期刊
HEART RHYTHM
卷 11, 期 3, 页码 452-457出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.hrthm.2013.11.012
关键词
Arrhythmia; Genetics; Atrial fibrillation; Epidemiology
资金
- National Institutes of Health (NIB) through the American Recovery and Reinvestment Act [5RC211L102419]
- National Heart, Lung, and Blood Institute (NHLBI) [HH5N268201100005C, HHSN268201100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN26820110000.E0C, HHSN2682011000011 C, HH5N2682011000012C]
- NHLBI in collaboration with the Boston University [N0I-HC-25195]
- Linux Cluster for Genetic Analysis
- NIILBI [N01-11C-85239, N01-11C-85079, NO 1-HC-85080, N01-HC-85081, NO1-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, NOI-HC-75150, NO1-HC-45133, HHSN268201200036C, HL080295, HL087652, HL105756]
- National Institute on Aging of the Nzitional Institutes of Public Health [AC 021629 AG-15928, AG-20098, AG-027058]
- NIH [NOI-HC 25195, 6R01-NS 17950, 1ROHIL092577, 5R21DA027021, 1R0111L104156, 1K24111-105780, IRO1 HL102214, 1RC1111-101056]
- American Heart Association [09SDG2280087, 016.136.055]
- Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation at Boston University
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 x 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 (r2 =.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. (C) 2014 Heart Rhythm Society. All rights reserved.
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