Abstract MP48: Genetic Variation, Human Metabolome and Incident Heart Failure among African-Americans in the Atherosclerosis Risk in Communities (ARIC) Study
Introduction: Heart failure (HF) results from the interaction of multiple genes and environmental factors. The human metabolome reflects multiple cellular and physiologic processes and forms a bridge between the genome and HF.
Hypothesis: We assessed the hypothesis that the human metabolome is associated with and may mediate the first hospitalization for HF.
Methods: We examined the association between the human serum metabolome, measured by GC-MS and LC-MS, and incident hospitalized HF with median 22 years of follow-up among 1850 African-Americans in the Atherosclerosis Risk in Communities (ARIC) Study (HF events = 355). We next tested the relationship of identified metabolites with LV ejection fraction, mass and wall thickness measured by echocardiography. We genotyped a candidate metabolomics-influencing variant, rs77271279, in the entire ARIC cohort (10,263 European-Americans and 3,543 African-Americans) to evaluate its effect on incident HF.
Results: Six out of 308 analyzed named metabolites were significantly associated with incident HF in African-Americans (p < 1.6⊆10-4 using Bonferroni correction taking into account the correlation among variables) after adjusting for traditional risk factors, including eGFR. Depending on the particular metabolite, per SD change was associated with 17-25% risk difference in incident HF, with an average effect at 21%. Five out of six metabolites were mutually independent, and the predictive ability for incident HF was improved over the traditional risk factors by adding the five metabolites (AUC = 0.761 vs. 0.748, p = 0.037). Three metabolites were nominally associated with LV ejection fraction or wall thickness (p < 0.05). Hexadecanedioate, a medium chain fatty acid, was the most significant metabolite for HF (HR = 1.22, p = 3.0⊆10-7) and was also associated with echocardiographically-determined reduced LV wall thickness. A loss-of-function variant in a hepatic organic ion transporter, SLCO1B1, (rs77271279) leads to high hexadecanedioate levels. By genotyping rs77271279 in the entire ARIC, we estimate that one copy of the T allele was associated with 29% increased risk for hospitalized HF (HR = 1.29, p = 0.048).
Conclusion: In conclusion, we identified six metabolites that influence incident hospitalized HF among African-Americans, and demonstrated that SLCO1B1 is a candidate causal gene for HF. If replicated, our results may provide new insights into biological mechanism for HF process.
Author Disclosures: B. Yu: None. A.C. Morrison: None. T.H. Mosley: None. A.M. Shah: None. S.D. Solomon: None. C. Macrae: None. P.P. Chang: None. R.A. Gibbs: None. E. Boerwinkle: None.
- © 2015 by American Heart Association, Inc.