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Genetic risk variants for heart failure onset and progression do not improve prediction of mortality beyond established prognostic neurohormonal and echocardiographic markers
Background: Genome-wide association studies and candidate gene studies have identified genetic risk variants associated with the onset and progression of heart failure.
Purpose: This study aimed to investigate whether genetic risk variants for heart failure onset and progression can improve prediction of mortality in heart failure patients, beyond established prognostic markers.
Methods: We genotyped 11 genetic variants identified from genome-wide association or candidate gene studies in two independent heart failure cohorts and investigated associations with neurohormone levels, echocardiographic indices and survival (discovery cohort, recruited from 1997–2000, 4 years follow-up, n=451; validation cohort, recruited from 2010–2014, median 2.6 years follow-up, n=900). Genotyping was performed for variants located at 1p36, 3p22, 10q22, 10q26, 15q13, 20p12 and within 3 genes of the renin-angiotensin system. To investigate a potential mechanism through which these variants may influence heart failure onset or progression, we tested associations between each variant and levels of gene expression in the left ventricle using Affymetrix microarrays, in 106 heart transplant patients and 108 heart donors with no history of cardiovascular disease.
Results: In the discovery cohort, we found that variants located at 3p22 (rs12638540), 10q26 (rs2234962) and within the angiotensinogen gene (AGT, rs699, rs4762) were independently predictive of mortality in the presence of established risk factors including age, history of myocardial infarction, history of heart failure, left ventricular ejection fraction, plasma creatinine, plasma amino-terminal pro-brain natriuretic peptide, angiotensin-converting enzyme inhibitor treatment and beta-blocker treatment (Hazard ratio and 95% confidence interval: 3p22, 2.9 [1.3–6.7] p=0.010; 10q26, 1.6 [1.2–2.3] p=0.004; AGT diplotype, 2.1 [1.4–3.0] p=0.001). In contrast, in the more recent validation cohort, in which a significantly higher proportion of patients received treatment with beta-blockers, statins and diuretics (p<0.001), we found no evidence for association with mortality for these variants. Lastly, we were unable to detect associations between any of the variants and expression of approximately 20,000 genes in the left ventricle of heart donors or heart failure patients (false discovery rate adjusted p<0.05). This lack of association was confirmed in publicly available data from 272 left ventricle samples from heart donors.
Conclusions: Our data suggest that genetic risk variants associated with heart failure onset or progression are unlikely to improve prediction of mortality beyond established prognostic markers in heart failure patients treated to recommended levels. These variants do not appear to alter levels of gene expression within the left ventricle of the heart, either before or after heart failure has become established, and may influence heart failure onset or progression via other mechanisms.
ESC 365 is supported by Bayer, Boehringer Ingelheim and Lilly Alliance, Bristol-Myers Squibb and Pfizer Alliance, Novartis Pharma AG and Vifor Pharma in the form of educational grants. The sponsors were not involved in the development of this platform and had no influence on its content.
Our mission: To reduce the burden of cardiovascular disease