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Heart Rhythm. 2014 Mar;11(3):452-7. doi: 10.1016/j.hrthm.2013.11.012. Epub 2013 Nov 14.

Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.

Author information

1
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; The NHLBI's Framingham Heart Study, Framingham, Massachusetts. Electronic address: hhlin@bu.edu.
2
The NHLBI's Framingham Heart Study, Framingham, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
3
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.
4
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
5
The NHLBI's Framingham Heart Study, Framingham, Massachusetts; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
6
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
7
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts.
8
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; The NHLBI's Framingham Heart Study, Framingham, Massachusetts.
9
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington; Division of Cardiology, University of Washington, Seattle, Washington.
10
Department of Biostatistics, University of Washington, Seattle, Washington.
11
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
12
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas.
13
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington; Group Health Research Institute, Group Health Cooperative, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington; Department of Health Services, University of Washington, Seattle, Washington.
14
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.
15
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
16
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
17
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
18
Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich, Germany; Munich Heart Alliance, Munich, Germany.
19
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington; Group Health Research Institute, Group Health Cooperative, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington.
20
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts; Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.

Abstract

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.

KEYWORDS:

Arrhythmia; Atrial fibrillation; Epidemiology; Genetics

PMID:
24239840
PMCID:
PMC3943920
DOI:
10.1016/j.hrthm.2013.11.012
[Indexed for MEDLINE]
Free PMC Article

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