Common Genetic Variants, Modifiable Risks Implicated In Hypertrophic Cardiomyopathy

Patients with hypertrophic cardiomyopathy (HCM) who don't carry a rare genetic mutation seem to be affected by common genetic variants, and diastolic blood pressure (BP) is likely a key modifiable risk factor, a genome-wide association study revealed.

"We always assumed that common variants would influence the risk of developing cardiomyopathy somewhat, but the effects we found were far greater than we had imagined. And that's why we think there are immediate clinical implications," Dr. Hugh Watkins of the University of Oxford, UK, told Reuters Health by email.

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"We now know that patients with HCM who do not have one of the rare inherited mutations, instead have developed it because they carry many of the common variants," he said. "This means that the risk of HCM developing in their children is much lower, especially at young ages, and instead we see that high blood pressure is an important component. So now we can both reassure and improve preventive treatment."

The study, reported in Nature Genetics, included 2,780 cases (64% sarcomere-negative) and 47,486 controls. The team identified 12 genome-wide significant susceptibility loci for HCM.

Single-nucleotide polymorphism heritability indicated a strong polygenic influence, especially for sarcomere-negative HCM. Specifically, the number of common variants, combined with the rare mutations, determined whether a person was protected or more susceptible to the disease.

Further analysis pinpointed diastolic BP as a modifiable risk factor for sarcomere-negative HCM; a one standard deviation increase boosted the HCM risk fourfold.

The authors state, "The strong association with hypertension raises the possibility that sarcomere-negative HCM may represent, in part, an exaggerated response to hypertension in genetically susceptible individuals. The association specifically with DBP probably reflects that this is the dominant form of hypertension in young and mid-adult life."

Dr. Steve Ommen of the Mayo Clinic in Rochester, Minnesota, who chaired the writing committee for the 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients with Hypertrophic Cardiomyopathy, commented in an email to Reuters Health, "The authors have shown a strong association between diastolic BP and development of phenotypic HCM. While this appears biologically plausible, these data don't prove causality."

"It is possible that the causality goes in the opposite direction - i.e., phenotypic HCM results in higher diastolic BP, or that some other, untested variable results in both higher diastolic BP and HCM," he said.

Also, he noted, it's not clear that lowering diastolic BP would reduce a patient's risk for subsequent HCM, and a longitudinal study is needed "to determine whether there is a clear call to action for clinical cardiologists," he said. "While treating hypertension is important in all individuals, these data suggest that it may be even more important in the context of sarcomere variant negative HCM."

—Marilynn Larkin

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