Genetics in hypertrophic cardiomyopathy: recent developments and clinical implications

Hypertrophic cardiomyopathy (HCM) is a common disorder, affecting approximately one out of 500 individuals, and presents substantial unmet medical need. It is a quite serious disease being the leading cause of sudden death, heart failure and embolic stroke in early and mid-adult life.

Among patients with HCM, ~30% to 60% have an identifiable pathogenic or likely pathogenic genetic variant and mutations in more than 20 genes are currently known to be associated with HCM. Nevertheless, a substantial proportion of patients with HCM are currently without any evidence of a genetic etiology to their disease, including a subgroup (up to 40% of patients) who also have no other affected family members (ie, “non-familial” HCM). These observations suggest that other novel pathophysiologic mechanisms may be responsible for or contribute to phenotypic expression in these affected patients with HCM.

In order to investigate the contribution of common genetic variants to HCM risk in patients with no identifiable myofilament mutation, Harper et al, performed two independent multi-ancestry, case–control, genome-wide association studies. In particular, 2,541 patients with HCM (64% sarcomere negative and 34% sarcomere positive) were recruited to the Hypertrophic Cardiomyopathy Registry, versus 40,000 controls as well as 239 HCM sarcomere-negative cases recruited from the BioResource for Rare Diseases versus 7,200 controls.
Analysis of all HCM cases (sarcomere-positive and sarcomere-negative) identified 13 independent genome-wide-significant susceptibility loci for HCM (p<5×10−8). Furthermore, single-nucleotide polymorphism (SNP) heritability indicated that 35% of risk of developing HCM was attributable to the additive effects of common SNPs (h2g= 0.35±0.01). The common variant contribution was even more pronounced in the HCM sarcomere negative group showing 67% risk (h2g=0.68±0.16).

In addition, 27 SNPs with independent association with HCM in the all-comer HCM meta-analysis, were aggregated into a scaled weighted genetic risk score (GRS). Individuals in the top quintile showed a 2-fold increase in odds of HCM as compared with the middle 60%. The impact of the GRS on left ventricular hypertrophy in groups of cases with similar mutational mechanisms was also evaluated. A 1 standard deviation (s.d.) increase in GRS conferred a 0.71±0.35 mm increase in maximum left ventricular wall thickness (p=0.048) in carriers of MYBPC3 truncating variants (n=232) and a 0.73±0.36 mm increase (p=0.037) in carriers of MYH7 missense variants (n=186).

Observational studies have shown that hypertension, obesity and type 2 diabetes are more prevalent in individuals with HCM. This could be secondary to reduced exercise (inability or contraindication to physical activity). However, after causality testing, diastolic blood pressure (DBP) appeared to be a substantial risk factor for the development of sarcomere-negative HCM. Actually, a 1 s.d. unit increase in DBP (11.3 mmHg) conferred a fourfold increased risk of HCM (OR=3.93 (95% CI=2.86–5.41, p=3.74×10−16). The strong association with diastolic hypertension raises the possibility that sarcomere-negative HCM may represent, at least in part, an exaggerated response to hypertension in genetically susceptible individuals and could have immediate implications in therapy in this group of patients.