The genomics of heart failure: design and rationale of the HERMES consortium

Abstract

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure.

Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10^-8 under an additive genetic model.

Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Keywords: Association studies; Biomarkers; Cardiomyopathy; Genetics; Heart failure.

Figure 1

Genetic architecture of heart failure (HF) onset and progression. Examples of genes in which common (allele frequency 5% and greater), low‐frequency (1–5%), or rare variants (<1%) have been shown to influence risk for HF onset or progression. Effect sizes are expressed in odds ratios for HF risk and hazard ratios for HF progression. Common variants can be identified in genome‐wide association studies as exemplified by BAG3, CLCNKA, and TSLP loci, whereas variations with low population allele frequencies such as familial variants in the MYH7, LMNA, and LAMP2 genes associated with cardiomyopathy will typically require sequencing‐based approaches (based on a recent review article). Familial variants in LMNA and LAMP2 have been associated poor prognosis and particular cardiac phenotypes, manifesting with cardiolaminopathy and Danon disease, respectively. *Although individually rare, protein‐truncating variants in the large gene encoding Titin (TTN) collectively have a reported prevalence of 1% in the population, confer increased risk of HF, and have evidence of interaction with environmental factors such as alcohol, chemotherapy, and pregnancy. **A 25‐basepair deletion of the gene encoding cardiac myosin‐binding protein C (MYBPC3) conferring risk for HF has been reported to have an allele frequency of 4% in Southern Asian populations, highlighting how low‐frequency variants of large effect may be population specific.

Figure 2

Component phenotypes of heart failure (HF). Schematic representation of HF phenotypes across the life course that will be studied in HERMES. HF diagnosis is typically preceded by cardiometabolic risk factors and genetic susceptibility factors for endophenotypes of structural and functional cardiac dysfunction. Circles on the left represent common structural endophenotypes, from top to bottom: normal ventricle, ventricle with symmetric hypertrophy, ventricle with asymmetric (septal) hypertrophy, and dilated ventricle. The natural history of HF extends from the initial time point of diagnosis (Dx) through a gradual decline with increasing episodes of worsening typically necessitating in‐hospital care (decompensations) towards terminal pump failure. Sudden death from arrhythmia may occur at any point. Heritable contributions have been described for both risk factors, endophenotypes, HF onset, and HF progression.

Figure 3

International participation in HERMES and distributed analysis workflow. The HERMES consortium includes investigators from 12 countries from North America and Europe. Activities are overseen by a scientific committee with representatives from each contributing cohort and an executive committee. Common analysis plans are developed by the analysis group and deployed by participating studies. Meta‐analysis is conducted by the analysis group and results shared with project working groups. Upon publication, the full genome‐wide association summary estimates from meta‐analysis are made available publicly through the Cardiovascular Disease Knowledge Portal (http://www.broadcvdi.org/).

Figure 4

Power estimates across the allele frequency spectrum for genome‐wide association studies of heart failure risk and prognosis in HERMES. Figure illustrating empirical power for detecting different genetic variant effect sizes by varying minor allele frequencies (MAF), for (A) heart failure risk (odds ratio) and (B) heart failure prognosis (hazard ratio). Based on current HERMES sample size, with 949 888 controls compared with 44 016 cases for risk and 68 157 cases for prognosis.