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Novel Genetic Signals for Heart Failure Identified

Key findings

  • Refining the HF phenotype to a subset of individuals with nonischemic cardiomyopathy facilitated detection of genetic loci that appear to operate independently of traditional HF risk factors
  • Genome-wide association analyses of individuals with heart failure (HF) produced evidence for distinct genetic mechanisms of HF, including some that operate through known HF risk factors
  • Certain genetic variants associated with nonischemic cardiomyopathy were associated with left ventricular dysfunction in individuals without clinical disease

Heart failure (HF) is now known to be a heritable disorder, although a limited number of susceptibility loci have been identified, and the biological mechanisms are still not completely understood.

Massachusetts General Hospital cardiologists Steven Lubitz, MD, MPH, and Krishna Aragam, MD, MS, led a population-based genome-wide association analysis (GWAS) of individuals with HF that yielded multiple genetic mechanisms for established risk factors. Moreover, phenotypic refinement of the analysis allowed the team to discover novel genetic signals that correlate with distinct subtypes of HF.

In Circulation, a team led by Dr. Lubitz and Dr. Aragam explains that they used the UK Biobank to find 6,504 individuals who met criteria for all-cause HF, were of European ancestry and had high-quality genetic data available.

In the study, the researchers compared the HF patients with 387,652 controls. They detected one locus that was statistically significant: rs1906609 (upstream of PITX2). In addition, four loci had suggestive association signals: rs7857118 (near CDKN2B-AS1), rs12627426 (near MAP3K7CL), rs73839819 (near RYBP) and rs2234962 (in BAG3).

The researchers note that most of these signals are known susceptibility loci for HF risk factors, such as atrial fibrillation (PITX2) and coronary artery disease (CDKN2B-AS1 and MAP3K-7CL).

Refining the Phenotype to NICM

The research team repeated the GWAS in a subgroup of 2,038 individuals who met criteria for nonischemic cardiomyopathy (NICM), which was defined as left ventricular dysfunction without coronary artery disease.

One locus reached genome-wide significance: rs2234962 (BAG3). Two others showed a trend toward significance: rs12138073 (near CLCNKA and ZBTB17) and rs2634071 in high linkage disequilibrium with rs1906609 (PITX2).

Replication of signals

To replicate the GWAS results, the researchers analyzed data on 1,060 participants in the GRADE study, a recruited cohort of patients with cardiomyopathy, and 9,432 participants in Vanderbilt University's Biobank (BioVU), a prospective, hospital-based cohort.

  • All-cause HF: Of the five lead variants, two were replicated in the GRADE cohort: those at BAG3 and MAP3K7CL. No variants were replicated in BioVU.
  • NICM: Of the three lead variants, the signal at BAG3 replicated strongly and consistently, and the variant at CLCNKA–ZBTB17 also replicated, albeit more modestly.

Genetic Variants and HF risk factors

The researchers then repeated genetic association analyses for all lead variants, adjusting for known risk factors. Associations at some top loci were attenuated when adjusting for coronary artery disease (rs7857118 (CDKN2B-AS1)), as well as atrial fibrillation (rs1906609 (PITX2)) indicating the importance of genetic predisposition to these conditions for the risk of developing heart failure. There were more modest, but still significant associations between other variants and hypertension.

Genetic Variants and Cardiac Structure/Function

Finally, the researchers examined cardiac imaging data in individuals free of HF. Specifically, they analyzed cardiac magnetic resonance imaging data from participants in the UK Biobank and echocardiographic data on 30,201 participants in an earlier genome-wide association study.

The variant at BAG3 and the variant at CLCNKA–ZBTB17 were both associated with traits of left ventricular structure and function in the general population, the researchers report. These findings suggest a subclinical process, they say, that may warn of a genetic predisposition to clinical HF.

Clinical Implications

The researchers draw several conclusions from their findings:

  • All-cause HF is a complex condition with several etiologic subtypes, driven in part by a genetic predisposition to prominent HF risk factors
  • Genetic drivers of nonischemic dilated cardiomyopathy, best identified by the NICM phenotype, may mediate a subclinical cardiomyopathic process that predisposes to clinical HF
  • Common genetic variants associated with both clinical and subclinical heart failure may be leveraged to improve HF risk prediction and prevention

Specifically for research, the authors say, is that phenotypic refinement of all-cause HF to a specific NICM subset may facilitate genetic discovery and should be considered for future studies seeking to uncover the genetic basis for heart failure.

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