Common Variants on FGD5 Increase Hazard of Mortality or Rehospitalization in Patients With Heart Failure From the ASCEND-HF Trial
Circulation: Heart Failure, Ahead of Print.
BACKGROUND:Heart failure remains a global health burden, and patients hospitalized are particularly at risk, but genetic associates for subsequent death or rehospitalization are still lacking.METHODS:The genetic substudy of the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) was used to perform genome-wide association study and transethnic meta-analysis. The overall trial included the patients of self-reported European ancestry (n=2173) and African ancestry (n=507). The end point was death or heart failure rehospitalization within 180 days. Cox models adjusted for 11 a priori predictors of rehospitalization and 5 genetic principal components were used to test the association between single-nucleotide polymorphisms and outcome. Summary statistics from the 2 populations were combined via meta-analysis with the significance threshold consideredP<5×10−8.RESULTS:Common variants (rs2342882 and rs35850039 in complete linkage disequilibrium) located inFGD5were significantly associated with the primary outcome in both ancestry groups (European Americans: hazard ratio [HR], 1.38;P=2.42×10−6; African ancestry: HR, 1.51;P=4.43×10−3; HR in meta-analysis, 1.41;P=4.25×10−8).FGD5encodes a regulator of VEGF (vascular endothelial growth factor)-mediated angiogenesis, and in silico investigation revealed several previous genome-wide association study hits in this gene, among which rs748431 was associated with our outcome (HR, 1.20; metaP<0.01). Sensitivity analysis provedFGD5common variants survival association did not appear to operate via coronary artery disease or nesiritide treatment (P>0.05); and the signal was still significant when changing the censoring time from 180 to 30 days (HR, 1.39;P=1.59×10−5).CONCLUSIONS:In this multiethnic genome-wide association study of ASCEND-HF, single-nucleotide polymorphisms inFGD5were associated with increased risk of death or rehospitalization. Additional investigation is required to examine biological mechanisms and whetherFGD5could be a therapeutic target.REGISTRATION:URL:https://www.clinicaltrials.gov; Unique identifier: NCT00475852.
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