain the connection between PM pollution and LBW.
Amin, Najaf; Hottenga, Jouke-Jan; Hansell, Narelle K; Janssens, A Cecile J W; de Moor, Marleen H M; Madden, Pamela A F; Zorkoltseva, Irina V; Penninx, Brenda W; Terracciano, Antonio; Uda, Manuela; Tanaka, Toshiko; Esko, Tonu; Realo, Anu; Ferrucci, Luigi; Luciano, Michelle; Davies, Gail; Metspalu, Andres; Abecasis, Goncalo R; Deary, Ian J; Raikkonen, Katri; Bierut, Laura J; Costa, Paul T; Saviouk, Viatcheslav; Zhu, Gu; Kirichenko, Anatoly V; Isaacs, Aaron; Aulchenko, Yurii S; Willemsen, Gonneke; Heath, Andrew C; Pergadia, Michele L; Medland, Sarah E; Axenovich, Tatiana I; de Geus, Eco; Montgomery, Grant W; Wright, Margaret J; Oostra, Ben A; Martin, Nicholas G; Boomsma, Dorret I; van Duijn, Cornelia M
Personality traits are complex phenotypes related to psychosomatic health. Individually, various gene finding methods have not achieved much success in finding genetic variants associated with personality traits. We performed a meta-analysis of four genome-wide linkage scans (N=6149 subjects) of five basic personality traits assessed with the NEO Five-Factor Inventory. We compared the significant regions from the meta-analysis of linkage scans with the results of a meta-analysis of genome-wide association studies (GWAS) (N∼17 000). We found significant evidence of linkage of neuroticism to chromosome 3p14 (rs1490265, LOD=4.67) and to chromosome 19q13 (rs628604, LOD=3.55); of extraversion to 14q32 (ATGG002, LOD=3.3); and of agreeableness to 3p25 (rs709160, LOD=3.67) and to two adjacent regions on chromosome 15, including 15q13 (rs970408, LOD=4.07) and 15q14 (rs1055356, LOD=3.52) in the individual scans. In the meta-analysis, we found strong evidence of linkage of extraversion to 4q34, 9q34, 10q24 and 11q22, openness to 2p25, 3q26, 9p21, 11q24, 15q26 and 19q13 and agreeableness to 4q34 and 19p13. Significant evidence of association in the GWAS was detected between openness and rs677035 at 11q24 (P-value=2.6 × 10(-06), KCNJ1). The findings of our linkage meta-analysis and those of the GWAS suggest that 11q24 is a susceptible locus for openness, with KCNJ1 as the possible candidate gene.
Song, Qi-Ying; Luo, Wei-Ping; Zhang, Cai-Xia
The exact cause of hypertensive disorders in pregnancy (HDP) has not been clearly elucidated. Some researchers have recently investigated the relationship between the serum iron level and the incidence of HDP. However, the results are inconsistent, and these data have not been systematically evaluated. Therefore, we conducted a meta-analysis to evaluate the real association between the serum iron level and the incidence of HDP. We searched for published and ongoing trials in PubMed, EMBASE, Scopus, Web of Science, the Chinese Biomedical Database, CNKI, and the WANFANG database from January 1990 to May 2015 to identify studies that met our predefined criteria. Finally, 26 studies, including 1 cross-sectional study, 23 case-control studies, and 2 prospective nested case-control studies, including 1349 patients and 1119 control participants, were selected for this meta-analysis. The pooled results show that a high serum iron level increased the incidence of HDP (standard mean deviation [SMD], 1.50; 95% confidence interval [CI], 0.94-2.06; P high serum iron level is associated with an increased risk of HDP, especially gestational hypertension and preeclampsia. Copyright © 2015 Elsevier Inc. All rights reserved.
Chen, Xin-Ping; Xu, Da-Feng; Xu, Wei-Hua; Ma, Zhi-Chao; Yao, Jia; Fu, Sheng-Miao
Although many epidemiological studies have investigated the CYP1A1 exon7 polymorphism and -GSTM1 interaction with esophageal cancer (EC), definite conclusions cannot be drawn. This study was conducted to explore this association in the Chinese population using meta-analysis. Relevant studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure, and Chinese Biology Medicine databases published through August 2015. The association of CYP1A1 exon7 polymorphisms and EC risk was estimated by odds ratio (ORs) with 95% confidence intervals (CIs). In addition, the interaction between the CYP1A1 exon7 and GSTM1 genotypes was assessed. A total of 13 case-control studies including 1781 EC cases and 1996 controls were included in this metaanalysis. Overall, significantly increased EC risk was associated with the CYP1A1 exon7 polymorphism (G vs. A OR = 1.36, 95% CI = 1.14 - 1.64; GG vs. AA: OR = 1.85, 95% CI = 1.22 - 2.79; GG vs. AG: OR = 1.41, 95% CI = 1.01 - 1.96; GG + AG vs. AA: OR = 1.47, 95% CI = 1.28 - 1.68; GG vs. AA + AG: OR = 1.60, 95% CI = 1.10 - 2.31). In a subgroup analyses stratified by geographic areas, histopathology type and source of controls, the significant risk was found in hospital-based population, in South and North China. Analysis of CYP1A1- GSTM1 interaction did find synergistic interaction between these two genes. This meta-analysis provides the evidence that CYP1A1 exon7 polymorphism may contribute to the EC development in the Chinese population, and CYP1A1- GSTM1 interaction might elevate the risk.
Wu, Ying; Gao, He; Li, Huaixing; Tabara, Yasuharu; Nakatochi, Masahiro; Chiu, Yen-Feng; Park, Eun Jung; Wen, Wanqing; Adair, Linda S.; Borja, Judith B.; Cai, Qiuyin; Chang, Yi-Cheng; Chen, Peng; Croteau-Chonka, Damien C.; Fogarty, Marie P.; Gan, Wei; He, Chih-Tsueng; Hsiung, Chao A.; Hwu, Chii-Min; Ichihara, Sahoko; Igase, Michiya; Jo, Jaeseong; Kato, Norihiro; Kawamoto, Ryuichi; Kuzawa, Christophor W.; Lee, Jeannette J.M.; Liu, Jianjun; Lu, Ling; Mcdade, Thomas W.; Osawa, Haruhiko; Sheu, Wayne H-H.; Teo, Yvonne; Vadlamudi, Swarooparani; Van Dam, Rob M.; Wang, Yiqin; Xiang, Yong-Bing; Yamamoto, Ken; Ye, Xingwang; Young, Terri L.; Zheng, Wei; Zhu, Jingwen; Shu, Xiao-Ou; Shin, Chol; Jee, Sun Ha; Chuang, Lee-Ming; Miki, Tetsuro; Yokota, Mitsuhiro; Lin, Xu; Mohlke, Karen L; Tai, E Shyong
Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10−14) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10−7). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10−165), ADIPOQ (P = 1.8 × 10−22), PEPD (P = 3.6 × 10−12), CMIP (P = 2.1 × 10−10), ZNF664 (P = 2.3 × 10−7) and GPR109A (P = 7.4 × 10−6). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10−7). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P = 3.3 × 10−4), high density lipoprotein cholesterol (HDL-C, P = 4.9 × 10−4) and body mass index (BMI)-adjusted waist–hip ratio (P = 9.8 × 10−3). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms. PMID:24105470
Shen, Xingrong; Li, Kaichun; Chen, Penglai; Feng, Rui; Liang, Han; Tong, Guixian; Chen, Jing; Chai, Jing; Shi, Yong; Xie, Shaoyu; Wang, Debin
The whole range of blood pressure (BP) has important implications. Yet, published studies focus primarily on hypertension and hypotension, the two extremes of BP continuum. This study aims at exploring quantile-specific associations of BP with common factors. The study used cross-sectional survey, collected information about gender, age, education, body mass index (BMI), alcohol intake, diet risk behavior, life event index, physical activity, fasting capillary glucose (FCG), and systolic/diastolic blood pressure (SBP/DBP) and pulse pressure (PP) from farmers living in 18 villages from rural Anhui, China, and performed descriptive and multivariate and quantile regression (QR) analysis of associations of SBP, DBP, or PP with the 9 factors surveyed. A total of 4040 (86.3%) eligible farmers completed the survey. Average hypertension prevalence rate and SBP, DBP, and PP values estimated 43.20 ± 0.50% and 141.37 ± 21.98, 87.76 ± 12.23, and 53.63 ± 15.72 mm Hg, respectively. Multivariate regression analysis revealed that all the 9 factors were significantly (P < 0.05) associated with one or more of SBP, DBP, and PP. QR coefficients of SBP, DBP, or PP with different factors demonstrated divergent patterns and age, BMI, FCG, and life event index showed substantial trends along the quantile axis. Hypertension prevalence rate was high among the farmers. QR modeling provided more detailed view on associations of SBP, DBP, or PP with different factors and uncovered apparent quantile-related patterns for part of the factors. Both the population group studied and the trends in QR coefficients identified merit specific attention.
Maggie C Y Ng
Full Text Available Type 2 diabetes (T2D is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1 and two novel loci (HLA-B and INS-IGF2 at genome-wide significance (4.15 × 10(-94
association (2.2 × 10(-23 < locus-wide P<0.05. These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.
Larson, Nicholas B; McDonnell, Shannon; Albright, Lisa Cannon; Teerlink, Craig; Stanford, Janet; Ostrander, Elaine A; Isaacs, William B; Xu, Jianfeng; Cooney, Kathleen A; Lange, Ethan; Schleutker, Johanna; Carpten, John D; Powell, Isaac; Bailey-Wilson, Joan; Cussenot, Olivier; Cancel-Tassin, Geraldine; Giles, Graham; MacInnis, Robert; Maier, Christiane; Whittemore, Alice S; Hsieh, Chih-Lin; Wiklund, Fredrik; Catolona, William J; Foulkes, William; Mandal, Diptasri; Eeles, Rosalind; Kote-Jarai, Zsofia; Ackerman, Michael J; Olson, Timothy M; Klein, Christopher J; Thibodeau, Stephen N; Schaid, Daniel J
Rare variants (RVs) have been shown to be significant contributors to complex disease risk. By definition, these variants have very low minor allele frequencies and traditional single-marker methods for statistical analysis are underpowered for typical sequencing study sample sizes. Multimarker burden-type approaches attempt to identify aggregation of RVs across case-control status by analyzing relatively small partitions of the genome, such as genes. However, it is generally the case that the aggregative measure would be a mixture of causal and neutral variants, and these omnibus tests do not directly provide any indication of which RVs may be driving a given association. Recently, Bayesian variable selection approaches have been proposed to identify RV associations from a large set of RVs under consideration. Although these approaches have been shown to be powerful at detecting associations at the RV level, there are often computational limitations on the total quantity of RVs under consideration and compromises are necessary for large-scale application. Here, we propose a computationally efficient alternative formulation of this method using a probit regression approach specifically capable of simultaneously analyzing hundreds to thousands of RVs. We evaluate our approach to detect causal variation on simulated data and examine sensitivity and specificity in instances of high RV dimensionality as well as apply it to pathway-level RV analysis results from a prostate cancer (PC) risk case-control sequencing study. Finally, we discuss potential extensions and future directions of this work. © 2016 WILEY PERIODICALS, INC.
Chen, Cai; Yang, Yan; Yu, Xuefeng; Hu, Shuhong; Shao, Shiying
Epidemiological evidence for the effect of omega-3 fatty acids on the risk of type 2 diabetes is controversial. A meta-analysis based on prospective cohorts was carried out to evaluate this issue. Pooled diabetic risk was calculated using a fixed or random effects model. The dose-response relationship was assessed by meta-regression analysis. The study showed that consumption of single omega-3 was associated with an increased risk of type 2 diabetes (relative risk [RR] = 1.45, P omega-3 was statistically insignificant. The dose-response curve presented an inverted U-shape of diabetes risk corresponding to the dose of omega-3 consumption. Subanalysis showed that omega-3 was inversely associated with type 2 diabetes risk in Asians (RR = 0.82, P omega-3 intake. The present findings suggest that dosage and composition of omega-3, ethnicity, trial duration, and age could influence the effect of omega-3 on type 2 diabetes progression. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.
Soutome, Sakiko; Yanamoto, Souichi; Funahara, Madoka; Hasegawa, Takumi; Komori, Takahide; Yamada, Shin-Ichi; Kurita, Hiroshi; Yamauchi, Chika; Shibuya, Yasuyuki; Kojima, Yuka; Nakahara, Hirokazu; Oho, Takahiko; Umeda, Masahiro
The aim of this study was to investigate the effectiveness of oral care in prevention of postoperative pneumonia associated with esophageal cancer surgery.Postoperative pneumonia is a severe adverse event associated with esophageal cancer surgery. It is thought to be caused by aspiration of oropharyngeal fluid containing pathogens. However, the relationship between oral health status and postoperative pneumonia has not been well investigated.This study included 539 patients with esophageal cancer undergoing surgery at 1 of 7 university hospitals. While 306 patients received perioperative oral care, 233 did not. Various clinical factors as well as occurrence of postoperative pneumonia were retrospectively evaluated. Propensity-score matching was performed to minimize selection biases associated with comparison of retrospective data between the oral care and control groups. Factors related to postoperative pneumonia were analyzed by logistic regression analysis.Of the original 539 patients, 103 (19.1%) experienced postoperative pneumonia. The results of multivariate analysis of the 420 propensity score-matched patients revealed longer operation time, postoperative dysphagia, and lack of oral care intervention to be significantly correlated with postoperative pneumonia.The present findings demonstrate that perioperative oral care can reduce the risk of postoperative pneumonia in patients undergoing esophageal cancer surgery.
Gao, Chuan; Hsu, Fang-Chi; Dimitrov, Latchezar M; Okut, Hayrettin; Chen, Yii-Der I; Taylor, Kent D; Rotter, Jerome I; Langefeld, Carl D; Bowden, Donald W; Palmer, Nicholette D
Insertions and deletions (INDELs) represent a significant fraction of interindividual variation in the human genome yet their contribution to phenotypes is poorly understood. To confirm the quality of imputed INDELs and investigate their roles in mediating cardiometabolic phenotypes, genome-wide association and linkage analyses were performed for 15 phenotypes with 1,273,952 imputed INDELs in 1,024 Mexican-origin Americans. Imputation quality was validated using whole exome sequencing with an average kappa of 0.93 in common INDELs (minor allele frequencies [MAFs] ≥ 5%). Association analysis revealed one genome-wide significant association signal for the cholesterylester transfer protein gene (CETP) with high-density lipoprotein levels (rs36229491, P = 3.06 × 10-12 ); linkage analysis identified two peaks with logarithm of the odds (LOD) > 5 (rs60560566, LOD = 5.36 with insulin sensitivity (SI ) and rs5825825, LOD = 5.11 with adiponectin levels). Suggestive overlapping signals between linkage and association were observed: rs59849892 in the WSC domain containing 2 gene (WSCD2) was associated and nominally linked with SI (P = 1.17 × 10-7 , LOD = 1.99). This gene has been implicated in glucose metabolism in human islet cell expression studies. In addition, rs201606363 was linked and nominally associated with low-density lipoprotein (P = 4.73 × 10-4 , LOD = 3.67), apolipoprotein B (P = 1.39 × 10-3 , LOD = 4.64), and total cholesterol (P = 1.35 × 10-2 , LOD = 3.80) levels. rs201606363 is an intronic variant of the UBE2F-SCLY (where UBE2F is ubiquitin-conjugating enzyme E2F and SCLY is selenocysteine lyase) fusion gene that may regulate cholesterol through selenium metabolism. In conclusion, these results confirm the feasibility of imputing INDELs from array-based single nucleotide polymorphism (SNP) genotypes. Analysis of these variants using association and linkage replicated previously identified SNP signals and identified multiple novel INDEL signals. These
Carrillo-Vega, María Fernanda; García-Peña, Carmen; Gutiérrez-Robledo, Luis Miguel; Pérez-Zepeda, Mario Ulises
Vitamin D deficiency was common in older adults from a country with adequate sun exposure. The variables associated with this deficiency provide insight into the next steps needed to characterize older adults with this deficiency and to treat it accordingly. The aim of this study was to describe the prevalence of and factors associated with vitamin D deficiency among Mexican older adults. This was a secondary analysis of the last wave of the Mexican Health and Aging Study. Vitamin D levels along with other biomarkers were obtained from a sub-sample of Mexican adults older than 60 years. Prevalence was described by sex and age group, and a multivariate analysis was performed to test the factors associated with this condition. Data from 1088 adults over the age of 60 years were analyzed. The mean serum vitamin D level was 23.1 ± 8.1 ng/mL and was significantly higher among men than women (25.6 ± 0.6 and 22.8 ± 0.5 ng/mL, respectively; p vitamin D deficiency, 65% of whom were women. Low 25-(OH)-vitamin D levels were associated with female sex (OR 1.74, 95% CI 1.59-2.42), current smoking (OR 2.21, 95% CI 1.47-3.39), education (OR 1.1, 95% CI 1.06-1.13), physical activity (OR 1.74, 95% CI 1.31-2.23), and high levels of glycated hemoglobin (OR 1.16, 95% CI 1.07-1.25). Vitamin D deficiency was highly prevalent in Mexican older adults and was associated with a number of factors, indicating the multifactorial causality of this deficiency.
