Key result
Four genetic loci associate with LV mass, septal thickness, diastolic diameter, and LVEF in African Americans.
Why the study?
Genome-wide association studies of cardiac structure and systolic function in African Americans were lacking, limiting understanding of genetic loci related to these phenotypes.
Are specific genome-wide single-nucleotide polymorphisms associated with cardiac structure and systolic function in African Americans?
Observational (n=6,765)
Yes
Are specific genome-wide single-nucleotide polymorphisms associated with cardiac structure and systolic function in African Americans?
p-value: p=2.57×10(-8) to 4.02×10(-7)
This genome-wide association study identified 4 novel genetic loci associated with cardiac structure and systolic function in African Americans, suggesting potential ancestry-specific genetic influences on cardiac remodeling.
Should not change practice; extends GWAS signals to African Americans but leaves prognostic and therapeutic roles open.
BACKGROUND: Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study. METHODS AND RESULTS: Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN. CONCLUSIONS: In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
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Fox et al. (2012) conducted an observational in Cardiac structure and systolic function (n=6,765). Single-nucleotide polymorphisms (SNPs) was evaluated on 9 cardiac phenotypes assessed by echocardiogram or magnetic resonance imaging (p=2.57×10(-8) to 4.02×10(-7)). Genome-wide association analysis identified 4 genetic loci significantly associated with left ventricular mass, septal wall thickness, diastolic diameter, and ejection fraction in African Americans.
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