Abstract 12095: A Variant in Angiotensin II Receptor, Type 1 (AGTR1) Gene Modifies the Effect of Pulse Pressure on the Risk of Atrial Fibrillation: The ARIC Cohort
Background: Renin-angiotensin system (RAS) genetic variants are associated with atrial fibrillation (AF). Higher pulse pressure (PP), a marker of aortic stiffness, is a risk factor for AF. It is unknown whether variants in RAS genes interact with PP to modify AF risk. We sought to identify such interactions in the ARIC cohort, a US prospective study.
Methods: We included 8,466 whites, 53% women, aged 45-64 yrs, free of AF at baseline (1987-89), and followed through 2005. Incident AF events were identified from study ECGs at 3 triennial follow-up visits and hospitalization discharge codes. We analyzed 33 SNPs genotyped by the Affymetrix 6.0 array and 32 haplotype-tagging SNPs imputed using the HapMap CEU panel in ACE, AGT, AGTR1. We ran proportional-hazards models to assess for interaction between SNP and PP adjusting for age, gender, center, BMI, hypertension, diabetes, myocardial infarction, and heart failure. We conducted a 2-stage analysis. First, SNPs were tested for main effects (P<0.20), assuming an additive model. Second, SNPs with main effects were tested for multiplicative interactions with PP, modeled continuously. Bonferroni correction was used to account for multiple testing.
Results: During follow-up (median 17 yrs), 746 AF cases were identified. Of 16 SNPs with main effects, we found a statistically significant interaction between rs1492100 in AGTR1 and PP in relation to AF (P=0.0005). Higher PP (P<0.0001) and rs1492100(T) (P=0.0001) were significantly associated with AF. Higher PP had a smaller effect on increasing AF risk in TT than AT or AA subjects (Figure). The HR (95% CI) of AF associated with a 10 mmHg increase in PP was 1.19 (1.12-1.28), 1.02 (0.70- 1.49), and 0.87 (0.65-1.17) in AA, AT, and TT subjects, respectively.
Conclusions: In ARIC, rs1492100 modifies the effect of PP on AF risk. This interaction should be validated in other cohorts. If confirmed, lowering aortic stiffness may be more effective to prevent AF in persons who have AA or AT than TT genotype.
- © 2010 by American Heart Association, Inc.