Grubbs, Vanessa; Vittinghoff, Eric; Taylor, George; Kritz-Silverstein, Donna; Powe, Neil; Bibbins-Domingo, Kirsten; Ishani, Areef; Cummings, Steven R
Identifying modifiable risk factors for chronic kidney disease (CKD) is essential for reducing its burden. Periodontal disease is common, modifiable and has been implicated as a novel potential CKD risk factor, but evidence of its association with kidney function decline over time is limited. In a longitudinal retrospective cohort of 761 elderly men with preserved kidney function [estimated glomerular filtration rate > 60 mL/min/1.73 m(2) using a calibrated creatinine and cystatin C (eGFRcr-cys) equation] at baseline, we performed multivariable Poisson's regression to examine the association of severe periodontal disease with incident CKD, defined as incident eGFRcr-cys 5% annualized) eGFRcr-cys decline. Severe periodontal disease was defined in two ways: (i) ≥5 mm proximal attachment loss in 30% of teeth examined (European Workshop in Periodontology Group C, European Workshop); and (ii) 2+ interproximal sites with attachment loss ≥6 mm and 1+ interproximal sites with probing depth ≥5 mm (Centers for Disease Control/American Academy of Periodontology, CDC/AAP). At baseline, the mean age was 73.4 (SD 4.8) years, the median eGFRcr-cys was 82.4 mL/min/1.73 m(2), and 35.5 and 25.4% of participants had severe periodontal disease by European Workshop and CDC/AAP criteria, respectively. After a mean follow-up of 4.9 years (SD 0.3), 56 (7.4%) participants had incident CKD. Severe periodontal disease was associated with a 2-fold greater rate of incident CKD [incidence rate ratio (IRR) 2.01 (1.21-3.44), P = 0.007] after adjusting for confounders compared with not severe periodontal disease by European Workshop criteria but did not reach statistical significance by CDC/AAP criteria [IRR 1.10 (0.63-1.91), P = 0.9]. Severe periodontal disease may be associated with incident clinically significant kidney function decline among a cohort of elderly men. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
Liu, Xu; Li, Qu; Zhu, Ruixia; He, Zhiyi
Interleukin-10 (IL-10) plays a vital part in the pathophysiology of vascular inflammation. Several studies have investigated the potential association between the IL-10-1082A/G polymorphism and the risk of ischemic stroke where the inflammatory process is involved, but the conclusions have been inconsistent. Three hundred eighty-six ischemic stroke patients and 386 healthy controls were recruited in the study. Genotyping was conducted by using the polymerase chain reaction-ligation detection reaction method. A meta-analysis was then performed by pooling our data with previous published studies. In our case-control study, a lack of association was revealed between IL-10-1082A/G and ischemic stroke (p > 0.05). When combined with previous studies, however, a significant relationship between IL-10-1082A/G and ischemic stroke risk was found (G vs. A: OR = 0.73, 95% CI = 0.60-0.88, p IL-10-1082A/G polymorphism is associated with ischemic stroke susceptibility.
Full Text Available BACKGROUND: Genetic variations in vitamin D receptor (VDR may contribute to tuberculosis (TB risk. Many studies have investigated the association between VDR BsmI gene polymorphism and TB risk, but yielded inconclusive results. METHODOLOGY/PRINCIPAL FINDINGS: We performed a comprehensive meta-analysis of 15 publications with a total of 2309 cases and 3568 controls. We assessed the strength of the association between VDR BsmI gene polymorphism and TB risk and performed sub-group analyses by ethnicity, sample size and Hardy-Weinberg equilibrium (HWE. We found a statistically significant correlation between VDR BsmI gene polymorphism and decreased TB risk in four comparison models: allele model (b vs. B: OR = 0.78, 95% CI = 0.67, 0.89; Pheterogeneity = 0.004, homozygote model (bb vs. BB: OR = 0.61, 95% CI = 0.43, 0.87; Pheterogeneity = 0.001, recessive model (bb vs. Bb+BB: OR = 0.70, 95% CI = 0.56, 0.88; Pheterogeneity = 0.005 and dominant model (bb+Bb vs. BB: OR = 0.77, 95% CI = 0.61, 0.97; Pheterogeneity = 0.010, especially in studies based on Asian population. Sub-group analyses also revealed that there was a statistically decreased TB risk in "small" studies (0.5. Meta-regression and stratification analysis both showed that the ethnicity and sample size contributed to heterogeneity. CONCLUSIONS: This meta-analysis suggests that VDR BsmI gene polymorphism is associated with a significant decreased TB risk, especially in Asian population.
Murabito, Joanne M; White, Charles C; Kavousi, Maryam
additive genetic models. Study-specific data were combined using fixed-effects inverse variance weighted meta-analyses. There were a total of 41,692 participants of European ancestry (~60% women, mean ABI 1.02 to 1.19), including 3,409 participants with PAD and with GWAS data available. In the discovery...
Full Text Available Methionine synthase (MTR is one of the key enzymes of folate pathway, which play a key role in the construction, repair, and methylation of DNA. In this study, an association of MTR A2756G gene transition with prostate cancer in men populations of Kashan-Iran was investigated by a case-control study and an in silico analysis. The 200 samples including 100 patients with prostate cancer, as case group and 100 healthy men, as control group included in this study. MTR-A2756G genotyping was performed by PCR-RFLP technique. Some in silico tools used to evaluate the effects of A2756G transition on the structure and function of MTR. Results showed that the AG genotype (OR: 2.4014, 95% CI: 1.3216-4.3636, P=0.0040, and GG genotype (OR: 3.6324, 95% CI: 1.2629-10.4475, P=0.0167 and G allele (OR: 2.0120, 95% CI: 1.3098-3.0905, P=0.0014 were associated with prostate cancer. In silico analysis showed that polymorphisms of the enzyme protein might change properties of MTR such as relative mutability and flexibility, which leads to alteration of stability and function of the enzyme. Based on the results, an MTR-A2756G polymorphism which changes activity and stability of the methionine synthase associated with prostate cancer in men. It is a preliminary study and is presenting data for future comprehensive study for making a clinical conclusion that this gene transition is a biomarker for susceptibility to prostate cancer.
Sampson, Joshua N; Wheeler, William A; Yeager, Meredith; Panagiotou, Orestis; Wang, Zhaoming; Berndt, Sonja I; Lan, Qing; Abnet, Christian C; Amundadottir, Laufey T; Figueroa, Jonine D; Landi, Maria Teresa; Mirabello, Lisa; Savage, Sharon A; Taylor, Philip R; Vivo, Immaculata De; McGlynn, Katherine A; Purdue, Mark P; Rajaraman, Preetha; Adami, Hans-Olov; Ahlbom, Anders; Albanes, Demetrius; Amary, Maria Fernanda; An, She-Juan; Andersson, Ulrika; Andriole, Gerald; Andrulis, Irene L; Angelucci, Emanuele; Ansell, Stephen M; Arici, Cecilia; Armstrong, Bruce K; Arslan, Alan A; Austin, Melissa A; Baris, Dalsu; Barkauskas, Donald A; Bassig, Bryan A; Becker, Nikolaus; Benavente, Yolanda; Benhamou, Simone; Berg, Christine; Van Den Berg, David; Bernstein, Leslie; Bertrand, Kimberly A; Birmann, Brenda M; Black, Amanda; Boeing, Heiner; Boffetta, Paolo; Boutron-Ruault, Marie-Christine; Bracci, Paige M; Brinton, Louise; Brooks-Wilson, Angela R; Bueno-de-Mesquita, H Bas; Burdett, Laurie; Buring, Julie; Butler, Mary Ann; Cai, Qiuyin; Cancel-Tassin, Geraldine; Canzian, Federico; Carrato, Alfredo; Carreon, Tania; Carta, Angela; Chan, John K C; Chang, Ellen T; Chang, Gee-Chen; Chang, I-Shou; Chang, Jiang; Chang-Claude, Jenny; Chen, Chien-Jen; Chen, Chih-Yi; Chen, Chu; Chen, Chung-Hsing; Chen, Constance; Chen, Hongyan; Chen, Kexin; Chen, Kuan-Yu; Chen, Kun-Chieh; Chen, Ying; Chen, Ying-Hsiang; Chen, Yi-Song; Chen, Yuh-Min; Chien, Li-Hsin; Chirlaque, María-Dolores; Choi, Jin Eun; Choi, Yi Young; Chow, Wong-Ho; Chung, Charles C; Clavel, Jacqueline; Clavel-Chapelon, Françoise; Cocco, Pierluigi; Colt, Joanne S; Comperat, Eva; Conde, Lucia; Connors, Joseph M; Conti, David; Cortessis, Victoria K; Cotterchio, Michelle; Cozen, Wendy; Crouch, Simon; Crous-Bou, Marta; Cussenot, Olivier; Davis, Faith G; Ding, Ti; Diver, W Ryan; Dorronsoro, Miren; Dossus, Laure; Duell, Eric J; Ennas, Maria Grazia; Erickson, Ralph L; Feychting, Maria; Flanagan, Adrienne M; Foretova, Lenka; Fraumeni, Joseph F; Freedman, Neal D; Beane Freeman, Laura E; Fuchs, Charles; Gago-Dominguez, Manuela; Gallinger, Steven; Gao, Yu-Tang; Gapstur, Susan M; Garcia-Closas, Montserrat; García-Closas, Reina; Gascoyne, Randy D; Gastier-Foster, Julie; Gaudet, Mia M; Gaziano, J Michael; Giffen, Carol; Giles, Graham G; Giovannucci, Edward; Glimelius, Bengt; Goggins, Michael; Gokgoz, Nalan; Goldstein, Alisa M; Gorlick, Richard; Gross, Myron; Grubb, Robert; Gu, Jian; Guan, Peng; Gunter, Marc; Guo, Huan; Habermann, Thomas M; Haiman, Christopher A; Halai, Dina; Hallmans, Goran; Hassan, Manal; Hattinger, Claudia; He, Qincheng; He, Xingzhou; Helzlsouer, Kathy; Henderson, Brian; Henriksson, Roger; Hjalgrim, Henrik; Hoffman-Bolton, Judith; Hohensee, Chancellor; Holford, Theodore R; Holly, Elizabeth A; Hong, Yun-Chul; Hoover, Robert N; Horn-Ross, Pamela L; Hosain, G M Monawar; Hosgood, H Dean; Hsiao, Chin-Fu; Hu, Nan; Hu, Wei; Hu, Zhibin; Huang, Ming-Shyan; Huerta, Jose-Maria; Hung, Jen-Yu; Hutchinson, Amy; Inskip, Peter D; Jackson, Rebecca D; Jacobs, Eric J; Jenab, Mazda; Jeon, Hyo-Sung; Ji, Bu-Tian; Jin, Guangfu; Jin, Li; Johansen, Christoffer; Johnson, Alison; Jung, Yoo Jin; Kaaks, Rudolph; Kamineni, Aruna; Kane, Eleanor; Kang, Chang Hyun; Karagas, Margaret R; Kelly, Rachel S; Khaw, Kay-Tee; Kim, Christopher; Kim, Hee Nam; Kim, Jin Hee; Kim, Jun Suk; Kim, Yeul Hong; Kim, Young Tae; Kim, Young-Chul; Kitahara, Cari M; Klein, Alison P; Klein, Robert J; Kogevinas, Manolis; Kohno, Takashi; Kolonel, Laurence N; Kooperberg, Charles; Kricker, Anne; Krogh, Vittorio; Kunitoh, Hideo; Kurtz, Robert C; Kweon, Sun-Seog; LaCroix, Andrea; Lawrence, Charles; Lecanda, Fernando; Lee, Victor Ho Fun; Li, Donghui; Li, Haixin; Li, Jihua; Li, Yao-Jen; Li, Yuqing; Liao, Linda M; Liebow, Mark; Lightfoot, Tracy; Lim, Wei-Yen; Lin, Chien-Chung; Lin, Dongxin; Lindstrom, Sara; Linet, Martha S; Link, Brian K; Liu, Chenwei; Liu, Jianjun; Liu, Li; Ljungberg, Börje; Lloreta, Josep; Lollo, Simonetta Di; Lu, Daru; Lund, Eiluv; Malats, Nuria; Mannisto, Satu; Marchand, Loic Le; Marina, Neyssa; Masala, Giovanna; Mastrangelo, Giuseppe; Matsuo, Keitaro; Maynadie, Marc; McKay, James; McKean-Cowdin, Roberta; Melbye, Mads; Melin, Beatrice S; Michaud, Dominique S; Mitsudomi, Tetsuya; Monnereau, Alain; Montalvan, Rebecca; Moore, Lee E; Mortensen, Lotte Maxild; Nieters, Alexandra; North, Kari E; Novak, Anne J; Oberg, Ann L; Offit, Kenneth; Oh, In-Jae; Olson, Sara H; Palli, Domenico; Pao, William; Park, In Kyu; Park, Jae Yong; Park, Kyong Hwa; Patiño-Garcia, Ana; Pavanello, Sofia; Peeters, Petra H M; Perng, Reury-Perng; Peters, Ulrike; Petersen, Gloria M; Picci, Piero; Pike, Malcolm C; Porru, Stefano; Prescott, Jennifer; Prokunina-Olsson, Ludmila; Qian, Biyun; Qiao, You-Lin; Rais, Marco; Riboli, Elio; Riby, Jacques; Risch, Harvey A; Rizzato, Cosmeri; Rodabough, Rebecca; Roman, Eve; Roupret, Morgan; Ruder, Avima M; Sanjose, Silvia de; Scelo, Ghislaine; Schned, Alan; Schumacher, Fredrick; Schwartz, Kendra; Schwenn, Molly; Scotlandi, Katia; Seow, Adeline; Serra, Consol; Serra, Massimo; Sesso, Howard D; Setiawan, Veronica Wendy; Severi, Gianluca; Severson, Richard K; Shanafelt, Tait D; Shen, Hongbing; Shen, Wei; Shin, Min-Ho; Shiraishi, Kouya; Shu, Xiao-Ou; Siddiq, Afshan; Sierrasesúmaga, Luis; Sihoe, Alan Dart Loon; Skibola, Christine F; Smith, Alex; Smith, Martyn T; Southey, Melissa C; Spinelli, John J; Staines, Anthony; Stampfer, Meir; Stern, Marianna C; Stevens, Victoria L; Stolzenberg-Solomon, Rachael S; Su, Jian; Su, Wu-Chou; Sund, Malin; Sung, Jae Sook; Sung, Sook Whan; Tan, Wen; Tang, Wei; Tardón, Adonina; Thomas, David; Thompson, Carrie A; Tinker, Lesley F; Tirabosco, Roberto; Tjønneland, Anne; Travis, Ruth C; Trichopoulos, Dimitrios; Tsai, Fang-Yu; Tsai, Ying-Huang; Tucker, Margaret; Turner, Jenny; Vajdic, Claire M; Vermeulen, Roel C H|info:eu-repo/dai/nl/216532620; Villano, Danylo J; Vineis, Paolo; Virtamo, Jarmo; Visvanathan, Kala; Wactawski-Wende, Jean; Wang, Chaoyu; Wang, Chih-Liang; Wang, Jiu-Cun; Wang, Junwen; Wei, Fusheng; Weiderpass, Elisabete; Weiner, George J; Weinstein, Stephanie; Wentzensen, Nicolas; White, Emily; Witzig, Thomas E; Wolpin, Brian M; Wong, Maria Pik; Wu, Chen; Wu, Guoping; Wu, Junjie; Wu, Tangchun; Wu, Wei; Wu, Xifeng; Wu, Yi-Long; Wunder, Jay S; Xiang, Yong-Bing; Xu, Jun; Xu, Ping; Yang, Pan-Chyr; Yang, Tsung-Ying; Ye, Yuanqing; Yin, Zhihua; Yokota, Jun; Yoon, Ho-Il; Yu, Chong-Jen; Yu, Herbert; Yu, Kai; Yuan, Jian-Min; Zelenetz, Andrew; Zeleniuch-Jacquotte, Anne; Zhang, Xu-Chao; Zhang, Yawei; Zhao, Xueying; Zhao, Zhenhong; Zheng, Hong; Zheng, Tongzhang; Zheng, Wei; Zhou, Baosen; Zhu, Meng; Zucca, Mariagrazia; Boca, Simina M; Cerhan, James R; Ferri, Giovanni M; Hartge, Patricia; Hsiung, Chao Agnes; Magnani, Corrado; Miligi, Lucia; Morton, Lindsay M; Smedby, Karin E; Teras, Lauren R; Vijai, Joseph; Wang, Sophia S; Brennan, Paul; Caporaso, Neil E; Hunter, David J; Kraft, Peter; Rothman, Nathaniel; Silverman, Debra T; Slager, Susan L; Chanock, Stephen J; Chatterjee, Nilanjan
BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.
