Genetic Variation Underlying the Risk of Hypertrophic Cardiomyopathy
- Using two large biobanks, genetic factors enhanced clinical risk prediction for HCM beyond what is achieved with conventional clinical factors.
- Prevalence of a pathogenic variant in 14 core genes was associated with a 55-fold increased risk for HCM. Rare variants in MYBPC3 and MYH7 were most prevalent in HCM cases.
- A polygenic risk score explained the greatest proportion of HCM susceptibility.
What is the contribution of rare and common genetic variants to risk of hypertrophic cardiomyopathy (HCM) in the general population?
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.
Recent guidelines endorse integrated risk assessments to improve diagnosis, prognostication, and management of HCM patients. As genetic testing becomes more widespread and with newer HCM therapies, early diagnosis by screening leading to treatment may provide a means of altering clinical course of this condition. In this study using two large biobanks, presence of a rare variant in 14 core genes was the strongest risk factor for developing HCM despite accounting for clinical factors. This establishes the importance of these variants in identifying high-risk individuals. In addition, this study validates a PRS in two large biobanks. High PRS explained the greatest proportion of HCM susceptibility. This study also highlights other clinical factors associated with incident HCM such as hypertension and obesity, but also atrial fibrillation and coronary artery disease, which have not been previously described. Noteworthy points include overall rare HCM prevalence, raising questions about cost-effectiveness of a population-based screening strategy. In addition, both cohorts were comprised of individuals of European ancestry.
Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Prevention, Atherosclerotic Disease (CAD/PAD), Genetic Arrhythmic Conditions, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Hypertension
Keywords: Atrial Fibrillation, Biological Specimen Banks, Cardiomyopathies, Cardiomyopathy, Hypertrophic, Coronary Artery Disease, Cost-Benefit Analysis, Genetic Testing, Genetic Variation, Genetics, Medical, Genome-Wide Association Study, Genomics, Heart Failure, Hypertension, Obesity, Risk Assessment, Risk Factors, Secondary Prevention
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