Polygenic component associated with HCM risk, offering prediction tool
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Rare and common genetic variants contribute substantially to susceptibility to hypertrophic cardiomyopathy in the general population and can help improve risk prediction beyond clinical factors, researchers reported.
In an analysis of genetic data from two large biobanks, researchers found that high polygenic risk, defined as the top quintile of the polygenetic risk score distribution, accounted for more than 5% of the population-wide variance in hypertrophic cardiomyopathy (HCM), greater than the combined variance explained by rare variant carrier status and hypertension.
“HCM has long been recognized as a ‘genetic cardiomyopathy’ on the basis of numerous, high-impact, rare genetic variants that have been associated with the disease,” Krishna G. Aragam, MD, MS, a cardiologist at Massachusetts General Hospital and associated scientist with the Broad Institute of MIT and Harvard, told Healio. “However, more recently, several lower-impact, but more common genetic variants have been linked to HCM, suggesting that the disorder may very well have a ‘polygenic’ component. We demonstrated that rare and common genetic variants contribute substantially to population-level risk of HCM and add significantly to clinical risk factors for the prediction of incident HCM.”
Aragam and colleagues assessed relative and joint contributions of rare genetic variants and a common variant (polygenic) score to risk for HCM, using patient data from the UK Biobank (2006-2010; n = 184,511; mean age, 57 years; 45% men) and the Mass General Brigham Biobank (2010-2019; n = 30,716; mean age, 57 years; 45% men). Researchers evaluated rare and common variant predictors in the context of relevant clinical risk factors.
Within the two cohorts, 0.11% of the UK Biobank cohort and 0.95% of the Mass General Brigham Biobank cohort had HCM.
Researchers performed gene-based, rare variant testing for 51 genes typically included on HCM sequencing panels using three variant masks. Of those, they found pathogenic or likely pathogenic variants in 14 core genes associated with 55-fold higher odds for HCM (OR = 55.04; 95% CI, 35.09-82.92), whereas variants in the remaining 37 genes were not significantly associated with HCM (OR = 1.8; 95% CI, 0.6-4).
ClinVar pathogenic or likely pathogenic mutations in MYBPC3 (OR = 72; 95% CI, 39-124) and MYH7 (OR = 61; 95% CI, 26-121) were strongly associated with HCM, as were loss-of-function variants in ALPK3 (OR = 13; 95% CI, 4.4-28).
“Notably, a strong and statistically significant association with HCM was observed for loss-of-function variants in ALPK3, a gene not frequently cited in prior HCM case-control analyses,” the researchers wrote. “Coupled with recent studies linking ALPK3 truncating variants to both pediatric and adult-onset HCM, this observation may support reprioritization of ALPK3 for genetic screening of HCM.”
A polygenic score was strongly associated with HCM, with an OR of 1.6 per standard deviation increase in score (95% CI, 1.4-1.8). Similar analyses conducted with the Mass General Brigham Biobank were concordant.
The researchers noted genetic factors enhanced clinical risk prediction for HCM. The addition of rare variant carrier status and polygenic score to clinical risk factors, including obesity, hypertension, atrial fibrillation and CAD, improved area under the receiver operator characteristic curve from 0.71 (95% CI, 0.65-0.77) to 0.82 (95% CI, 0.77-0.87).
“Our findings suggest the potential value of quantifying a polygenic liability as part of routine, clinical genetic testing for HCM which, at present, only comprises assessments for rare variants,” Aragam told Healio. “Coupled with the advent of novel therapies, such as mavacamten (Camzyos, Bristol Myers Squibb), improved prediction of HCM through enhanced genetic screening may catalyze efforts towards HCM prevention.”
Aragam said analyses of larger populations are needed to confirm the observed trend of modification of rare variant penetrance by polygenic risk.
“In addition, studies in more diverse populations are required to better understand the potential differences in inherited susceptibility to HCM across different race and ancestral groups,” Aragam said.
For more information:
Krishna G. Aragam, MD, MS, can be reached at karagam@partners.org; Twitter: @KrishnaAragam.
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