Associations of pregnancy-associated plasma protein-A level with essential hypertension and hypertensive disorders in pregnancy in Chinese population: a meta-analysis of 20 research studies involving 3332 individuals.
Cai, Gaojun; Zhang, Bifeng; Weng, Weijin; Yang, Liping; Shi, Ganwei; Xue, Sheliang; Fu, Xingli
To explore the associations between serum pregnancy-associated plasma protein-A (PAPP-A) level, and essential hypertension (EH) and hypertensive disorders in pregnancy (HDP) in Chinese population. Pertinent studies were independently searched in PubMed, Embase, Cochrane Library, Chinese Biomedical Database (CBM), Wanfang databases and China National Knowledge Infrastructure (CNKI). The standardised mean difference (SMD) with 95% CIs was used to estimate the size of the effect. The subgroup analyses and meta-regression analysis were performed to identify the sources of heterogeneity among studies. Sensitivity analysis was conducted to assess the stability of the results. The publication bias between studies was examined by using Begg's funnel plots and Egger's test. A total of 20 studies involving 1493 patients and 1839 controls were included in the current meta-analysis. The PAPP-A level was significantly higher in EH patients than in controls (SMD=1.960, 95% CI 1.305 to 2.615, pPAPP-A level was also significantly higher in HDP patients than in healthy pregnant women (SMD=2.249; 95% CI 1.324 to 3.173, pPAPP-A level and the risk of HDP was consistently observed in all subgroups except the subgroup with low NOS score. The present meta-analysis suggests that an elevated PAPP-A level may be associated with susceptibilities to EH and HDP. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Full Text Available OBJECTIVES Although the effect of physical activity (PA on the incidence of atrial fibrillation (AF has been studied, contradictory results have been reported. Such discrepancies may reflect the different effects of various types of PA upon AF, as well as gender interactions. Therefore, we aimed to evaluate the associations of PA types (total, moderate/vigorous, and intentional, as well as walking pace, with AF risk in men and women. METHODS Using the Multi-Ethnic Study of Atherosclerosis Typical Week Physical Activity Survey, 3 PA measures and walking pace were calculated among 6,487 men and women aged 45-84 years. The incidence of AF over approximately 11 years of follow-up was ascertained. The association of each PA measure and walking pace with AF incidence was estimated using multivariable Cox proportional hazard models. An extended Cox model with Heaviside functions (hv of time was used to estimate the effects of time-varying covariates. RESULTS During 11 years of follow-up (49,557 person-years, 242 new AF cases occurred. The incidence rate of AF was 48.83 per 10,000 person-years. The proportional hazard (PH assumption for total PA among women was not met; hence, we used the hv to calculate the hazard ratio. Total PA in women in the hv2 analysis was negatively associated with AF in all 3 models, although for hv1 no significant association was observed. The PH assumption for walking pace among men was not met, and none of the hv showed a statistically significant association between walking pace and AF in men. CONCLUSIONS These results suggest that PA is inversely associated with AF in women.
Full Text Available Purpose. To investigate the ocular features of children with congenital cataract in a tertiary referral eye center in East China. Methods. We retrospectively reviewed the clinical data of congenital cataract children who underwent cataract surgery between April 2009 and April 2014 at the Eye and ENT Hospital of Fudan University and identified factors associated with the axial length (AXL and corneal curvature (K value. Results. We included 493 children, 210 with unilateral and 283 with bilateral cataract. The mean AXL was 22.03 ± 1.97 mm and the mean K value was 43.61 ± 1.86 D. Age showed a linear correlation with AXL in unilateral cataract eyes and a logarithmic correlation with AXL in bilateral cataract eyes (both P<0.001. AXL was longer and the K value was smaller (both P<0.01 in boys than in girls after adjusting for age and cataract laterality. AXL was longer in unilateral cataract eyes than in bilateral cataract eyes after adjusting for age and gender (P=0.004. In children with unilateral cataract, AXL was significantly longer in the affected eye than in the contralateral eye (P<0.001. Conclusion. Age, gender, and cataract laterality together contribute to the development of ocular features of congenital cataract children, especially for AXL.
Aman, Michael G; Kasper, William; Manos, George; Mathew, Suja; Marcus, Ronald; Owen, Randall; Mankoski, Raymond
The aim of this study was to evaluate the efficacy of aripiprazole in the treatment of discrete symptoms of irritability associated with autistic disorder, as well as other symptoms captured on the Aberrant Behavior Checklist (ABC). This was a post hoc analysis of data from two 8-week, randomized, double-blind, multicenter trials to evaluate the efficacy of aripiprazole dosed flexibly (2-15 mg/day, n=47) or fixed (5, 10, or 15 mg/day, n = 166) versus placebo (flexibly dosed, n = 51; fixed dose, n = 52). The effects of treatment on the 58 ABC items were evaluated. Statistically significantly greater improvement was seen with aripiprazole versus placebo (p autistic disorder, particularly with respect to symptoms associated with tantrum behavior.
Progress in the study of the intensity of the urban heat island is reported. The intensity of the heat island is commonly defined as the temperature difference between the center of the city and the surrounding suburban and rural regions. The intensity is considered as a function of changes in the season and changes in meteorological conditions in order to derive various parameters which may be used in numerical models for urban climate. Twelve case studies were selected and CCT's were ordered. In situ data was obtained from sixteen stations scattered about the city of St. Louis. Upper-air meteorological data were obtained and the water vapor and the temperature data were processed. Atmospheric transmissivities were computed for each of the case studies.
Nhung, Nguyen Thi Trang; Amini, Heresh; Schindler, Christian; Kutlar Joss, Meltem; Dien, Tran Minh; Probst-Hensch, Nicole; Perez, Laura; Künzli, Nino
Ambient air pollution has been associated with respiratory diseases in children. However, its effects on pediatric pneumonia have not been meta-analyzed. We conducted a systematic review and meta-analysis of the short-term association between ambient air pollution and hospitalization of children due to pneumonia. We searched the Web of Science and PubMed for indexed publications up to January 2017. Pollutant-specific excess risk percentage (ER%) and confidence intervals (CI) were estimated using random effect models for particulate matter (PM) with diameter ≤ 10 (PM 10 ) and ≤2.5 μm (PM 2.5 ), sulfur dioxide (SO 2 ), ozone (O 3 ), nitrogen dioxide (NO 2 ), and carbon monoxide (CO). Results were further stratified by subgroups (children under five, emergency visits versus hospital admissions, income level of study location, and exposure period). Seventeen studies were included in the meta-analysis. The ER% per 10 μg/m 3 increase of pollutants was 1.5% (95% CI: 0.6%-2.4%) for PM 10 and 1.8% (95% CI: 0.5%-3.1%) for PM 2.5 . The corresponding values per 10 ppb increment of gaseous pollutants were 2.9% (95% CI: 0.4%-5.3%) for SO 2 , 1.7% (95% CI: 0.5%-2.8%) for O 3 , and 1.4% (95% CI: 0.4%-2.4%) for NO 2 . ER% per 1000 ppb increment of CO was 0.9% (95% CI: 0.0%-1.9%). Associations were not substantially different between subgroups. This meta-analysis shows a positive association between daily levels of ambient air pollution markers and hospitalization of children due to pneumonia. However, lack of studies from low-and middle-income countries limits the quantitative generalizability given that susceptibilities to the adverse effects of air pollution may be different in those populations. The meta-regression in our analysis further demonstrated a strong effect of country income level on heterogeneity. Copyright © 2017 Elsevier Ltd. All rights reserved.
Li, Jing; Lin, Shuang-Yan; Lv, Yan-Bo; Tang, Hai-Min; Peng, Fang
Matrix metalloproteinase-9 (MMP-9) -1562 C/T gene polymorphism has been identified as a susceptible gene for multiple autoimmune diseases (ADs), but studies are inconsistent. The aim of this study was to assess the overall association between MMP-9 gene polymorphism and multiple ADs using a meta-analysis. Databases of Pubmed, Embase and Web of Science updated to March 1, 2016 were retrieved. Odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) as effect size were calculated by fixed-effect or random-effect model on the basis of heterogeneity. A total of 12 relevant studies containing 2,034 cases and 1,861 controls were included in this meta-analysis. A significant association between MMP-9 -1562 T allele and AD susceptibility was found in the overall population (OR = 1.269, 95% CI = 1.114-1.444, p <0.001) and the Caucasian populations (OR = 1.222, 95% CI = 1.051-1.422, p = 0.009), but not in the Asian populations (OR = 1.337, 95% CI = 0.989-0.808, p = 0.059). Stratified by disease type, we detected a significant association in other ADs (OR = 1.501, 95% CI = 1.212-1.859, p <0.001), but not in patients with multiple sclerosis (OR = 1.150, 95% CI = 0.977-1.354, p = 0.092). No publication bias was detected in the current meta-analysis. Data from the present study suggest that the MMP-9 -1562 C/T polymorphism may be associated with multiple AD susceptibility, especially in the Caucasian populations and other ADs. Further epidemiological studies with a larger sample size are needed to confirm these findings. Copyright © 2017 IMSS. Published by Elsevier Inc. All rights reserved.
Marc A Rodger
Full Text Available BACKGROUND: Factor V Leiden (FVL and prothrombin gene mutation (PGM are common inherited thrombophilias. Retrospective studies variably suggest a link between maternal FVL/PGM and placenta-mediated pregnancy complications including pregnancy loss, small for gestational age, pre-eclampsia and placental abruption. Prospective cohort studies provide a superior methodologic design but require larger sample sizes to detect important effects. We undertook a systematic review and a meta-analysis of prospective cohort studies to estimate the association of maternal FVL or PGM carrier status and placenta-mediated pregnancy complications. METHODS AND FINDINGS: A comprehensive search strategy was run in Medline and Embase. Inclusion criteria were: (1 prospective cohort design; (2 clearly defined outcomes including one of the following: pregnancy loss, small for gestational age, pre-eclampsia or placental abruption; (3 maternal FVL or PGM carrier status; (4 sufficient data for calculation of odds ratios (ORs. We identified 322 titles, reviewed 30 articles for inclusion and exclusion criteria, and included ten studies in the meta-analysis. The odds of pregnancy loss in women with FVL (absolute risk 4.2% was 52% higher (OR = 1.52, 95% confidence interval [CI] 1.06-2.19 as compared with women without FVL (absolute risk 3.2%. There was no significant association between FVL and pre-eclampsia (OR = 1.23, 95% CI 0.89-1.70 or between FVL and SGA (OR = 1.0, 95% CI 0.80-1.25. PGM was not associated with pre-eclampsia (OR = 1.25, 95% CI 0.79-1.99 or SGA (OR 1.25, 95% CI 0.92-1.70. CONCLUSIONS: Women with FVL appear to be at a small absolute increased risk of late pregnancy loss. Women with FVL and PGM appear not to be at increased risk of pre-eclampsia or birth of SGA infants. Please see later in the article for the Editors' Summary.
Díaz-Cerrillo, Juan Luis; Rondón-Ramos, Antonio; Clavero-Cano, Susana; Pérez-González, Rita; Martinez-Calderon, Javier; Luque-Suarez, Alejandro
To describe some sociodemographics and clinical characteristics of subjects with Non-specific Chronic Low Back Pain (NCLBP) in Primary Care, as well as to investigate their association with Fear-Avoidance (FA). Cross-sectional. Secondary analysis of an intervention study. Basic Health Areas in Costa del Sol Health District (Málaga, Spain). An analysis was performed on 147 subjects with NCLBP from a previous intervention study database in Primary Care Physiotherapy (PCP). Characteristics: age 18-65; understanding of the Spanish language; absence of cognitive disorders, fibromyalgia or dorsolumbar surgery, and to be able to perform physical exercise. The main variable was FA level (FABQ and the FABQ-PA and FABQ-W) sub-scales. Clinical variables included: pain (NRPS-11), disability (RMQ), evolution, previous treatments and diagnostic imaging. The sociodemographic variables included: gender, age, educational level, and employment status. Just over half (51.7%) of the subjects had high FA on the FABQ-PA sub-scale. Sick leave (SL) [β=24.45 (P=.009 * ); β=13.03 (P=.016 * ); β=14.04 (P=.011 * ) for FABQ, FABQ-PA and FABQ-W, respectively]; primary studies level [β=15.09 (P=.01 * ); β=9.73 (P=.01 * ) for FABQ and FABQ-PA], and disability [β=1.45 (P<.001); β=0.61 (P<.001); β=0.68 (P<.001) for FABQ, FABQ-PA and FABQ-W, respectively] were associated with FA when they were modeled by multivariate regression. Some sociodemographic and clinical features of the NCLBP population are presented. Imaging tests (81.63%) and previous passive treatments (55.78%) could reflect problems of adherence to recommendations of CPGs. Sick leave, primary studies level, and disability were associated with FA. The findings should be interpreted in the light of possible limitations. Some suggestions for clinical practice are provided. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.
