03677nas a2200613 4500008004100000022001400041245016900055210006900224260001300293300001000306490000700316520181200323653000902135653002402144653001102168653003802179653002202217653003402239653002502273653001102298653002702309653000902336653001602345653003602361653002902397100001902426700002202445700002302467700001902490700002402509700002202533700002202555700002202577700002202599700002202621700002202643700002102665700002002686700002202706700001902728700002202747700001702769700002302786700002402809700001902833700002102852700001902873700002302892700001902915700002402934700002402958710004502982856003603027 2014 eng d a1556-387100aTargeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.0 aTargeted sequencing in candidate genes for atrial fibrillation t c2014 Mar a452-70 v113 a
BACKGROUND: Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.
OBJECTIVE: To study the association of genetic variants with AF at GWAS top loci.
METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.
RESULTS: One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).
CONCLUSIONS: We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.
10aAged10aAtrial Fibrillation10aFemale10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aHomeodomain Proteins10aHumans10aLinkage Disequilibrium10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aReceptors, Interleukin-61 aLin, Honghuang1 aSinner, Moritz, F1 aBrody, Jennifer, A1 aArking, Dan, E1 aLunetta, Kathryn, L1 aRienstra, Michiel1 aLubitz, Steven, A1 aMagnani, Jared, W1 aSotoodehnia, Nona1 aMcKnight, Barbara1 aMcManus, David, D1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aBis, Joshua, C1 aGibbs, Richard, A1 aMuzny, Donna1 aKovar, Christie, L1 aMorrison, Alanna, C1 aGupta, Mayetri1 aFolsom, Aaron, R1 aKääb, Stefan1 aHeckbert, Susan, R1 aAlonso, Alvaro1 aEllinor, Patrick, T1 aBenjamin, Emelia, J1 aCHARGE Atrial Fibrillation Working Group uhttps://chs-nhlbi.org/node/6149