Population-specific genetic variations increase hazard of mortality or rehospitalization in heart failure patients

Background: Heart failure (HF) is a global health burden despite effective therapies, and patients hospitalized for HF are particularly at risk. Identifying genetic associates of death or rehospitalization may identify new targets for therapy or especially high risk patient subgroups. Methods: The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated HF (ASCEND) was a multinational clinical trial of 7141 patients hospitalized for HF randomized to nesiritide or placebo. A genetic substudy was conducted including 2795 patients that underwent genome-wide (GW) genotyping using Axiom Biobank Array (Affymetrix). Of these, 2680 subjects of European Ancestry (EA, n=2173) and African Ancestry (AA, n=507) had additional genotypes imputed via 1000 Genome reference panel resulting in roughly 8.9 million SNPs in AA and 6.7 million SNPs in EA. Cox proportional hazard regression models were used to test the association between each SNP and time to death or HF hospitalization, adjusted for the published ASCEND rehospitalization score (11 clinical factors) and the frst fve principal components. A fxed-effect meta-analysis was used to combine results from the two populations. Threshold for GW signifcance was p\u3c5E-8. Results: Four population-specific GW signifcant SNPs were identifed; one in EA (rs704926, p=3.8E-08, HR=1.83), and 3 in AA (rs5008759, rs4127449, and chr18:65470717:D, p=1.2E-8, HR=2.95); both in or near noncoding RNA (NCRNA) genes. The meta-analysis yielded no GW signifcant SNPs but two near-signifcant loci; rs2342882 (p=7.0E-8, HR=1.4) in FGD5 (a possible regulator of VEGF-mediated angiogenesis) and an interesting peak at 5q21.3 (rs293652, p =1.2E-7, HR=1.4) including 42 SNPs with p\u3c1E-6, near another NCRNA gene. Conclusion: Genetic predictors of death or rehospitalization after HF admission can be identifed in ancestry specific populations, and suggest a role for NCRNA genes. These data require validation