Yin, Jieyun; Liu, Hongliang; Liu, Zhensheng; Owzar, Kouros; Han, Younghun; Su, Li; Wei, Yongyue; Hung, Rayjean J; Brhane, Yonathan; McLaughlin, John; Brennan, Paul; Bickeboeller, Heike; Rosenberger, Albert; Houlston, Richard S; Caporaso, Neil; Landi, Maria Teresa; Heinrich, Joachim; Risch, Angela; Christiani, David C; Amos, Christopher I; Wei, Qingyi
The fatty acids (FAs) metabolism is suggested to play a pivotal role in the development of lung cancer, and we explored that by conducting a pathway-based analysis. We performed a meta-analysis of published datasets of six genome wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium, which included 12 160 cases with lung cancer and 16 838 cancer-free controls. A total of 30 722 single-nucleotide polymorphisms (SNPs) from 317 genes relevant to FA metabolic pathways were identified. An additional dataset from the Harvard Lung Cancer Study with 984 cases and 970 healthy controls was also added to the final meta-analysis. In the initial meta-analysis, 26 of 28 SNPs that passed false discovery rate multiple tests were mapped to the CYP4F3 gene. Among the 26 top ranked hits was a proxy SNP, CYP4F3 rs4646904 (P = 8.65 × 10-6 , FDR = 0.018), which is suggested to change splicing pattern/efficiency and to be associated with gene expression levels. However, after adding data of rs4646904 from the Harvard GWAS, the significance in the combined analysis was reduced to P = 3.52 × 10-3 [odds ratio (OR) = 1.07, 95% confidence interval (95%CI) = 1.03-1.12]. Interestingly, the small Harvard dataset also pointed to the same direction of the association in subgroups of smokers (OR = 1.07) and contributed to a combined OR of 1.13 (95% CI = 1.06-1.20, P = 6.70 × 10-5 ). The results suggest that a potentially functional SNP in CYP4F3 (rs4646904) may contribute to the etiology of lung cancer, especially in smokers. Additional mechanistic studies are warranted to unravel the potential biological significance of the finding. © 2017 Wiley Periodicals, Inc.
Tromp, Gerard; Kuivaniemi, Helena; Gretarsdottir, Solveig; Baas, Annette F.; Giusti, Betti; Strauss, Ewa; van‘t Hof, Femke N.G.; Webb, Thomas R.; Erdman, Robert; Ritchie, Marylyn D.; Elmore, James R.; Verma, Anurag; Pendergrass, Sarah; Kullo, Iftikhar J.; Ye, Zi; Peissig, Peggy L.; Gottesman, Omri; Verma, Shefali S.; Malinowski, Jennifer; Rasmussen-Torvik, Laura J.; Borthwick, Kenneth M.; Smelser, Diane T.; Crosslin, David R.; de Andrade, Mariza; Ryer, Evan J.; McCarty, Catherine A.; Böttinger, Erwin P.; Pacheco, Jennifer A.; Crawford, Dana C.; Carrell, David S.; Gerhard, Glenn S.; Franklin, David P.; Carey, David J.; Phillips, Victoria L.; Williams, Michael J.A.; Wei, Wenhua; Blair, Ross; Hill, Andrew A.; Vasudevan, Thodor M.; Lewis, David R.; Thomson, Ian A.; Krysa, Jo; Hill, Geraldine B.; Roake, Justin; Merriman, Tony R.; Oszkinis, Grzegorz; Galora, Silvia; Saracini, Claudia; Abbate, Rosanna; Pulli, Raffaele; Pratesi, Carlo; Saratzis, Athanasios; Verissimo, Ana R.; Bumpstead, Suzannah; Badger, Stephen A.; Clough, Rachel E.; Cockerill, Gillian; Hafez, Hany; Scott, D. Julian A.; Futers, T. Simon; Romaine, Simon P.R.; Bridge, Katherine; Griffin, Kathryn J.; Bailey, Marc A.; Smith, Alberto; Thompson, Matthew M.; van Bockxmeer, Frank M.; Matthiasson, Stefan E.; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Blankensteijn, Jan D.; Teijink, Joep A.W.; Wijmenga, Cisca; de Graaf, Jacqueline; Kiemeney, Lambertus A.; Lindholt, Jes S.; Hughes, Anne; Bradley, Declan T.; Stirrups, Kathleen; Golledge, Jonathan; Norman, Paul E.; Powell, Janet T.; Humphries, Steve E.; Hamby, Stephen E.; Goodall, Alison H.; Nelson, Christopher P.; Sakalihasan, Natzi; Courtois, Audrey; Ferrell, Robert E.; Eriksson, Per; Folkersen, Lasse; Franco-Cereceda, Anders; Eicher, John D.; Johnson, Andrew D.; Betsholtz, Christer; Ruusalepp, Arno; Franzén, Oscar; Schadt, Eric E.; Björkegren, Johan L.M.; Lipovich, Leonard; Drolet, Anne M.; Verhoeven, Eric L.; Zeebregts, Clark J.; Geelkerken, Robert H.; van Sambeek, Marc R.; van Sterkenburg, Steven M.; de Vries, Jean-Paul; Stefansson, Kari; Thompson, John R.; de Bakker, Paul I.W.; Deloukas, Panos; Sayers, Robert D.; Harrison, Seamus C.; van Rij, Andre M.; Samani, Nilesh J.
Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies. Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease. PMID:27899403
Background The aim of the current study was to investigate the association between anxiety and cannabis use/cannabis use disorders in the general population. Methods A total of N = 267 studies were identified from a systematic literature search (any time- March 2013) of Medline and PsycInfo databases, and a hand search. The results of 31 studies (with prospective cohort or cross-sectional designs using non-institutionalised cases) were analysed using a random-effects meta-analysis with the inverse variance weights. Lifetime or past 12-month cannabis use, anxiety symptoms, and cannabis use disorders (CUD; dependence and/or abuse/harmful use) were classified according to DSM/ICD criteria or scores on standardised scales. Results There was a small positive association between anxiety and either cannabis use (OR = 1.24, 95% CI: 1.06-1.45, p = .006; N = 15 studies) or CUD (OR = 1.68, 95% CI: 1.23-2.31, p = .001; N = 13 studies), and between comorbid anxiety + depression and cannabis use (OR = 1.68, 95% CI: 1.17-2.40, p = .004; N = 5 studies). The positive associations between anxiety and cannabis use (or CUD) were present in subgroups of studies with ORs adjusted for possible confounders (substance use, psychiatric illness, demographics) and in studies with clinical diagnoses of anxiety. Cannabis use at baseline was significantly associated with anxiety at follow-up in N = 5 studies adjusted for confounders (OR = 1.28, 95% CI: 1.06-1.54, p = .01). The opposite relationship was investigated in only one study. There was little evidence for publication bias. Conclusion Anxiety is positively associated with cannabis use or CUD in cohorts drawn from some 112,000 non-institutionalised members of the general population of 10 countries. PMID:24884989
Xu, Kuanfeng; Liu, Xiaoyun; Yang, Fan; Cui, Dai; Shi, Yun; Shen, Chong; Tang, Wei; Yang, Tao
A meta-analysis was performed to assess the association between the PAI-1 -675 4G/5G polymorphism and susceptibility to diabetes mellitus (DM), diabetic nephropathy (DN), diabetic retinopathy (DR) and diabetic coronary artery disease (CAD). A literature-based search was conducted to identify all relevant studies. The fixed or random effect pooled measure was calculated mainly at the allele level to determine heterogeneity bias among studies. Further stratified analyses and sensitivity analyses were also performed. Publication bias was examined by the modified Begg's and Egger's test. Twenty published articles with twenty-seven outcomes were included in the meta-analysis: 6 studies with a total of 1,333 cases and 3,011 controls were analyzed for the PAI-1 -675 4G/5G polymorphism with diabetes risk, 7 studies with 1,060 cases and 1,139 controls for DN risk, 10 studies with 1,327 cases and 1,557 controls for DR and 4 studies with 610 cases and 1,042 controls for diabetic CAD risk respectively. Using allelic comparison (4G vs. 5G), the PAI-1 -675 4G/5G polymorphism was observed to have no significant association with diabetes (REM OR 1.07, 95% CI 0.96, 1.20), DN (REM OR 1.10, 95% CI 0.98, 1.25), DR (REM OR 1.09, 95% CI 0.97, 1.22) or diabetic CAD risk (REM OR 1.07, 95% CI 0.81, 1.42), and similar results were obtained in the dominant, recessive and co-dominant models. Our meta-analyses suggest that the PAI-1 -675 4G/5G polymorphism might not be a risk factor for DM, DN, DR or diabetic CAD risk in the populations investigated. This conclusion warrants confirmation by further studies.
Desnoyers, M; Giger-Reverdin, S; Sauvant, D; Duvaux-Ponter, C
This study examined feeding patterns and their relation to rumen pH. The measured variables were the cumulative time spent chewing (eating or ruminating) and the mean rumen pH, per 20-min intervals (46 intervals altogether). A total of 333 feeding patterns, defined as time-series of measurements for 1 animal and 1 given day during 15 h and 20 min following the afternoon feeding, were collected from 12 stall-housed dairy goats fed a total mixed ration twice daily. The first objective of this study was to analyze the within-day variability of feeding behavior to characterize different feeding patterns. The second objective was to analyze, for each goat, the between-day variability of its feeding behavior. The third objective was to study the influence of feeding behavior on rumen pH. A multivariate method (principal component analysis) was performed on the time spent eating or ruminating during each of the 46 intervals. The factor score plots generated by the principal component analysis highlighted the evolution in time of chewing activities. They also were used to determine 4 different types of feeding behavior in the extreme patterns of the first 2 axes. These feeding patterns were associated with different rumen pH patterns in goats with the same total dry matter intake and mean rumen pH. Some goats had a major eating period immediately after feeding, followed by a period of rumination; this pattern was associated with a marked decrease in rumen pH and a pH nadir below 6.0. Other goats performed alternate periods of eating and ruminating throughout the studied period. The latter feeding pattern was associated with a shorter total duration of rumination, but a more stable rumen pH than the feeding pattern described previously. Feeding pattern was quite constant between days for some goats, but highly variable for others. However, the continuum observed between these 4 groups shows that many intermediate types of behavior can be observed. In conclusion
Mazurowski, Maciej A.; Clark, Kal; Czarnek, Nicholas M.; Shamsesfandabadi, Parisa; Peters, Katherine B.; Saha, Ashirbani
Recent studies showed that genomic analysis of lower grade gliomas can be very effective for stratification of patients into groups with different prognosis and proposed specific genomic classifications. In this study, we explore the association of one of those genomic classifications with imaging parameters to determine whether imaging could serve a similar role to genomics in cancer patient treatment. Specifically, we analyzed imaging and genomics data for 110 patients from 5 institutions from The Cancer Genome Atlas and The Cancer Imaging Archive datasets. The analyzed imaging data contained preoperative FLAIR sequence for each patient. The images were analyzed using the in-house algorithms which quantify 2D and 3D aspects of the tumor shape. Genomic data consisted of a cluster of clusters classification proposed in a very recent and leading publication in the field of lower grade glioma genomics. Our statistical analysis showed that there is a strong association between the tumor cluster-of-clusters subtype and two imaging features: bounding ellipsoid volume ratio and angular standard deviation. This result shows high promise for the potential use of imaging as a surrogate measure for genomics in the decision process regarding treatment of lower grade glioma patients.
Lange, D; Wahrendorf, M; Siegrist, J; Plachta-Danielzik, S; Landsberg, B; Müller, M J
To understand determinants of overweight, several studies addressed the association between neighbourhood characteristics and adult obesity. However, little is known about the association of such characteristics with adolescents' overweight. This study aims at the influence of neighbourhood characteristics on adolescent body mass index (BMI) and lifestyle and to what extent BMI and lifestyle variation between neighbourhoods can be explained by neighbourhood characteristics. We used cross-sectional data from the Kiel Obesity Prevention Study collected between 2004 and 2008 in 28 different residential districts of the city of Kiel (North Germany). Anthropometric data were available for 1675 boys and 1765 girls (n=3440) aged 13-15 years, and individual lifestyle factors and sociodemographic data were included in the analysis. At the macro level, six different neighbourhood characteristics were used: unemployment rate, population density, traffic density, prevalence of energy-dense food supply, number of sports fields and parks, and crime rate. To test our main hypothesis, linear and logistic multilevel regression analyses were performed to predict BMI and lifestyle factors in individuals nested in neighbourhoods. Findings of multilevel analysis show little between-neighbourhood variations in BMI and health-related behaviours. In all, 2% of BMI variation, 4% of media time variation and 3% of variation in snacking behaviour could be attributed to differences in neighbourhoods. Environmental factors are significantly associated with adolescent BMI and health-related behaviour; however, their total effect is small. Owing to these results, recommendations for structural policy measures as part of prevention of overweight in adolescents must be made cautiously.
Wiseman, S J; Bastin, M E; Hamilton, I F; Hunt, D; Ritchie, S J; Amft, E N; Thomson, S; Belch, J F F; Ralston, S H; Wardlaw, J M
Objective The objective of this study was to investigate fatigue and cognitive impairments in systemic lupus erythematous (SLE) in relation to diffuse white matter microstructural brain damage. Methods Diffusion tensor MRI, used to generate biomarkers of brain white matter microstructural integrity, was obtained in patients with SLE and age-matched controls. Fatigue and cognitive function were assessed and related to SLE activity, clinical data and plasma biomarkers of inflammation and endothelial dysfunction. Results Fifty-one patients with SLE (mean age 48.8 ± 14.3 years) were included. Mean diffusivity (MD) was significantly higher in all white matter fibre tracts in SLE patients versus age-matched healthy controls ( p < 0.0001). Fatigue in SLE was higher than a normal reference range ( p < 0.0001) and associated with lower MD ( ß = -0.61, p = 0.02), depression ( ß = 0.17, p = 0.001), anxiety ( ß = 0.13, p = 0.006) and higher body mass index ( ß = 0.10, p = 0.004) in adjusted analyses. Poorer cognitive function was associated with longer SLE disease duration ( p = 0.003) and higher MD ( p = 0.03) and, in adjusted analysis, higher levels of IL-6 ( ß = -0.15, p = 0.02) but not with MD. Meta-analysis (10 studies, n = 261, including the present study) confirmed that patients with SLE have higher MD than controls. Conclusion Patients with SLE have more microstructural brain white matter damage for age than the general population, but this does not explain increased fatigue or lower cognition in SLE. The association between raised IL-6 and worse current cognitive function in SLE should be explored in larger datasets.
Gerson A. Müller
Full Text Available The efficiency of an alternative method of collection (by suction of water for the study of Culicidae and Chironomidae (Diptera, Scirtidae (Coleoptera and Coenagrionidae (Odonata in bromeliads with different foliar architecture in a restinga at Florianópolis, SC, Brazil, was studied. The alternative method was less efficient to collect Culicidae and Chironomidae (Wilcoxon test p 0.05 from Aechmea lindenii. This method was less efficient to collect insects of all groups from Vriesea friburgensis (Wilcoxon test p A eficiência do método alternativo de coleta (por sucção da água para o estudo de Culicidae e Chironomidae (Diptera, Scirtidae (Coleoptera e Coenagrionidae (Odonata em bromélias com diferentes estruturas foliares de restinga em Florianópolis, SC, Brasil, foi estudada. O método alternativo foi menos eficiente para coletar Culicidae e Chironomidae (teste de Wilcoxon p 0, 05 a partir de Aechmea lindenii. Esse foi menos eficiente para coletar insetos de todos os grupos a partir de Vriesea friburgensis (teste de Wilcoxon p < 0,05. O método alternativo se mostrou eficiente em estimar a diversidade desses insetos nas duas espécies de bromélias. A alta mobilidade das formas imaturas dos coleópteros e libélulas e a disponibilidade de apenas um tanque em Aechea lindenii, em contraste com as várias axilas e Vriesea friburgensis, facilitando a sucção destas formas imaturas provavelmente influenciaram os resultados. Os resultados indicam que o método de sucção não deve substituir o desmanche no estudo de Culicidae e Chironomidae; ele pode ser útil para a obtenção de formas imaturas de Scirtidae e Coenagrionidae em bromélias de um só tanque.
