The response to therapy with a fixed dose combination of isosorbide dinitrate and hydralazine (FDC I/H) is enhanced in African Americans with heart failure and reduced ejection fraction (HFrEF) when compared to similar white cohorts. Despite the clear survival benefit with FDC I/H in the African American Heart Failure Trial (AHeFT), the drug is prescribed in only 25% of black subjects who would potentially benefit. In terms of the enhanced response, race is likely a marker of differences in genomic background. Genetic variation of the G protein beta sub unit GNB3 has been studied extensively for its role in hypertension. A polymorphism exists at position 825 (T/C) which is functionally silent but tightly linked to a splicing variant resulting in a truncated protein. The GNB3 T haplotype is far more prevalent in blacks and associated with low renin hypertension. Evaluation of 350 subjects in the genetic sub-study of AHeFT suggests that the GNB3 TT genotype, found in 50% of African Americans but only 10-15% of whites, was linked to an enhanced therapeutic response to FDC I/H. This proposal will evaluate the hypothesis that the GNB3 TT genotype is a marker of enhanced therapeutic response to FDC I/H in African Americans with HFrEF. The study will enroll a cohort of 500 African Americans with HFrEF, initiate therapy with FDC I/H and follow them for up to two years. Subjects will be genotyped at entry for the GNB3 polymorphism and response to therapy compared by genotype. Therapeutic response will be quantified using the composite score, the primary endpoint of AHeFT, which incorporates mortality, heart failure hospitalizations, and a change in QoL score at six months.
Aim 2 will do a similar analysis of response to therapy by GNB3 genotype using improvement in LVEDD or LVEF by echocardiogram after six months on therapy as the outcomes measure.
Aim 3 will use admixture analysis to determine first how global ancestry (the % African ancestral DNA for an individual) impacts on the outcome measures of drug response, and how the global ancestry acts as a modifier for the effect of GNB3.

Public Health Relevance

Clinical outcomes are poorer in African Americans with heart failure than in whites. Treatment with a fixed dose combination of isosorbide dinitrate and hydralazine was demonstrated to improve survival specifically in African Americans;however these drugs are not prescribed for the majority of patients who would benefit. This proposal will investigate whether a variant of a gene which appears to regulate blood pressure, GNB3, will predict the 50% of black subjects who get the greatest benefit from this therapy. This genetic marker would help to target heart failure therapy based on benefit and improve clinical outcomes in African Americans with heart failure.

National Institute of Health (NIH)
National Institute on Minority Health and Health Disparities (NIMHD)
Research Project (R01)
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Special Emphasis Panel (ZMD1-MLS (02))
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Rajapakse, Nishadi
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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