Abstract 3144: Association of Polymorphisms in Genes Related to Renin-Angiotensin-Aldosterone System with Left Ventricular Structure and Function and Incident Heart Failure in Four Ethnic Groups; The Multi-Ethnic Study of Atherosclerosis
Introduction: Previously, we have shown differences in left ventricular (LV) remodeling and incident congestive heart failure (CHF) among four ethnic groups in MESA. Our objective was to determine the associations of the genes encoding the renin-angiotensin-aldosterone (RAA) system with MRI-measured parameters of cardiovascular structure/function and incident CHF in four ethnic groups.
Methods: 55 tagging SNPs were genotyped in angiotensinogen (AGT), angiotensin converting enzyme (ACE), and angiotensin II receptors 1 and 2 (AGTR1 and AGTR2) genes in 2,847 participants [712 Caucasians (CA), 712 African Americans (AA), 705 Hispanics (HIS) and 718 Chinese Americans (CHN)]. Multiple linear regression was used to determine the associations of these SNPs with LV mass, LV ejection fraction (LVEF), cardiac output, and Cox regression models for CHF, while adjusting for age, gender, diabetes, blood pressure, antihypertensive medication, ACE inhibitor, BMI, smoking, total cholesterol and lipid-lowering medication stratified by racial/ethnic group. A p-value ≤0.0125 was considered significant to account for multiple genes tested. Empirical p-values were then calculated using permutation tests.
Results: During a median follow-up time of 4.1 years, 38 participants developed CHF. SNPs in AGTR1 [rs422858-C (adjusted HR: 2.9, p:0.011) and rs2638363-A (adjusted HR: 2.4, p<0.001)] were associated with increased risk of CHF in AA; these associations were more pronounced after adjustment for risk factors. SNPs in AGT (rs2478545-A, coefficient: −1.4%, p:0.002) and AGTR1 (rs275645-G, coefficient: −2.3%, p<0.001) were independently associated with lower LVEF in CA and HIS, respectively. Lower cardiac output was independently related to polymorphisms in AGTR1 (rs275646-A, p<0.001) in HIS and in AGTR1 (rs4681443-G and rs718858-G, p: 0.002) and AGT (rs3789671-T, p:0.001) in CHN. A SNP in the AGTR2 (rs5950586-A, p:0.0075) was an independent predictor of increased LV mass in Hispanic men.
Conclusions: Polymorphisms in genes encoding RAA system, particularly in AGTR1, appear to be associated with LV function (in HIS & CHN) and incident CHF (in AA). This potential genetic heterogeneity may contribute to ethnic differences in LV function and incidence of CHF.