Núñez-Pizarro, Jorge L; González-Luna, Alejandro; Mezones-Holguín, Edward; Blümel, Juan E; Barón, Germán; Bencosme, Ascanio; Benítez, Zully; Bravo, Luz M; Calle, Andrés; Flores, Daniel; Espinoza, María T; Gómez, Gustavo; Hernández-Bueno, José A; Martino, Mabel; Lima, Selva; Monterrosa, Alvaro; Mostajo, Desiree; Ojeda, Eliana; Onatra, William; Sánchez, Hugo; Tserotas, Konstantinos; Vallejo, María S; Witis, Silvina; Zúñiga, María C; Chedraui, Peter
To evaluate associations between anxiety and severe impairment of quality of life (QoL) in Latin American postmenopausal women. This was a secondary analysis of a multicenter cross-sectional study among postmenopausal women aged 40 to 59 from 11 Latin American countries. We evaluated anxiety (The Goldberg Depression and Anxiety Scale), and QoL (Menopause Rating Scale [MRS]), and included sociodemographic, clinical, lifestyle, and anthropometric variables in the analysis. Poisson family generalized linear models with robust standard errors were used to estimate prevalence ratios (PRs) and 95% CIs. There were two adjusted models: a statistical model that included variables associated with the outcomes in bivariate analyses, and an epidemiologic model that included potentially confounding variables from literature review. Data from 3,503 women were included; 61.9% had anxiety (Goldberg). Severe QoL impairment (total MRS score ≥17) was present in 13.7% of women, as well as severe symptoms (MRS subscales): urogenital (25.5%), psychological (18.5%), and somatic (4.5%). Anxiety was independently associated with severe QoL impairment and severe symptoms in the epidemiological (MRS total score: PR 3.6, 95% CI, 2.6-5.0; somatic: 5.1, 95% CI, 2.6-10.1; psychological: 2.8, 95% CI, 2.2-3.6; and urogenital: 1.4, 95% CI, 1.2-1.6) and the statistical model (MRS total score: PR 3.5, 95% CI, 2.6-4.9; somatic: 5.0, 95% CI, 2.5-9.9; psychological: 2.9, 95% CI, 2.2-3.7; and urogenital: 1.4; 95% CI, 1.2-1.6). In this postmenopausal Latin American sample, anxiety was independently associated with severe QoL impairment. Hence, screening for anxiety in this population is important.
Full Text Available This study aimed to increase the understanding of health resource utilization (HRU associated with skeletal-related events (SREs occurring in patients with bone metastases secondary to advanced prostate cancer. A total of 120 patients from Germany, Italy, Spain and the United Kingdom were enrolled in this observational study. They had bone metastases secondary to prostate cancer and had experienced at least one SRE in the 97 days before giving informed consent. HRU data were collected retrospectively for 97 days before enrolment and prospectively for up to 18–21 months. HRU, including the number and duration of inpatient hospitalizations, number of outpatient and emergency department visits and procedures, was independently attributed by investigators to an SRE. Of the 222 SREs included in this analysis, 26% were associated with inpatient stays and the mean duration per SRE was 21.4 days (standard deviation (SD 17.8 days. Overall, 174 SREs (78% required an outpatient visit and the mean number of visits per SRE was 4.6 (SD 4.6. All SREs are associated with substantial HRU. Preventing SREs in patients with advanced prostate cancer and bone metastases may help to reduce the burden to both patients and European healthcare systems.
Full Text Available Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD and rheumatoid arthritis (RA, but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls and RA (5,539 cases and 17,231 controls. After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5 × 10(-8 in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (P(combined = 1.2 × 10(-12, rs864537 near CD247 (P(combined = 2.2 × 10(-11, rs2298428 near UBE2L3 (P(combined = 2.5 × 10(-10, and rs11203203 near UBASH3A (P(combined = 1.1 × 10(-8. We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5 × 10(-8 (SH2B3, 8q24, STAT4, and TRAF1-C5. From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.
Full Text Available Abstract Background Microarray gene differential expression analysis is a widely used technique that deals with high dimensional data and is computationally intensive for permutation-based procedures. Microarray gene differential association analysis is even more computationally demanding and must take advantage of multicore computing technology, which is the driving force behind increasing compute power in recent years. In this paper, we present a two-layer hierarchical parallel implementation of gene differential association analysis. It takes advantage of both fine- and coarse-grain (with granularity defined by the frequency of communication parallelism in order to effectively leverage the non-uniform nature of parallel processing available in the cutting-edge systems of today. Results Our results show that this hierarchical strategy matches data sharing behavior to the properties of the underlying hardware, thereby reducing the memory and bandwidth needs of the application. The resulting improved efficiency reduces computation time and allows the gene differential association analysis code to scale its execution with the number of processors. The code and biological data used in this study are downloadable from http://www.urmc.rochester.edu/biostat/people/faculty/hu.cfm. Conclusions The performance sweet spot occurs when using a number of threads per MPI process that allows the working sets of the corresponding MPI processes running on the multicore to fit within the machine cache. Hence, we suggest that practitioners follow this principle in selecting the appropriate number of MPI processes and threads within each MPI process for their cluster configurations. We believe that the principles of this hierarchical approach to parallelization can be utilized in the parallelization of other computationally demanding kernels.
Yao, Song; Kwan, Marilyn L; Ergas, Isaac J; Roh, Janise M; Cheng, Ting-Yuan David; Hong, Chi-Chen; McCann, Susan E; Tang, Li; Davis, Warren; Liu, Song; Quesenberry, Charles P; Lee, Marion M; Ambrosone, Christine B; Kushi, Lawrence H
There are long-standing interests in the potential benefits of vitamin D for preventing breast cancer recurrence and mortality, yet data from prospective cohort studies are limited. To investigate a serum biomarker of vitamin D status, 25-hydroxyvitamin D (25OHD) measured at the time of breast cancer diagnosis, to determine the association with prognosis. The Pathways Study is a prospective cohort study of breast cancer survivors established in 2006. Enrollment was completed in 2013; follow-up is ongoing. The cohort was established in Kaiser Permanente Northern California, a large integrated health care delivery system in northern California. Women with a diagnosis of incident invasive breast cancer were typically consented and enrolled within 2 months of diagnosis. The overall enrollment rate was 46% (4505 of 9820). Participants are followed for health outcomes and comorbidities at 12, 24, 48, 72, and 96 months after baseline interview. A case-cohort design was used for efficiency assay of 25OHD, selecting 1666 cohort members with serum samples and ensuring representation in the subcohort of races and clinical subtypes. The data analysis was performed from January 5, 2014, to March 15, 2015. Primary outcomes are breast cancer recurrence, second primary cancer, and death. Mean (SD) age was 58.7 (12.4) years. Serum 25OHD concentrations were lower in women with advanced-stage tumors, and the lowest in premenopausal women with triple-negative cancer. Levels were also inversely associated with hazards of disease progression and death. Compared with the lowest tertile, women with the highest tertile of 25OHD levels had superior overall survival (OS). This association remained after adjustment for clinical prognostic factors (hazard ratio [HR], 0.72; 95% CI, 0.54-0.98). Among premenopausal women, the association with OS was stronger, and there were also associations with breast cancer-specific survival and invasive disease-free survival (OS: HR, 0.45; 95% CI, 0
Full Text Available Accumulating evidence demonstrates that microRNA-29 (miR-29 expression is prominently decreased in patients with hepatic fibrosis, which consequently stimulates hepatic stellate cells’ (HSCs activation. We used a cDNA microarray study to gain a more comprehensive understanding of genome-wide gene expressions by adjusting miR-29a expression in a bile duct-ligation (BDL animal model. Methods: Using miR-29a transgenic mice and wild-type littermates and applying the BDL mouse model, we characterized the function of miR-29a with regard to cholestatic liver fibrosis. Pathway enrichment analysis and/or specific validation were performed for differentially expressed genes found within the comparisons. Results: Analysis of the microarray data identified a number of differentially expressed genes due to the miR-29a transgene, BDL, or both. Additional pathway enrichment analysis revealed that TGF-β signaling had a significantly differential activated pathway depending on the occurrence of miR-29a overexpression or the lack thereof. Furthermore, overexpression was found to elicit changes in Wnt/β-catenin after BDL. Conclusion: This study verified that an elevated miR-29a level could alleviate liver fibrosis caused by cholestasis. Furthermore, the protective effects of miR-29a correlate with the downregulation of TGF-β and associated with Wnt/β-catenin signal pathway following BDL.
Full Text Available Fang Wang,1,2,* Qian Zhao,1,2,* Hai-rong He,3 Ya-jing Zhai,4 Jun Lu,3 Hai-bo Hu,1 Jin-song Zhou,1 Yong-hua Yang,5 Yuan-jie Li1 1Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Centre, 2College of Pharmacy, Xi’an Medical University, 3Clinical Research Center, 4Department of Pharmacy, 5Department of Pediatrics, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, People’s Republic of China *These authors contributed equally to this work Background: Associations between Arg399Gln single-nucleotide polymorphism (SNP in the XRCC1 gene and leukemia susceptibility have been studied extensively, however, the results are inconsistent. The aim of this study was to determine these associations using meta-analytical methods.Methods: A meta-analysis was performed to examine the associations between XRCC1 Arg399Gln SNP and leukemia risk. A literature search of PubMed and Web of Science databases was conducted to identify relevant studies published up to March 10, 2015. The references of the retrieved articles were also screened. All the statistical analyses were conducted using Review Manager software.Results: The XRCC1 Arg399Gln SNP was found to be associated with increased childhood risk of acute lymphoblastic leukemia among Asians under the dominant (odds ratio [OR] 2.11, 95% confidence interval [CI] 1.50–2.97, P<0.0001, allele contrast (OR 1.72, 95% CI 1.33–2.23, P<0.0001, and homozygote contrast (OR 2.34, 95% CI 1.25–4.36, P=0.008 models. However, no association was found in Caucasians between the SNP and risk of either chronic myeloid leukemia or chronic lymphocytic leukemia under any contrast model.Conclusion: The findings of the current meta-analysis indicate that the XRCC1 Arg399Gln SNP is a risk factor for childhood lymphoblastic leukemia in Asians. Keywords: Arg399Gln, AML, ALL, CML, CLL, susceptibility
Claire M. Marchetta
Full Text Available Folate is found naturally in foods or as synthetic folic acid in dietary supplements and fortified foods. Adequate periconceptional folic acid intake can prevent neural tube defects. Folate intake impacts blood folate concentration; however, the dose-response between natural food folate and blood folate concentrations has not been well described. We estimated this association among healthy females. A systematic literature review identified studies (1 1992–3 2014 with both natural food folate intake alone and blood folate concentration among females aged 12–49 years. Bayesian methods were used to estimate regression model parameters describing the association between natural food folate intake and subsequent blood folate concentration. Seven controlled trials and 29 observational studies met the inclusion criteria. For the six studies using microbiologic assay (MA included in the meta-analysis, we estimate that a 6% (95% Credible Interval (CrI: 4%, 9% increase in red blood cell (RBC folate concentration and a 7% (95% CrI: 1%, 12% increase in serum/plasma folate concentration can occur for every 10% increase in natural food folate intake. Using modeled results, we estimate that a natural food folate intake of ≥450 μg dietary folate equivalents (DFE/day could achieve the lower bound of an RBC folate concentration (~1050 nmol/L associated with the lowest risk of a neural tube defect. Natural food folate intake affects blood folate concentration and adequate intakes could help women achieve a RBC folate concentration associated with a risk of 6 neural tube defects/10,000 live births.
Hodge, James; Chang, Howard H.; Boisson, Sophie; Collin, Simon M.; Peletz, Rachel; Clasen, Thomas
Background: Fecally contaminated drinking water is believed to be a major contributor to the global burden of diarrheal disease and a leading cause of mortality among young children. However, recent systematic reviews and results from blinded studies of water quality interventions have raised questions about the risk associated with fecally contaminated water, particularly as measured by thermotolerant coliform (TTC) bacteria, a WHO-approved indicator of drinking water quality. Objectives: We investigated the association between TTC in drinking water and diarrhea using data from seven previous studies. Methods: We obtained individual-level data from available field studies that measured TTC levels in household-drinking water and reported prevalence of diarrhea among household members during the days prior to the visit. Results: The combined data set included diarrhea prevalence for 26,518 individuals and 8,000 water samples from 4,017 households, yielding 45,052 observations. The odds of diarrhea increased for each log10 increase in TTC/100 mL by 18% (95% CI: 11, 26%) for children 1,000 TTC/100 mL, respectively compared to coliforms in drinking water and diarrhea: an analysis of individual level data from multiple studies. Environ Health Perspect 124:1560–1567; http://dx.doi.org/10.1289/EHP156 PMID:27164618
Hodge, James; Chang, Howard H; Boisson, Sophie; Collin, Simon M; Peletz, Rachel; Clasen, Thomas
Fecally contaminated drinking water is believed to be a major contributor to the global burden of diarrheal disease and a leading cause of mortality among young children. However, recent systematic reviews and results from blinded studies of water quality interventions have raised questions about the risk associated with fecally contaminated water, particularly as measured by thermotolerant coliform (TTC) bacteria, a WHO-approved indicator of drinking water quality. We investigated the association between TTC in drinking water and diarrhea using data from seven previous studies. We obtained individual-level data from available field studies that measured TTC levels in household-drinking water and reported prevalence of diarrhea among household members during the days prior to the visit. The combined data set included diarrhea prevalence for 26,518 individuals and 8,000 water samples from 4,017 households, yielding 45,052 observations. The odds of diarrhea increased for each log10 increase in TTC/100 mL by 18% (95% CI: 11, 26%) for children 1,000 TTC/100 mL, respectively compared to coliforms in drinking water and diarrhea: an analysis of individual level data from multiple studies. Environ Health Perspect 124:1560-1567; http://dx.doi.org/10.1289/EHP156.
Larson, Nicholas B.; McDonnell, Shannon; Albright, Lisa Cannon; Teerlink, Craig; Stanford, Janet; Ostrander, Elaine A.; Isaacs, William B.; Xu, Jianfeng; Cooney, Kathleen A.; Lange, Ethan; Schleutker, Johanna; Carpten, John D.; Powell, Isaac; Bailey-Wilson, Joan; Cussenot, Olivier; Cancel-Tassin, Geraldine; Giles, Graham; MacInnis, Robert; Maier, Christiane; Whittemore, Alice S.; Hsieh, Chih-Lin; Wiklund, Fredrik; Catolona, William J.; Foulkes, William; Mandal, Diptasri; Eeles, Rosalind; Kote-Jarai, Zsofia; Ackerman, Michael J.; Olson, Timothy M.; Klein, Christopher J.; Thibodeau, Stephen N.; Schaid, Daniel J.
