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Novel Genetic Markers Associate With Atrial Fibrillation Risk in Europeans and Japanese
Study Questions:
Do multiple genetic susceptibility signals exist at the known atrial fibrillation (AF) loci?
Methods:
The investigators performed association testing between single nucleotide polymorphisms and AF in 64,683 individuals of European ancestry. Association testing was performed at the nine established AF loci. Risk scores were generated and tested for association with AF in Europeans and an independent sample of 11,309 Japanese individuals.
Results:
The authors found evidence for multiple genome-wide significant susceptibility signals at chromosome 4q25, but not at any of the other loci. These identified variants reside upstream of PITX2, a transcription factor, involved in left-right cardiac asymmetry, development of pulmonary vein myocardial sleeves, and inhibiting formation of a sinus node in the left atrium. After adjusting for age and gender, a gradient of risk was found that correlated with the number of risk alleles present. Similar findings were observed in the Japanese sample.
Conclusions:
The chromosome 4q25 AF locus contains multiple AF susceptibility signals in individuals of European and Japanese ancestry. The number of genetic risk markers of AF correlated with a gradient of AF risk.
Perspective:
This study strengthens the previously reported association between common genetic variants at chromosome 4q25 and AF. The fact that similar findings were observed in divergent populations makes the observations more generalizable. Prior studies suggest that patients with risk alleles at 4q25 demonstrate a suboptimal response to both medical and catheter-based therapy for AF. This study raises several important questions. What are the mechanisms by which these risk alleles contribute to AF? Is there an opportunity to intervene (e.g., more intensive screening for obesity, hypertension, sleep apnea, and other modifiable factors associated with AF) in patients with high-risk genetic markers in order to prevent AF? Can we use these findings in tailoring therapy for patients with AF?
Keywords: Polymorphism, Single Nucleotide, Genetic Markers
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