Genetic Variation Underlying the Risk of Hypertrophic Cardio
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This was an analysis of the UK Biobank and the Mass General Brigham Biobank participants with genomic data available. HCM patients were identified using International Classification of Diseases (ICD)-10 codes and medical chart review. Rare nonmitochrondrial pathogenic variants were identified in 51 genes included in the testing panel for HCM. These were stratified as high impact (i.e., pathogenic or likely pathogenic in 14 core genes for HCM, as designated by the American College of Medical Genetics) or nonhigh impact. Next, a polygenic risk score (PRS) was constructed using data from a recent genome-wide association study of HCM. Odds for HCM were compared across strata of the PRS variant carrier status divided into low, intermediate, and high risk. These were further identified into rare variant carriers and noncarriers. Longitudinal risk trajectories were modeled across these six strata of lifetime and cumulative risk at age 80 years for HCM.

In the UK Biobank, mean age was 56 years, 45% were men, and 204 (0.11%) participants had HCM. In the Mass General Brigham Biobank, mean age was 57 years, 45% were men, and 292 (0.95%) had HCM. Presence of a high-impact rare variant was associated with 55-fold increased odds of HCM, but non–high-impact variants were not associated with HCM risk. Rare variants in MYBPC3 and MYH7 were most prevalent in HCM cases. Per standard deviation increase in PRS was associated with increased odds for HCM in both biobanks. Lifetime HCM risk in low, intermediate, and high PRS were 0.09%, 0.14%, and 0.43%. A high-impact rare variant was the strongest risk factor for developing HCM after accounting for other clinical factors followed by atrial fibrillation and a high PRS score. A high PRS score explained the greatest proportion of HCM susceptibility.

In this study of two large biobanks, genetic factors enhanced clinical risk prediction for HCM beyond what is achieved with conventional clinical factors. Important clinical risk factors included atrial fibrillation, coronary artery disease, obesity, and hypertension.