Rare variants have been shown to be significant contributors to complex disease risk. By definition, these variants have very low minor allele frequencies and traditional single-marker methods for statistical analysis are underpowered for typical sequencing study sample sizes. Multi-marker burden-type approaches attempt to identify aggregation of rare variants across case-control status by analyzing relatively small partitions of the genome, such as genes. However, it is generally the case that the aggregative measure would be a mixture of causal and neutral variants, and these omnibus tests do not directly provide any indication of which rare variants may be driving a given association. Recently, Bayesian variable selection approaches have been proposed to identify rare variant associations from a large set of rare variants under consideration. While these approaches have been shown to be powerful at detecting associations at the rare variant level, there are often computational limitations on the total quantity of rare variants under consideration and compromises are necessary for large-scale application. Here, we propose a computationally efficient alternative formulation of this method using a probit regression approach specifically capable of simultaneously analyzing hundreds to thousands of rare variants. We evaluate our approach to detect causal variation on simulated data and examine sensitivity and specificity in instances of high rare variant dimensionality as well as apply it to pathway-level rare variant analysis results from a prostate cancer risk case-control sequencing study. Finally, we discuss potential extensions and future directions of this work. PMID:27312771
Liu, Jiang-Bo; Feng, Chen-Yi; Deng, Miao; Ge, Dong-Feng; Liu, De-Chun; Mi, Jian-Qiang; Feng, Xiao-Shan
This retrospective study and meta-analysis was designed to explore the relationship between E-cadherin (E-cad) expression and the molecular subtypes of invasive non-lobular breast cancer, especially in early-stage invasive ductal carcinoma (IDC). A total of 156 post-operative cases of early-stage IDCs were retrospectively collected for the immunohistochemistry (IHC) detection of E-cad expression. The association of E-cad expression with molecular subtypes of early-stage IDCs was analyzed. A literature search was conducted in March 2016 to retrieve publications on E-cad expression in association with molecular subtypes of invasive non-lobular breast cancer, and a meta-analysis was performed to estimate the relational statistics. E-cad was expressed in 82.7% (129/156) of early-stage IDCs. E-cad expression was closely associated with the molecular types of early-stage IDCs (P molecular subtypes were an independent factor influencing E-cad expression in early-stage IDCs. A total of 12 observational studies (including our study) were included in the meta-analysis. The meta-analytical results show a significantly greater risk of E-cad expression loss in triple-negative breast cancer (TNBC) than in other molecular subtypes (TNBC vs. luminal A: RR = 3.45, 95% CI = 2.79-4.26; TNBC vs. luminal B: RR = 2.41, 95% CI = 1.49-3.90; TNBC vs. HER2-enriched: RR = 1.95, 95% CI = 1.24-3.07). Early-stage IDCs or invasive non-lobular breast cancers with the TNBC molecular phenotype have a higher risk for the loss of E-cad expression than do tumors with non-TNBC molecular phenotypes, suggesting that E-cad expression phenotypes were closely related to molecular subtypes and further studies are needed to clarify the underlying mechanism.
Limited numbers of large effectiveness studies on routine dental implant treatment are available in the literature. To report retro-prospective data on prevalence of early implant failures in a large number of routine patients/operations at 1 referral clinic. A total of 2848 patients were consecutively provided with 9582 implants with an anodized surface (Nobel Biocare AB) during 3448 implant operations between 2003 and 2011. All patients were invited to a follow-up program and early implant failures up to first annual examination were consecutively identified. A logistic multivariate data analysis was performed to identify possible factors with an association to early implant failures. A total of 43, 73, and 81 implant operations were denoted as early failures depending on when cut-off time was defined, using: abutment connection, prosthesis placement, or at first year of follow-up, respectively. Five factors showed significant association to "early implant failures," where the highest risk for a failure was associated to "surgeon" (hazard ratio [HR] 5.13), followed by "not prosthetic treatment at the referral clinic" (HR 2.71). When all 5 significant factors were present, the risk for an early failure after an operation was 7.0%, and the risk decreased to 0.1% when none/lowest risk factors were present. The role of the surgeons/dentists involved in the rehabilitation of the implant patients and numbers of placed implants (degree of tooth loss) showed the strongest associations to early implant failures in the present clinic. Also increased bone resorption was associated to increased risk for implant failure. © 2017 Wiley Periodicals, Inc.
Fan, Ruzong; Zhang, Yiwei; Albert, Paul S.; Liu, Aiyi; Wang, Yuanjia; Xiong, Momiao
Longitudinal genetic studies provide a valuable resource for exploring key genetic and environmental factors that affect complex traits over time. Genetic analysis of longitudinal data that incorporate temporal variations is important for understanding genetic architecture and biological variations of common complex diseases. Although they are important, there is a paucity of statistical methods to analyze longitudinal human genetic data. In this article, longitudinal methods are developed for temporal association mapping to analyze population longitudinal data. Both parametric and nonparametric models are proposed. The models can be applied to multiple diallelic genetic markers such as single-nucleotide polymorphisms and multiallelic markers such as microsatellites. By analytical formulae, we show that the models take both the linkage disequilibrium and temporal trends into account simultaneously. Variance-covariance structure is constructed to model the single measurement variation and multiple measurement correlations of an individual based on the theory of stochastic processes. Novel penalized spline models are used to estimate the time-dependent mean functions and regression coefficients. The methods were applied to analyze Framingham Heart Study data of Genetic Analysis Workshop (GAW) 13 and GAW 16. The temporal trends and genetic effects of the systolic blood pressure are successfully detected by the proposed approaches. Simulation studies were performed to find out that the nonparametric penalized linear model is the best choice in fitting real data. The research sheds light on the important area of longitudinal genetic analysis, and it provides a basis for future methodological investigations and practical applications. PMID:22965819
Li, Su-yi; Ye, Jie-yu; Liang, En-yu; Zhou, Li-xia; Yang, Mo
Background Studies and systematic reviews have reached inconsistent conclusions on the role of 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T in acute lymphoblastic leukemia (ALL) risk. Material/Methods The present meta-analysis comprising of 51 case-control studies, including 7892 cases and 14 280 controls was performed to reevaluate the association between MTHFR C677T polymorphism and ALL risk. Results Statistical differences were found in the dominant model (TT+CT vs. CC, odd ratio (OR)=0.89, 95% CI, 0.79–1.00, P=0.04) and the CT vs. CC (OR=0.89, 95% CI, 0.80–1.00, P=0.05), but not in the allele contrast model (T vs. C, OR=0.92, 95% CI, 0.84–1.01, P=0.08), additive model (TT vs. CC, OR=0.87, 95% CI, 0.73–1.05, P=0.15), or recessive model (TT vs. CT+CC, OR=0.94, 95% CI, 0.81–1.10, P=0.44) in overall populations. In the subgroup analyses stratified by age (children and adults) and ethnicity (Asian and Caucasian), no significant associations between MTHFR C677T polymorphism and ALL risk were observed. Conclusions The current study found no sufficient evidence of a protective role of MTHFR C677T polymorphism in ALL susceptibility. PMID:25761797
Goto, Tadahiro; Watase, Hiroko; Morita, Hiroshi; Nagai, Hideya; Brown, Calvin A; Brown, David F M; Hasegawa, Kohei
To determine whether the success rate of repeated attempts at tracheal intubation by a single intubator was lower than those by alternate intubators in the emergency department (ED). An analysis of data from a multicentre prospective registry (Japanese Emergency Airway Network Registry) of 13 academic and community EDs in Japan between April 2010 and August 2012. We included all adult and paediatric patients who underwent repeated attempts at tracheal intubation in the ED. We compared the intubation success rates at the second and third attempts between attempts at intubation by a single intubator who performed the previous attempts, and the attempts by alternate intubators. We recorded 4094 patients (capture rate, 96%); 1289 patients with repeated attempts at tracheal intubation were eligible for this study. Among these, 871 patients (68%) had a second attempt at intubation by single intubators. At the second attempt, tracheal intubation by a single intubator was associated with a decreased success rate (adjusted odds ratio or AOR, 0.50; 95% CI 0.36 to 0.71), compared with alternate intubators. At the third attempt, intubation by a single intubator was also associated with a decreased success rate (58% vs 70%; unadjusted OR, 0.58; 95% CI 0.38 to 0.89). However, after adjustment for potential confounders, the association lost statistical significance (AOR, 0.89; 95% CI 0.52 to 1.56). In this large multicentre study of ED patients undergoing tracheal intubation, second attempts at intubation by a single intubator, compared with those by alternate intubators, were independently associated with a decreased success rate. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Full Text Available Five-to-eighteen percent of pregnancies worldwide end in preterm birth, which is the major cause of neonatal death and morbidity. Approximately 30% of the variation in gestational age at birth can be attributed to genetic factors. Genome-wide association studies (GWAS have not shown robust evidence of association with genomic loci yet.We separately investigated 1921 Norwegian mothers and 1199 children from pregnancies with spontaneous onset of delivery. Individuals were further divided based on the onset of delivery: initiated by labor or prelabor rupture of membranes. Genetic association with ultrasound-dated gestational age was evaluated using three genetic models and adaptive permutations. The top-ranked loci were tested for enrichment in 12 candidate gene-sets generated by text-mining PubMed abstracts containing pregnancy-related keywords.The six GWAS did not reveal significant associations, with the most extreme empirical p = 5.1 × 10-7. The top loci from maternal GWAS with deliveries initiated by labor showed significant enrichment in 10 PubMed gene-sets, e.g., p = 0.001 and 0.005 for keywords "uterus" and "preterm" respectively. Enrichment signals were mainly caused by infection/inflammation-related genes TLR4, NFKB1, ABCA1, MMP9. Literature-informed analysis of top loci revealed further immunity genes: IL1A, IL1B, CAMP, TREM1, TFRC, NFKBIA, MEFV, IRF8, WNT5A.Our analyses support the role of inflammatory pathways in determining pregnancy duration and provide a list of 32 candidate genes for a follow-up work. We observed that the top regions from GWAS in mothers with labor-initiated deliveries significantly more often overlap with pregnancy-related genes than would be expected by chance, suggesting that increased sample size would benefit similar studies.
Schormair, Barbara; Zhao, Chen; Bell, Steven; Tilch, Erik; Salminen, Aaro V; Pütz, Benno; Dauvilliers, Yves; Stefani, Ambra; Högl, Birgit; Poewe, Werner; Kemlink, David; Sonka, Karel; Bachmann, Cornelius G; Paulus, Walter; Trenkwalder, Claudia; Oertel, Wolfgang H; Hornyak, Magdolna; Teder-Laving, Maris; Metspalu, Andres; Hadjigeorgiou, Georgios M; Polo, Olli; Fietze, Ingo; Ross, Owen A; Wszolek, Zbigniew; Butterworth, Adam S; Soranzo, Nicole; Ouwehand, Willem H; Roberts, David J; Danesh, John; Allen, Richard P; Earley, Christopher J; Ondo, William G; Xiong, Lan; Montplaisir, Jacques; Gan-Or, Ziv; Perola, Markus; Vodicka, Pavel; Dina, Christian; Franke, Andre; Tittmann, Lukas; Stewart, Alexandre F R; Shah, Svati H; Gieger, Christian; Peters, Annette; Rouleau, Guy A; Berger, Klaus; Oexle, Konrad; Di Angelantonio, Emanuele; Hinds, David A; Müller-Myhsok, Bertram; Winkelmann, Juliane
Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10 -8 ) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. Deutsche Forschungsgemeinschaft, Helmholtz Zentrum
Smith, Justin S; Lafage, Virginie; Ryan, Devon J; Shaffrey, Christopher I; Schwab, Frank J; Patel, Alpesh A; Brodke, Darrel S; Arnold, Paul M; Riew, K Daniel; Traynelis, Vincent C; Radcliff, Kris; Vaccaro, Alexander R; Fehlings, Michael G; Ames, Christopher P
Post hoc analysis of prospectively collected data. Development of methods to determine in vivo spinal cord dimensions and application to correlate preoperative alignment, myelopathy, and health-related quality-of-life scores in patients with cervical spondylotic myelopathy (CSM). CSM is the leading cause of spinal cord dysfunction. The association between cervical alignment, sagittal balance, and myelopathy has not been well characterized. This was a post hoc analysis of the prospective, multicenter AOSpine North America CSM study. Inclusion criteria for this study required preoperative cervical magnetic resonance imaging (MRI) and neutral sagittal cervical radiography. Techniques for MRI assessment of spinal cord dimensions were developed. Correlations between imaging and health-related quality-of-life scores were assessed. Fifty-six patients met inclusion criteria (mean age = 55.4 yr). The modified Japanese Orthopedic Association (mJOA) scores correlated with C2-C7 sagittal vertical axis (SVA) (r = -0.282, P = 0.035). Spinal cord volume correlated with cord length (r = 0.472, P sagittal balance (C2-C7 SVA) to myelopathy severity. We found a moderate negative correlation in kyphotic patients of cord volume and cross-sectional area to mJOA scores. The opposite (positive correlation) was found for lordotic patients, suggesting a relationship of cord volume to myelopathy that differs on the basis of sagittal alignment. It is interesting to note that sagittal balance but not kyphosis is tied to myelopathy score. Future work will correlate alignment changes to cord morphology changes and myelopathy outcomes. SUMMARY STATEMENTS: This is the first study to correlate sagittal balance (C2-C7 SVA) to myelopathy severity. We found a moderate negative correlation in kyphotic patients of cord volume and cross-sectional area to mJOA scores. The opposite (positive correlation) was found for lordotic patients, suggesting a relationship of cord volume to myelopathy that differs on
Xie, Cheng-Long; Pan, Jia-Lin; Wang, Wen-Wen; Zhang, Yu; Zhang, Su-Fang; Gan, Jing; Liu, Zhen-Guo
Clinical diagnosis of Parkinson's disease (PD) is essential but misdiagnosis of PD-like diseases is quite common. LRRK2 G2385R variants have been extensively examined for the association to the risk of Parkinson's disease. However, results from different studies are inconsistent. The purpose of this meta-analysis was to assess the association between the LRRK2 G2385R variants and the risk of PD. A systematic literature search was performed for 6 databases up to January of 2014 to identify case-control studies involving LRRK2 G2385R variants and the risk of PD. A total of 12,915 cases and 12,451 controls in 23 case-control studies were included in this meta-analysis. The results indicated that the variant A allele carriers (GA + AA) increased risk of PD when compared with the homozygote GG (GA + AA vs. GG: OR = 2.4, 95 % CI = 1.97 to 2.92, P risks were identified among Chinese (OR = 2.69, 95 % CI = 2.1-3.45, P LOPD) and early-onset PD (EOPD) cases. And there was no significant difference of the allele frequency between patients with LOPD and EOPD (OR = 1.18, 95 % CI = 0.77-1.80, P = 0.45). Our results suggest that the LRRK2 G2385R variants contribute to the susceptibility of PD especially in Chinese PD. Meanwhile, it is possible that age is not the risk factor to facilitate G2385R gene mutation.
Speed, Doug; Hoggart, Clive; Petrovski, Slave; Tachmazidou, Ioanna; Coffey, Alison; Jorgensen, Andrea; Eleftherohorinou, Hariklia; De Iorio, Maria; Todaro, Marian; De, Tisham; Smith, David; Smith, Philip E.; Jackson, Margaret; Cooper, Paul; Kellett, Mark; Howell, Stephen; Newton, Mark; Yerra, Raju; Tan, Meng; French, Chris; Reuber, Markus; Sills, Graeme E.; Chadwick, David; Pirmohamed, Munir; Bentley, David; Scheffer, Ingrid; Berkovic, Samuel; Balding, David; Palotie, Aarno; Marson, Anthony; O'Brien, Terence J.; Johnson, Michael R.
