Abstract 10742: The Common 4q25 Risk Variant for Atrial Fibrillation Interacts with a Variant in the G Protein, Beta Polypeptide 3 Gene (GNB3) to Modify the Risk of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS)
Background Gene-gene interactions in disease can be identified by considering interactions between common risk variants identified from genome-wide association studies and risk variants identified from linkage or candidate gene association studies. We hypothesized that the common 4q25 risk variant for atrial fibrillation (AF), rs2200733 interacts with known risk variants from linkage and association studies to modify the risk of AF. We tested our hypothesis in the Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS).
Methods We included 9,523 and 3,941 white participants from ARIC and CHS, respectively, who were genotyped using the IBC array-a cardiovascular gene-centric array. We analyzed 431 SNPs in 23 genes (AGT, AGTR1, ACE, SCN5A, KCNQ1, KCNE1, KCNE2, KCNE4, KCNH2, KCNJ2, KCNA5, ABCC9, GJA5, EMD, NPPA, LMNA, GNB3, SLN, SCN2B, NOS3, MMP2, IL10, and PITX2). These genes were selected from linkage and association studies for AF. Assuming an additive model, Cox proportional hazards models including an interaction term rs2200733*SNP were used to assess SNP*SNP interaction in relation to incident AF. β coefficients of interaction terms in ARIC and CHS were meta-analyzed. Significance threshold was defined as P<1.6x10-4 which corresponds to Bonferroni correction of 312 tests, accounting for SNPs in linkage disequilibrium.
Results During follow-up, there were 820 and 917 incident AF cases, in ARIC and CHS, respectively. We found a significant interaction between rs2200733 and rs5446 (ARIC: β=0.277, SE=0.101, P=0.006; CHS: β=0.252, SE=0.097, P=0.01; meta-analyzed P=1.6x10-4). The presence of minor alleles for both rs2200733 and rs5446 increases the risk of AF beyond that is expected from the product of the main effects (Table 1A & 1B).
Conclusions The common AF risk variant, rs2200733 may interact with rs5446 in G protein, beta polypeptide 3 gene (GNB3) to modify the risk of AF. These findings will need to be replicated in other cohorts.
- © 2012 by American Heart Association, Inc.