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Common Variants on FGD5 Increase Hazard of Mortality or Rehospitalization in Patients With Heart Failure From the ASCEND-HF Trial.

Authors :
Hongsheng Gui
Tang, W. H. Wilson
Francke, Stephan
Jia Li
Ruicong She
Bazeley, Peter
Pereira, Naveen L.
Adams, Kirkwood
Luzum, Jasmine A.
Connolly, Thomas M.
Hernandez, Adrian F.
McNaughton, Candace D.
Williams, L. Keoki
Lanfear, David E.
Source :
Circulation: Heart Failure; Sep2023, Vol. 16 Issue 9, p776-786, 11p
Publication Year :
2023

Abstract

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 considered P<5×10-8. RESULTS: Common variants (rs2342882 and rs35850039 in complete linkage disequilibrium) located in FGD5 were 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). FGD5 encodes 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; meta P<0.01). Sensitivity analysis proved FGD5 common 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 in FGD5 were associated with increased risk of death or rehospitalization. Additional investigation is required to examine biological mechanisms and whether FGD5 could be a therapeutic target. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
19413289
Volume :
16
Issue :
9
Database :
Supplemental Index
Journal :
Circulation: Heart Failure
Publication Type :
Academic Journal
Accession number :
172339245
Full Text :
https://doi.org/10.1161/CIRCHEARTFAILURE.122.010438