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Single SNP Mediates Some Differences in Atrial Fibrillation Risk Between Europeans, African Americans

NEW YORK (GenomeWeb) – A University of California, San Francisco-led team of researchers has homed in on a SNP that seems to mediate some of the difference in atrial fibrillation risk that's seen between European Americans and African Americans.

Atrial fibrillation, a type of cardiac arrhythmia, affects more than 33 million people around the world, and more than 5 percent of adults in the US over the age of 65. It's associated with an increased risk of stroke, heart failure, and overall mortality. Individuals of European descent are at a higher risk of atrial fibrillation than individuals of African descent, even though white individuals usually exhibit fewer established clinical risk factors, like diabetes and hypertension, suggesting that there may be genetic factors at play.

As it reported today in JAMA Cardiology, the UCSF-led team examined whether nine SNPs previously linked to atrial fibrillation might affect this differential risk in three population-based cohorts. One SNP, rs10824026 on chromosome 10q22, mediates a portion of the increased atrial fibrillation risk among European Americans as compared to African Americans, the team found. At the same time, genome-wide admixture mapping in black participants to search for novel risk loci came up empty.

"Taken together, these findings demonstrate that additional genetic or environmental influences beyond single SNPs in isolation are likely operational," UCSF's Gregory Marcus and his colleagues wrote in their paper. "Given the consistent observations that race is a powerful risk factor for AF that can supersede conventional risk factors, our data suggest that this phenomenon is primarily driven by polygenic influences, gene-environment interactions, or environmental influences in isolation."

The researchers examined the allele frequencies of nine SNPs previously linked with atrial fibrillation in more than 16,500 people from the population-based Cardiovascular Health Study and Atherosclerosis Risk in Communities study. Participants from CHS were genotyped on Illumina microarrays, while ARIC participants were genotyped on Affymetrix arrays. Not all the SNPs were directly genotyped, and the researchers imputed the missing ones after phasing using the IMPUTE2 program.

From this, Marcus and his colleagues found significant differences in the allele frequencies between European-American and African-American participants for each of the nine SNPs.

In particular, rs10824026 appeared to mediate the race-atrial fibrillation relationship. The researchers estimated that it accounts for 11.4 percent and 31.7 percent of the increased arrhythmia risk in white participants as compared to black participants in the CHS and ARIC cohorts, respectively.

The researchers noted that the minor G allele — previously shown to have a protective effect against atrial fibrillation — was more common in black participants.

This SNP maps to 10q22 and is located 5 kilobases upstream of SYNPO2L and 20 kilobases upstream of MYOZ1. Though both genes are expressed in cardiac tissue, the researchers said that their exact roles aren't known.

Still, genome-wide SNP and RNA transcript data from the Expression Quantitative Trait Loci Genotype-Tissue Expression database suggest that the effect of rs10824026 is mediated by MYOZ1 rather than by the more closely located SYNPO2L. MYOZ1 encodes the myozenin 1 protein, which itself affects calcineurin signaling and interacts with proteins at the Z-disc of the cardiac sarcomere, such as α-actinin and γ-filamin.

At the same time, Marcus and his colleagues conducted a genome-wide admixture mapping study of African-American participants from the CHS and ARIC cohorts as well as from the Health, Aging, and Body Composition Study — a total of nearly 5,000 individuals — to look for additional risk SNPs.

However, they were unable to identify any further risk loci. This failure was likely due to inadequate power, the researchers said.

In a related editorial, Thomas Stamos and Dawood Darbar, both from University of Illinois at Chicago, noted that this meta-analysis included the largest African-American cohort that has undergone GWAS analysis.

"The findings of Roberts et al suggest that some of this missing heritability may be related to multiple low-level genetic variants that cannot be uncovered by current approaches or by gene-gene and/or gene-environment interactions," they wrote.