We present the analysis of a prospective multicentre study to investigate genetic effects on the prognosis of newly treated epilepsy. Patients with a new clinical diagnosis of epilepsy requiring medication were recruited and followed up prospectively. The clinical outcome was defined as freedom from seizures for a minimum of 12 months in accordance with the consensus statement from the International League Against Epilepsy (ILAE). Genetic effects on remission of seizures after starting treatment were analysed with and without adjustment for significant clinical prognostic factors, and the results from each cohort were combined using a fixed-effects meta-analysis. After quality control (QC), we analysed 889 newly treated epilepsy patients using 472 450 genotyped and 6.9 × 106 imputed single-nucleotide polymorphisms. Suggestive evidence for association (defined as Pmeta analysis using two independent methods implicated a number of pathways in the prognosis of epilepsy, including KEGG categories ‘calcium signaling pathway’ and ‘phosphatidylinositol signaling pathway’. Through a series of power curves, we conclude that it is unlikely any single common variant explains >4.4% of the variation in the outcome of newly treated epilepsy. PMID:23962720
Yang, L; Parimi, N; Orwoll, E S; Black, D M; Schousboe, J T; Eastell, R
Finite element model can estimate bone strength better than BMD. This study used such a model to determine its association with hip fracture risk and found that the strength estimate provided limited improvement over the hip BMDs in predicting femoral neck (FN) fracture risk only. Bone fractures occur only when it is loaded beyond its ultimate strength. The goal of this study was to determine the association of femoral strength, as estimated by finite element (FE) analysis of DXA scans, with incident hip fracture as a single condition or with femoral neck (FN) and trochanter (TR) fractures separately in older men. This prospective case-cohort study included 91 FN and 64 TR fracture cases and a random sample of 500 men (14 had a hip fracture) from the Osteoporotic Fractures in Men study during a mean ± SD follow-up of 7.7 ± 2.2 years. We analysed the baseline DXA scans of the hip using a validated plane-stress, linear-elastic FE model of the proximal femur and estimated the femoral strength during a sideways fall. The estimated strength was significantly (P fracture independent of the TR and total hip (TH) BMDs but not FN BMD, and combining the strength with BMD did not improve the hip fracture prediction. The strength estimate was associated with FN fractures independent of the FN, TR and TH BMDs; the age-BMI-BMD adjusted hazard ratio (95% CI) per SD decrease of the strength was 1.68 (1.07-2.64), 2.38 (1.57, 3.61) and 2.04 (1.34, 3.11), respectively. This association with FN fracture was as strong as FN BMD (Harrell's C index for the strength 0.81 vs. FN BMD 0.81) and stronger than TR and TH BMDs (0.8 vs. 0.78 and 0.81 vs. 0.79). The strength's association with TR fracture was not independent of hip BMD. Although the strength estimate provided additional information over the hip BMDs, its improvement in predictive ability over the hip BMDs was confined to FN fracture only and limited.
Full Text Available BACKGROUND: Antiretroviral therapy (ART has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV drug used. METHODS AND FINDINGS: The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines. We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388 were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT and Metropolitan Atlanta Congenital Defects Program (MACDP classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%-4.7%, according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267, adjusted odds ratio (AOR = 2.2 (95% CI 1.3-3.7, p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%. Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1-10.4, p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1-13.8, p = 0
Full Text Available Pathway analysis of genome-wide association studies (GWAS offer a unique opportunity to collectively evaluate genetic variants with effects that are too small to be detected individually. We applied a pathway analysis to a bladder cancer GWAS containing data from 3,532 cases and 5,120 controls of European background (n = 5 studies. Thirteen hundred and ninety-nine pathways were drawn from five publicly available resources (Biocarta, Kegg, NCI-PID, HumanCyc, and Reactome, and we constructed 22 additional candidate pathways previously hypothesized to be related to bladder cancer. In total, 1421 pathways, 5647 genes and ∼90,000 SNPs were included in our study. Logistic regression model adjusting for age, sex, study, DNA source, and smoking status was used to assess the marginal trend effect of SNPs on bladder cancer risk. Two complementary pathway-based methods (gene-set enrichment analysis [GSEA], and adapted rank-truncated product [ARTP] were used to assess the enrichment of association signals within each pathway. Eighteen pathways were detected by either GSEA or ARTP at P≤0.01. To minimize false positives, we used the I(2 statistic to identify SNPs displaying heterogeneous effects across the five studies. After removing these SNPs, seven pathways ('Aromatic amine metabolism' [P(GSEA = 0.0100, P(ARTP = 0.0020], 'NAD biosynthesis' [P(GSEA = 0.0018, P(ARTP = 0.0086], 'NAD salvage' [P(ARTP = 0.0068], 'Clathrin derived vesicle budding' [P(ARTP = 0.0018], 'Lysosome vesicle biogenesis' [P(GSEA = 0.0023, P(ARTP<0.00012], 'Retrograde neurotrophin signaling' [P(GSEA = 0.00840], and 'Mitotic metaphase/anaphase transition' [P(GSEA = 0.0040] remained. These pathways seem to belong to three fundamental cellular processes (metabolic detoxification, mitosis, and clathrin-mediated vesicles. Identification of the aromatic amine metabolism pathway provides support for the ability of this approach to identify pathways
P.B. Ryan (Patrick); D. Madigan (David); P.E. Stang (Paul); M.J. Schuemie (Martijn); G. Hripcsak (G.)
textabstractUndiscovered side effects of drugs can have a profound effect on the health of the nation, and electronic health-care databases offer opportunities to speed up the discovery of these side effects. We applied a "medication-wide association study" approach that combined multivariate
Siddiq, Afshan; Couch, Fergus J.; Chen, Gary K.; Lindström, Sara; Eccles, Diana; Millikan, Robert C.; Michailidou, Kyriaki; Stram, Daniel O.; Beckmann, Lars; Rhie, Suhn Kyong; Ambrosone, Christine B.; Aittomäki, Kristiina; Amiano, Pilar; Apicella, Carmel; Baglietto, Laura; Bandera, Elisa V.; Beckmann, Matthias W.; Berg, Christine D.; Bernstein, Leslie; Blomqvist, Carl; Brauch, Hiltrud; Brinton, Louise; Bui, Quang M.; Buring, Julie E.; Buys, Saundra S.; Campa, Daniele; Carpenter, Jane E.; Chasman, Daniel I.; Chang-Claude, Jenny; Chen, Constance; Clavel-Chapelon, Françoise; Cox, Angela; Cross, Simon S.; Czene, Kamila; Deming, Sandra L.; Diasio, Robert B.; Diver, W. Ryan; Dunning, Alison M.; Durcan, Lorraine; Ekici, Arif B.; Fasching, Peter A.; Feigelson, Heather Spencer; Fejerman, Laura; Figueroa, Jonine D.; Fletcher, Olivia; Flesch-Janys, Dieter; Gaudet, Mia M.; Gerty, Susan M.; Rodriguez-Gil, Jorge L.; Giles, Graham G.; van Gils, Carla H.; Godwin, Andrew K.; Graham, Nikki; Greco, Dario; Hall, Per; Hankinson, Susan E.; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Hoover, Robert N.; Hopper, John L.; Hu, Jennifer J.; Huntsman, Scott; Ingles, Sue A.; Irwanto, Astrid; Isaacs, Claudine; Jacobs, Kevin B.; John, Esther M.; Justenhoven, Christina; Kaaks, Rudolf; Kolonel, Laurence N.; Coetzee, Gerhard A.; Lathrop, Mark; Le Marchand, Loic; Lee, Adam M.; Lee, I-Min; Lesnick, Timothy; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Martin, Nicholas G.; McLean, Catriona A.; Meijers-Heijboer, Hanne; Meindl, Alfons; Miron, Penelope; Monroe, Kristine R.; Montgomery, Grant W.; Müller-Myhsok, Bertram; Nickels, Stefan; Nyante, Sarah J.; Olswold, Curtis; Overvad, Kim; Palli, Domenico; Park, Daniel J.; Palmer, Julie R.; Pathak, Harsh; Peto, Julian; Pharoah, Paul; Rahman, Nazneen; Rivadeneira, Fernando; Schmidt, Daniel F.; Schmutzler, Rita K.; Slager, Susan; Southey, Melissa C.; Stevens, Kristen N.; Sinn, Hans-Peter; Press, Michael F.; Ross, Eric; Riboli, Elio; Ridker, Paul M.; Schumacher, Fredrick R.; Severi, Gianluca; dos Santos Silva, Isabel; Stone, Jennifer; Sund, Malin; Tapper, William J.; Thun, Michael J.; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Waisfisz, Quinten; Wang, Xianshu; Wang, Zhaoming; Weaver, JoEllen; Schulz-Wendtland, Rüdiger; Wilkens, Lynne R.; Van Den Berg, David; Zheng, Wei; Ziegler, Regina G.; Ziv, Elad; Nevanlinna, Heli; Easton, Douglas F.; Hunter, David J.; Henderson, Brian E.; Chanock, Stephen J.; Garcia-Closas, Montserrat; Kraft, Peter; Haiman, Christopher A.; Vachon, Celine M.
Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10-5 in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10−8) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10–6) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10−9), and with both ER-positive (OR = 1.09; P = 1.5 × 10−5) and ER-negative (OR = 1.16, P = 2.5 × 10−7) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci. PMID:22976474
Jones, Gregory T; Tromp, Gerard; Kuivaniemi, Helena
Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. To identify additional AAA risk loci using data from all available genome-wide association...... studies (GWAS). Through a meta-analysis of 6 GWAS datasets and a validation study totalling 10,204 cases and 107,766 controls we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches we observed no new...... associations between the lead AAA SNPs and coronary artery disease, blood pressure, lipids or diabetes. Network analyses identified ERG, IL6R and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. The 4 new risk loci for AAA appear to be specific for AAA compared with other...
Full Text Available Traditional permutation (TradPerm tests are usually considered the gold standard for multiple testing corrections. However, they can be difficult to complete for the meta-analyses of genetic association studies based on multiple single nucleotide polymorphism loci as they depend on individual-level genotype and phenotype data to perform random shuffles, which are not easy to obtain. Most meta-analyses have therefore been performed using summary statistics from previously published studies. To carry out a permutation using only genotype counts without changing the size of the TradPerm P-value, we developed a Monte Carlo permutation (MCPerm method. First, for each study included in the meta-analysis, we used a two-step hypergeometric distribution to generate a random number of genotypes in cases and controls. We then carried out a meta-analysis using these random genotype data. Finally, we obtained the corrected permutation P-value of the meta-analysis by repeating the entire process N times. We used five real datasets and five simulation datasets to evaluate the MCPerm method and our results showed the following: (1 MCPerm requires only the summary statistics of the genotype, without the need for individual-level data; (2 Genotype counts generated by our two-step hypergeometric distributions had the same distributions as genotype counts generated by shuffling; (3 MCPerm had almost exactly the same permutation P-values as TradPerm (r = 0.999; P<2.2e-16; (4 The calculation speed of MCPerm is much faster than that of TradPerm. In summary, MCPerm appears to be a viable alternative to TradPerm, and we have developed it as a freely available R package at CRAN: http://cran.r-project.org/web/packages/MCPerm/index.html.
Li, Quan; Shen, Hongxing; Li, Ming
Hypothesis that loss of integrity of the membranes in the craniocervical junction might be the cause of neck pain in patients with whiplash-associated disorders (WADs) has been proposed. In recent years, with development of more detailed magnetic resonance imaging (MRI) techniques, morphologic changes of the ligaments and membranes in the craniocervical junction, especially alar and transverse ligaments have been discussed. A meta-analysis was performed to evaluate the relationship of MRI signal changes of alar and transverse ligaments and WADs. A systematic search of EMBASE, PUBMED, and Cochrane Library and references from eligible articles were conducted. Comparative studies reporting on evaluating the relationship between MRI high-signal changes of alar and transverse ligaments and WADs were regarded eligible. A pooled estimate of effect size was produced. Alar ligaments: Six studies (total n = 622) were included. MRI signal changes of alar ligaments did not appear to be related with WADs (P = 0.20, OR = 1.54, 95 % CI = 0.80-2.94). Heterogeneity was present (I (2) = 46 %, P = 0.10), which was eliminated upon sensitivity analysis bringing the OR to 1.27 (95 % CI = 0.87-1.86, I (2) = 0 %). Transverse ligaments: Four studies (total n = 489) were included. MRI signal changes of transverse ligament did not appear to be related with WADs (P = 0.51, OR = 1.44, 95 % CI = 0.49-4.21). Heterogeneity was present (I (2) = 77 %, P = 0.005), which was eliminated upon sensitivity analysis bringing the OR to 0.79 (95 % CI = 0.49-1.28, I (2) = 0 %). MRI signal changes of alar and transverse ligaments are not supposed to be caused by whiplash injury, and MRI examination of alar and transverse ligaments should not be used as the routine workup of patients with WADs.
Peixoto de Miranda, É J F; Bittencourt, M S; Pereira, A C; Goulart, A C; Santos, I S; Lotufo, P A; Bensenor, I M
Although subclinical hypothyroidism (SCH) is associated with cardiovascular risk, there is scarce data about subclinical atherosclerosis in subjects with SCH. We aimed to analyze the association between SCH and carotid intima-media thickness (IMT) using baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). We included subjects with normal thyroid function (TSH: 0.4-4.0 mIU/l, and normal free thyroxine (FT4): 0.8-1.9 ng/dl) and SCH (TSH ≥ 4.0 mIU/l and normal FT4) evaluated for IMT in a cross-sectional analysis. We excluded individuals using medications that affect thyroid function and those with a history of cardiovascular disease. We performed logistic and linear regression models to evaluate the association with IMT (mean values and categorized at the 75th percentile) as a dependent variable and SCH as an independent variable, adjusted for other cardiovascular risk factors. From 8623 subjects (median age of 50 years; interquartile range: 44-57), 4624 (53.6%) were women, 8095 (93.9%) were euthyroid, and 528 (6.1%) had SCH. Groups varied in age, body mass index, Framingham risk score, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), C-reactive protein, as well as, IMT, that were all higher in SCH compared to euthyroid participants. SCH is associated with IMT as a continuous variable (β = 0.010, P = 0.036) and IMT >75th percentile: OR = 1.30 (95% CI = 1.06-1.59) in logistic models. Individuals with SCH presented higher IMT compared with euthyroid subjects, even after adjustment for potential confounders. IMT was independently associated with SCH in the baseline of the ELSA-Brasil study. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.
