Pharmacogenomics of Heart Failure in African-Americans and Hispanic-Americans
The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors. Patients & methods: The following were assessed in a cohort of 260 African–Americans and 53 Hispanic–Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes. Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs 0.18; p < 0.05) allele frequencies were higher in Hispanic–Americans compared with African–Americans. Multiple regression analysis in the Hispanic–American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African–Americans after adjusting for known genetic and clinical predictors. In our cohort of inner-city Hispanic–Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic–Americans. The renin-angiotensin-aldosterone system is central to the pathogenesis of heart failure (HF) and atrial fibrillation (AF). Aldosterone synthase catalyzes the final reaction to generate aldosterone. The aldosterone synthase (CYP11B2) c.-344T>C (rs1799998) variant has been linked to aldosterone synthase activity and presence of AF in HF in Caucasians. We, therefore, evaluated the possible association between the -344T>C SNP and AF in African–Americans (AA) with HF. We enrolled 199 self-reported AA adults with HF on optimal conventional medical therapies. After obtaining written informed consent, a genetic sample was obtained, and clinical data and echocardiographic measurements of left ventricular (LV) ejection fraction, left atrial size, LV diastolic diameter and severity of mitral regurgitation (MR) were recorded. Individual genetic ancestry was determined using 105 DNA ancestry informative markers for West African and European ancestry. Multiple logistic regression permitted tests of association between CYP11B2 -344T>C and presence of AF while holding clinical factors, echocardiographic measurements, and genetic ancestry constant. The mean age of the study population was 55±14 years, 23% were ischemic in etiology, and the mean LV ejection fraction was 29±14%. The CYP11B2 -344 CC genotype was observed in 3.7% of patients, and AF was present in 20% of patients. The prevalence of AF was 71% among patients with the CC genotype and 29% among the CT or TT genotype group (OR 11.3, 95% CI 2.1-60.4, p=0.003). No patient with the CC genotype was on an aldosterone antagonist. After adjustments for age, gender, body size, renal function, systemic hypertension, coronary artery disease, echocardiographic parameters, and European ancestry, the CYP11B2 -344 CC genotype was a strong independent predictor of AF (OR 12.7, 95% CI 1.6 to 98, p=0.015, empiric p=0.011). In this cohort of AAs with HF, the CYP11B2 CC genotype was a significant predictor of AF while holding clinical and echocardiographic predictors of AF and genetic ancestry constant. Whether strategies, such as additional aldosterone antagonism, ameliorate this risk remains to be determined.