Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23

Abstract

Aims Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. Methods and results We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 27% increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. Conclusion This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.

Targeted therapies in genetic dilated and hypertrophic cardiomyopathies: from molecular mechanisms to therapeutic targets. A position paper from the Heart Failure Association (HFA) and the Working Group on Myocardial Function of the European Society of Cardiology (ESC)

“…Identification of DCM phenogroups associated with significant differences in clinical presentation, underlying molecular profiles, and outcome, will help to pave the way for individual treatment. In particular, genetic modifiers may be discovered by large genome‐wide association studies (GWAS), and these have already generated several genetic loci associated with early onset DCM 66,67 . Still, studies to determine the additional genetics (epigenetic and transcriptional) in different cells (single cell/nuclear sequencing) along epidemiological data (acquired factors, family members) are required to come to individualized therapy for DCM patients.…”

“…In particular, genetic modifiers may be discovered by large genome-wide association studies (GWAS), and these have already generated several genetic loci associated with early onset DCM. 66,67 Still, studies to determine the additional genetics…”

Insights on Human Small Heat Shock Proteins and Their Alterations in Diseases

“…HSPB7 has been also indicated as a candidate gene involved in heart development and cardiac failure (Villard et al, 2011;Aung et al, 2019). GWAS and EWAS defined HSPB7 gene locus as a risk factor to develop DCM or heart failure (Cappola et al, 2010;Stark et al, 2010;Villard et al, 2011;Garnier et al, 2015;Wang et al, 2016;Esslinger et al, 2017;Garnier et al, 2021). HSPB7 has also been detected in plasma, with HSPB7 plasmatic concentrations apparently higher in subjects and mouse models of myocardial infarction from 3 up to 24 h after the onset of symptoms (Chiu et al, 2012).…”

Effect of taurine administration on symptoms, severity, or clinical outcome of dilated cardiomyopathy and heart failure in humans: a systematic review

“…Genome-wide association studies have been recently published identifying common variants associated with risk of DCM 5,6 , and significant associations have been identified in the locus of the sodium-and chloride-dependent taurine transporter gene (SLC6A6). SLC6A6 encodes a multi-pass membrane protein that transports the amino acid taurine and is found at highest expression in whole blood 7 .…”