Genetic Role in Heart Failure Seen in Adoption Study

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Heart failure may be moderately heritable, according to a study of families involved with adoption.

In a Swedish cohort, the risk of heart failure was higher for adoptees whose biological parents had heart failure compared with peers with unaffected biological parents (adjusted OR 1.45, 95% CI 1.04 to 2.03), which persisted after excluding cardiomyopathies (adjusted OR 1.58, 95% CI 1.03 to 2.42).

On the other hand, risk of heart failure among adoptees wasn't any higher if their adoptive parents had heart failure -- cardiomyopathies included (adjusted OR 0.83, 95% CI 0.57 to 1.20) or excluded (adjusted OR 0.79, 95% CI 0.49 to 1.29), Magnus Lindgren, MD, of Skåne University Hospital in Sweden, and colleagues reported in JAMA Cardiology.

Heritability was estimated at 26% (or 34% excluding cardiomyopathies).

"[A] history of HF [heart failure] in a biological parent is an important risk factor for HF," the authors wrote. "To our knowledge, this is the first adoption study of HF and also the first study to estimate heritability for HF. We found a moderate heritability, which suggests that it could be meaningful to search for genetic variants that cause HF."

Lindgren and colleagues' results support data from the Framingham Offspring Study cohort and a Swedish sibling study in which the inheritance of heart failure was consistent with non-Mendelian inheritance, making it a complex trait.

"In this study, heritability was found to be lower with the inclusion of cardiomyopathies, which might be because especially dilated cardiomyopathy could be brought on by nongenetic causes, such as myocarditis and alcohol cardiomyopathy, but also to recessive or X-linked inheritance (although dominant inheritance is known to be most common in familial cases)," they commented.

The study included individuals born in Sweden who were adopted in 1942-1990 (n=21,643), 194 of whom had heart failure and were a median 55 years of age at first-time diagnosis. The investigators accessed data taken from Swedish registers and healthcare records.

In case-control analyses matching adoptees with heart failure to five unaffected controls, the method of tetrachoric correlation put heritability at 24% with cardiomyopathies and 29% without these.

"Monogenic syndromes of familial hypertrophic or dilated cardiomyopathy are well documented and arise from rare mutations in genes encoding proteins that regulate the contractile function of the heart, including sarcomere and cytoskeletal components. However, for more common forms of heart failure, the spectrum of underlying etiologies is considered complex, and genetic association studies in large heart failure populations have yielded comparatively limited insight," Christopher O'Donnell, MD, MPH, of Boston Veterans Affairs Healthcare System, and colleagues wrote in an accompanying editor's note.

The heritability estimates by the Swedish investigators suggested a "substantial contribution of heritability to heart failure" and seem to suggest "genetic variants impart risk more so than previously considered," they added.

"Future studies of genomewide associations in large databases, e.g., The Heart Failure Molecular Epidemiology for Therapeutic Targets [HERMES] Consortium and biobanks such as All of Us, may yield insights into the oligo or polygenic nature of heart failure, potentially adding to prior knowledge from monogenic causes. These coming studies provide hope that we can better define the complexity of heart failure and establish precision approaches for prevention beyond conventional risk factors," O'Donnell's group said.

The study investigators acknowledged that they relied on registry data and were missing several pieces of important information including BMI, smoking, and other clinical data. Notably, age at adoption was also missing, which meant the investigators didn't know how long adoptees shared environmental factors with their biological parents -- a potential confounder.