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Hypertrophic Cardiomyopathy Studies Reveal Common Contributors, Risk Score

NEW YORK – Investigators from the UK and elsewhere have narrowed in on genetic contributors tohypertrophic cardiomyopathy (HCM) — a form of heart muscle thickening linked to sudden cardiac death in young people — and have begun developing a polygenic risk score for the condition.

Reporting in Nature Genetics on Monday, researchers from the UK, US, and Canada shared findings from a genome-wide association study and GWAS meta-analyses that together included 2,780 individuals with HCM and almost 47,500 unaffected controls from the Hypertrophic Cardiomyopathy Registry, UK Biobank, and BioResource for Rare Diseases studies, including cases with or without rare mutations in genes making up the sarcomere structures involved in heart muscle contraction.

Their search led to a dozen loci with genome-wide significant ties to the difficult-to-predict, "hidden" heart condition, along with common risk variants that coincided with either the sarcomere mutation-positive or -negative HCM cases. Both rare and common contributors can ramp up an individual's risk for the heart condition, they noted, though HCM appeared far less likely to be passed on to subsequent generations in cases linked to common, polygenic risk that lacked rare sarcomere gene mutations.

From there, the investigators came up with a genetic risk score that was subsequently validated using data for thousands more individuals with or without HCM from three other cohorts. The risk of HCM appeared to fall by half for individuals into the lowest risk category defined by the polygenic risk score, for example, while those in the highest risk group by had double the average risk for the disease.

"We now have a new genetic tool that we believe will better predict which members of affected families will have a bad form of the disease, identifying those who need early intervention," co-senior and corresponding author Hugh Watkins, a cardiovascular medicine and human genetics researcher affiliated with the University of Oxford and John Radcliffe Hospital, said in a statement.

Better HCM prediction will "take away the worry for many families as it enables us to identify those who are unlikely to pass faulty genes onto their children," Watkins predicted, and may eventually "reduce the need for unnecessary genetic testing and regular follow-ups."

A related Nature Genetics study by members of the same team used GWAS, GWAS meta-analysis, and multi-trait analyses to look at the genetic overlap between HCM and another heart condition, dilated cardiomyopathy, as well as the distinct contributors to these conditions.

Using genetic data for more than 1,700 HCM cases and more than 5,500 individuals with DCM, along with data for unaffected controls and for 19,260 UK Biobank participants with left ventricular (LV) heart measurements and no heart structure abnormalities, the investigators defined dozens of HCM-, DCM-, or LV-linked loci — a set that pointed to some overlap between LV and the heart conditions.

Notably, though, genetic contributors to LV volume traits appeared to coincide with an increased risk of DCM, while DCM risk declined in individuals who had variants related to the contractibility of the left ventricle. On the other hand, LV hyper-contractibility appeared to share closer ties to HCM, which was negatively associated with the LV volume traits considered, University of Amsterdam clinical and experimental cardiology researcher Connie Bezzina, co-senior author on both papers, explained in an email.

Such findings hint that treatments influencing heart contractibility, such as a cardiac myosin inhibitor known as mavacamten, may help in treating HCM, she added, noting that that drug appeared to benefit individuals with obstructive HCM in a recent Phase III clinical trial.

Also on the clinical front, Bezzina noted that the polygenic risk score comprised of common HCM-associated variants "may explain inter-individual differences in disease severity in HCM patients with a pathogenic variant in a sarcomeric gene.

"[S]uch a polygenic risk score may be used for individualized screening and management in sarcomeric HCM patients in the future," Bezzina said, though she noted that additional studies are needed to shore up and expand on the current findings.