Pletcher Mathew T
Full Text Available Abstract Background Finding the genetic causes of quantitative traits is a complex and difficult task. Classical methods for mapping quantitative trail loci (QTL in miceuse an F2 cross between two strains with substantially different phenotype and an interval mapping method to compute confidence intervals at each position in the genome. This process requires significant resources for breeding and genotyping, and the data generated are usually only applicable to one phenotype of interest. Recently, we reported the application of a haplotype association mapping method which utilizes dense genotyping data across a diverse panel of inbred mouse strains and a marker association algorithm that is independent of any specific phenotype. As the availability of genotyping data grows in size and density, analysis of these haplotype association mapping methods should be of increasing value to the statistical genetics community. Results We describe a detailed comparative analysis of variations on our marker association method. In particular, we describe the use of inferred haplotypes from adjacent SNPs, parametric and nonparametric statistics, and control of multiple testing error. These results show that nonparametric methods are slightly better in the test cases we study, although the choice of test statistic may often be dependent on the specific phenotype and haplotype structure being studied. The use of multi-SNP windows to infer local haplotype structure is critical to the use of a diverse panel of inbred strains for QTL mapping. Finally, because the marginal effect of any single gene in a complex disease is often relatively small, these methods require the use of sensitive methods for controlling family-wise error. We also report our initial application of this method to phenotypes cataloged in the Mouse Phenome Database. Conclusion The use of inbred strains of mice for QTL mapping has many advantages over traditional methods. However, there are also
Full Text Available Abstract Background Despite the recent success of genome-wide association studies in identifying novel loci contributing effects to complex human traits, such as type 2 diabetes and obesity, much of the genetic component of variation in these phenotypes remains unexplained. One way to improving power to detect further novel loci is through meta-analysis of studies from the same population, increasing the sample size over any individual study. Although statistical software analysis packages incorporate routines for meta-analysis, they are ill equipped to meet the challenges of the scale and complexity of data generated in genome-wide association studies. Results We have developed flexible, open-source software for the meta-analysis of genome-wide association studies. The software incorporates a variety of error trapping facilities, and provides a range of meta-analysis summary statistics. The software is distributed with scripts that allow simple formatting of files containing the results of each association study and generate graphical summaries of genome-wide meta-analysis results. Conclusions The GWAMA (Genome-Wide Association Meta-Analysis software has been developed to perform meta-analysis of summary statistics generated from genome-wide association studies of dichotomous phenotypes or quantitative traits. Software with source files, documentation and example data files are freely available online at http://www.well.ox.ac.uk/GWAMA.
Screening and breeding low-oxalate germplasm is a major objective in spinach breeding. This research aims to conduct association analysis and identify SNP markers associated with oxalate concentration in spinach germplasm. A total of 310 spinach genotypes including 300 USDA germplasm accessions and ...
Præstegaard, Camilla; Kjaer, Susanne K; Nielsen, Thor S S; Jensen, Signe M; Webb, Penelope M; Nagle, Christina M; Høgdall, Estrid; Risch, Harvey A; Rossing, Mary Anne; Doherty, Jennifer A; Wicklund, Kristine G; Goodman, Marc T; Modugno, Francesmary; Moysich, Kirsten; Ness, Roberta B; Edwards, Robert P; Goode, Ellen L; Winham, Stacey J; Fridley, Brooke L; Cramer, Daniel W; Terry, Kathryn L; Schildkraut, Joellen M; Berchuck, Andrew; Bandera, Elisa V; Paddock, Lisa; Kiemeney, Lambertus A; Massuger, Leon F; Wentzensen, Nicolas; Pharoah, Paul; Song, Honglin; Whittemore, Alice S; McGuire, Valerie; Sieh, Weiva; Rothstein, Joseph; Anton-Culver, Hoda; Ziogas, Argyrios; Menon, Usha; Gayther, Simon A; Ramus, Susan J; Gentry-Maharaj, Aleksandra; Wu, Anna H; Pearce, Celeste L; Pike, Malcolm C; Lee, Alice W; Chang-Claude, Jenny; Jensen, Allan
Socioeconomic status (SES) is a known predictor of survival for several cancers and it has been suggested that SES differences affecting tumour stage at diagnosis may be the most important explanatory factor for this. However, only a limited number of studies have investigated SES differences in tumour stage at diagnosis of ovarian cancer. In a pooled analysis, we investigated whether SES as represented by level of education is predictive for advanced tumour stage at diagnosis of ovarian cancer, overall and by histotype. The effect of cigarette smoking and body mass index (BMI) on the association was also evaluated. From 18 case-control studies, we obtained information on 10,601 women diagnosed with epithelial ovarian cancer. Study specific odds ratios (ORs) with corresponding 95% confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio (pOR) using a random effects model. Overall, women who completed ≤high school had an increased risk of advanced tumour stage at diagnosis compared with women who completed >high school (pOR 1.15; 95% CI 1.03-1.28). The risk estimates for the different histotypes of ovarian cancer resembled that observed for ovarian cancers combined but did not reach statistical significance. Our results were unchanged when we included BMI and cigarette smoking. Lower level of education was associated with an increased risk of advanced tumour stage at diagnosis of ovarian cancer. The observed socioeconomic difference in stage at diagnosis of ovarian cancer calls for further studies on how to reduce this diagnostic delay. Copyright © 2016 Elsevier Ltd. All rights reserved.
Spencer T. Plumb
Full Text Available The REDD Programme is predicated on the assumption that developed countries will provide sufficient funds to offset opportunity costs associated with avoiding deforestation. The role of non-market values in indigenous land management may challenge the efficacy of compensation schemes targeted at meeting opportunity costs as calculated in traditional opportunity cost analysis (OCA. Furthermore it is unclear how these economic incentives might affect social and cultural values linked to land-use norms, livelihoods, and local governance. This study explores the economic, social and cultural values of forest uses for a Miskito community in the Rio Plátano Biosphere Reserve in Honduras. Data were collected using household surveys, farm visits, and community workshops. OCA indicates potential for successful REDD+ payment schemes; however it is an inadequate method to account for subsistence and cultural opportunity costs associated with avoided deforestation. Compensation to change land-use practices may undermine governance institutions necessary to address deforestation in the region. Our results indicate that small-scale agriculture and other forest-based subsistence activities are important cultural practices for maintaining Miskito identity and forest management institutions. Recommendations are offered for using OCA to develop REDD+ projects that recognize the linkages between social and cultural values and forest management by focusing on approaches that consider a full range of economic, social and cultural opportunity costs.
Lee, Heeyoung; Song, Seungyeon; Oh, Yun-Kyoung; Kang, WonKu; Kim, Eunyoung
To evaluate the role of gender as a risk factor for developing contrast media-associated adverse drug reactions (CM-ADRs) by comparing the incidence of CM-ADR between male and female patients according to study design, ADR type, and computed tomography (CT) examination. We systematically searched three electronic databases for eligible studies. In the studies included (n=18), we assessed effect estimates of the relative incidence of CM-ADR, analysed by experimental design, ADR type and CT examination. This was calculated by using a random effects model if clinical conditions showed heterogeneity; otherwise, a fixed effects model was used. We identified 10,776 patients administered CM. According to the designs, studies were classified into randomised controlled trials (RCTs) and observational studies. Results were as follows: risk ratio (RR)=1.07 (95% confidence interval (CI): 0.79-1.46, P=0.66) for RCTs, and RR=0.77 (95% CI: 0.58-1.04, P=0.09) for observational studies. The results of analysis according to ADR type and for undergoing CT demonstrated that the incidence of CM-ADR did not differ between males and females. We found no significant difference in the incidence of CM-ADRs between male and female patients according to study design, ADR type, or CT examination. Future studies to determine why gender has shown different roles as a risk factor between CM-ADRs and non-CM ADRs are needed. Copyright © 2017 Elsevier B.V. All rights reserved.
Ascencio-Montiel, Iv?n de Jes?s; Parra, Esteban J.; Valladares-Salgado, Ad?n; G?mez-Zamudio, Jaime H; Kumate-Rodriguez, Jes?s; Escobedo-de-la-Pe?a, Jorge; Cruz, Miguel
Background Several studies in type 2 diabetes patients have shown significant associations between the SOD2 gene Val16Ala polymorphism and albuminuria, but this association has not been explored in the Mexican population. Methods We evaluated the association between the SOD2 gene Val16Ala polymorphism (rs4880) and macroalbuminuria in a sample of 994 unrelated Mexican type 2 diabetes patients. The study included 119 subjects with urinary albumin >300 mg/dL and 875 subjects with urinary albumin...
Burgdorf, Kristoffer Sølvsten; Grarup, Niels; Justesen, Johanne Marie
A study of 222 candidate genes in type 2 diabetes reported association of variants in RAPGEF1, ENPP1, TP53, NRF1, SLC2A2, SLC2A4 and FOXC2 with type 2 diabetes in 4,805 Finnish individuals. We aimed to replicate these associations in a Danish case-control study and to substantiate any replicated ...
Full Text Available To satisfy future demands, the increase of wheat (Triticum aestivum L. yield is inevitable. Simultaneously, maintaining high crop productivity and efficient use of nutrients, especially nitrogen use efficiency (NUE, are essential for sustainable agriculture. NUE and its components are inherently complex and highly influenced by environmental factors, nitrogen management practices and genotypic variation. Therefore, a better understanding of their genetic basis and regulation is fundamental. To investigate NUE-related traits and their genetic and environmental regulation, field trials were evaluated in a Central European wheat collection of 93 cultivars at two nitrogen input levels across three seasons. This elite germplasm collection was genotyped on DArTseq® genotypic platform to identify loci affecting N-related complex agronomic traits. To conduct robust genome-wide association mapping, the genetic diversity, population structure and linkage disequilibrium were examined. Population structure was investigated by various methods and two subpopulations were identified. Their separation is based on the breeding history of the cultivars, while analysis of linkage disequilibrium suggested that selective pressures had acted on genomic regions bearing loci with remarkable agronomic importance. Besides NUE, genetic basis for variation in agronomic traits indirectly affecting NUE and its components, moreover genetic loci underlying response to nitrogen fertilisation were also determined. Altogether, 183 marker-trait associations (MTA were identified spreading over almost the entire genome. We found that most of the MTAs were environmental-dependent. The present study identified several associated markers in those genomic regions where previous reports had found genes or quantitative trait loci influencing the same traits, while most of the MTAs revealed new genomic regions. Our data provides an overview of the allele composition of bread wheat
William S Bush
Full Text Available Genome-wide association studies (GWAS have evolved over the last ten years into a powerful tool for investigating the genetic architecture of human disease. In this work, we review the key concepts underlying GWAS, including the architecture of common diseases, the structure of common human genetic variation, technologies for capturing genetic information, study designs, and the statistical methods used for data analysis. We also look forward to the future beyond GWAS.
Full Text Available Zhisen Shen,1 Chongchang Zhou,1,2 Jinyun Li,2 Hongxia Deng,1 Qun Li,1 Jian Wang3 1Department of Otorhinolaryngology-Head and Neck Surgery, Lihuili Hospital, Ningbo University, 2Department of Biochemistry and Molecular Biology, Medical School of Ningbo University, 3Department of Otorhinolaryngology-Head and Neck Surgery, Ningbo Yinzhou People’s Hospital, Ningbo, Zhejiang, People’s Republic of China Abstract: Epithelial cadherin (encoded by the CDH1 gene is a tumor suppressor glycoprotein that plays a role in the invasion and metastasis of human cancers. As previous studies regarding the association between CDH1 promoter methylation and head and neck squamous cell carcinoma (HNSCC have yielded inconsistent conclusions, a meta-analysis was performed. A systematic literature review was undertaken from four databases: PubMed, Embase, Google Scholar, and Web of Science. Finally, a total of 23 studies (including 1,727 cases of HNSCC and 555 normal controls were included in the present study. Our results showed that the frequency of CDH1 promoter methylation in HNSCC was statistically greater than in controls (odds ratio [OR] =5.94, 95% confidence interval [CI]: 3.36–10.51, P<0.001. In reported cases of HNSCC, CDH1 promoter methylation was statistically associated with tumor stage (OR =0.46, 95% CI: 0.27–0.78, P=0.004 and a history of alcohol consumption (OR =6.04, 95% CI: 2.41–15.14, P<0.001. Moreover, the sensitivity, specificity, and area under the curve of the summary receiver operator characteristic for the included studies were 0.50 (95% CI: 0.4–0.61, 0.89 (95% CI: 0.79–0.95, and 0.74 (95% CI: 0.70–0.78, respectively. In conclusion, our meta-analyses indicated that CDH1 promoter methylation was associated with HNSCC risk, and may be utilized as a valuable diagnostic biomarker for HNSCC. Keywords: CDH1, methylation, diagnosis, head and neck squamous cell carcinoma, HNSCC
Hou, Fengsu; Cerulli, Catherine; Wittink, Marsha N; Caine, Eric D; Qiu, Peiyuan
To estimate the prevalence of intimate partner violence (IPV) among a sample of rural Chinese women and to explore associated factors. Cross-sectional study. Rural areas of Guangyuan City, Sichuan, China. We recruited 1501 women, aged 16 years and older, who had been living locally for at least 2 years and reported being married or in a relationship during the past 12 months. They were among a sample of 1898 potential participants from our larger parent study on the prevalence of depressive-distress symptoms. Participants completed demographic and social economic measures, the Short Form of the Revised Conflict Tactics Scale and the Duke Social Support Index. We applied χ2 test, analysis of variance and confirmatory factor analysis for analysis. The overall prevalence of IPV in the past 12 months was 29.05%; the prevalence of physical, psychological and sexual violence was 7.66%, 26.58% and 3.20%, respectively. The overall prevalence was highest among women aged 16-29 years, and was more common among those without a high school diploma and who saw their family's financial status as very poor or stagnant. Women who were not victims of IPV had higher levels of social support. Confirmatory factor analysis showed that the total effects of social support on physical, psychological and sexual violence were -0.12, -0.35 and -0.12, respectively. The indirect effects of objective economic status on physical, psychological and sexual violence were -0.047, -0.014 and -0.047, respectively, but the total effect was not significant. The indirect effect of education on psychological violence was -0.056. IPV is common in rural Guangyuan. Our data are comparable with the findings from north-west of China. Social support is an important protective factor. Future work is needed to develop, test and later disseminate potential IPV interventions, with a focus on building actual and perceived supportive social networks. © Article author(s) (or their employer(s) unless otherwise stated
Helmerhorst, Hendrik J. F.; Roos-Blom, Marie-José; van Westerloo, David J.; de Jonge, Evert
Oxygen is vital during critical illness, but hyperoxia may harm patients. Our aim was to systematically evaluate the methodology and findings of cohort studies investigating the effects of hyperoxia in critically ill adults. A meta-analysis and meta-regression analysis of cohort studies published
van der Voort, Paul; Pijls, Bart G; Nieuwenhuijse, Marc J; Jasper, Jorrit; Fiocco, Marta; Plevier, Josepha W M; Middeldorp, Saskia; Valstar, Edward R; Nelissen, Rob G H H
Few studies have addressed the association between early migration of femoral stems and late aseptic revision in total hip arthroplasty. We performed a meta-regression analysis on 2 parallel systematic reviews and meta-analyses to determine the association between early migration and late aseptic revision of femoral stems. Of the 2 reviews, one covered early migration data obtained from radiostereometric analysis (RSA) studies and the other covered long-term aseptic revision rates obtained from survival studies with endpoint revision for aseptic loosening. Stems were stratified according to the design concept: cemented shape-closed, cemented force-closed, and uncemented. A weighted regression model was used to assess the association between early migration and late aseptic revision, and to correct for confounders. Thresholds for acceptable and unacceptable migration were determined in accordance with the national joint registries (≤ 5% revision at 10 years) and the NICE criteria (≤ 10% revision at 10 years). 24 studies (731 stems) were included in the RSA review and 56 studies (20,599 stems) were included in the survival analysis review. Combining both reviews for the 3 design concepts showed that for every 0.1-mm increase in 2-year subsidence, as measured with RSA, there was a 4% increase in revision rate for the shape-closed stem designs. This association remained after correction for age, sex, diagnosis, hospital type, continent, and study quality. The threshold for acceptable migration of shape-closed designs was defined at 0.15 mm; stems subsiding less than 0.15 mm in 2 years had revision rates of less than 5% at 10 years, while stems exceeding 0.15 mm subsidence had revision rates of more than 5%. There was a clinically relevant association between early subsidence of shape-closed femoral stems and late revision for aseptic loosening. This association can be used to assess the safety of shape-closed stem designs. The published research is not sufficient