Abstract 10294: A Common Variant in the Left-Right Determination Factor 2 Gene (LEFTY2) Interacts With Advancing Age to Modify the Risk of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS)
Background: Advancing age is a strong risk factor for incident atrial fibrillation (AF). However, it is unknown whether single nucleotide polymorphisms (SNPs) interact with advancing age to modify the risk of AF. We aimed to identify SNP and age interactions in relation to incident AF in the Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS).
METHODS: We included 9,231 and 3,774 white participants from ARIC and CHS, respectively, who were genotyped using the IBC array-a cardiovascular gene-centric array. After excluding SNPs with minor allele frequency (MAF) <5%, we analyzed a total of 28,438 SNPs. We used Cox proportional hazards models including an interaction term-SNP*Baseline age-and adjusting for sex and study center to identify SNP and age interactions in relation to incident AF. We assumed an additive genetic model. β coefficients of interaction terms in ARIC and CHS were meta-analyzed. Significance threshold was defined as P<1.76 x10-6 (Bonferroni correction of 28,438 tests).
RESULTS: During median follow-up of 15.4 years, there were 785 and 908 incident AF cases in ARIC and CHS, respectively. Of 28,438 interaction tests, we found a significant interaction between rs2273405 and age (ARIC: β=0.049, SE=0.013, P=2.19 x10-4; CHS: β=0.036, SE=0.009, P=8.46 x10-5; meta-analyzed P=9.75x10-8). The MAF of rs2273405 was 16.6% and 16.0% in ARIC and CHS, respectively.Compared with the presence of both common alleles GG, or heterozygous GA, the presence of both minor alleles AA significantly increased the incidence of AF with advancing age (Figure).
Conclusions: The common variant rs2273405 in the LEFTY2 gene interacts with advancing age to modify the risk of AF. Similar to PITX2-an AF susceptibility gene identified from GWAS for AF-the LEFTY2 gene plays a role in the determination of left-right asymmetry during development. Our finding will need to be replicated in other cohorts.
- © 2013 by American Heart Association, Inc.