Association of Pathogenic DNA Variants Predisposing to Cardiomyopathy With Cardiovascular Disease Outcomes and All-Cause Mortality

Abstract

IMPORTANCE Pathogenic variants associated with inherited cardiomyopathy are recognized as important and clinically actionable when identified, leading some clinicians to recommend population-wide genomic screening.OBJECTIVE To determine the prevalence and clinical importance of pathogenic variants associated with inherited cardiomyopathy within the context of contemporary clinical care. DESIGN, SETTING, AND PARTICIPANTS This was a genetic association study of participants in Atherosclerosis in Risk Communities (ARIC), recruited from 1987 to 1989, with median follow-up of 27 years, and the UK Biobank, recruited from 2006 to 2010, with median follow-up of 10 years. ARIC participants were recruited from 4 sites across the US. UK Biobank participants were recruited from 22 sites across the UK. Participants in the US were of African and European ancestry; those in the UK were of African, East Asian, South Asian, and European ancestry. Statistical analyses were performed between August 1, 2021, and February 9, 2022. EXPOSURES Rare genetic variants predisposing to inherited cardiomyopathy. MAIN OUTCOMES AND MEASURES Pathogenicity of observed DNA sequence variants in sequenced exomes of 13 genes (ACTC1,

Genetic Testing for Early-Onset Atrial Fibrillation—Is It Time to Personalize Care?

“…Additionally in the UK Biobank, ventricular tachycardia risk was elevated (HR, 3.7; 95% CI, 1.9-7.1). 10 Together, these data support the concept that AF can be an early presentation of P/LP cardiomyopathy gene variants with sequelae, including progression to HF and other major adverse cardiovascular events.…”

“…In a related study, Patel et al 10 evaluated outcomes associated with carrying rare cardiomyopathy gene P/LP variants in a community-based sample: the Atherosclerosis in Risk Communities (ARIC) cohort. 10 Although this study did not specifically evaluate EOAF, AF was seen more frequently in cardiomyopathy P/LP gene carriers. The authors examined 13 cardiomyopathy genes (ACTC1, FLNC, GLA, LMNA, MYBPC3, MYH7, MYL2, MYL3, PRKAG2, TNNI3, TNNT2, TPM1, and TTN) and found an increased risk for AF (HR, 2.9; 95% CI, 1.9-4.5), HF (HR, 1.7; 95% CI, 1.1-2.8), and all-cause mortality (HR, 1.5; 95% CI, 1.1-2.2) over a median follow-up of 24 years.…”

“…Indeed, the UK Biobank and the Vanderbilt AF registry in the Yoneda study 8,9 are mainly inclusive of participants who self-reported White race in contrast with the Patel study that now extends similar conclusions to participants of African ancestry from the ARIC cohort. 10 A prior genotype-first, electronic health records study using the Geisinger and University of Pennsylvania biobanks demonstrated that TTNtv were associated with diagnostic codes for AF, HF, ventricular arrhythmias, and sudden death. 11 Notably, this study was unable to associate TTNtv with dilated cardiomyopathy in individuals of African ancestry.…”

Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts

“…A recent study of inherited cardiomyopathy observed a similar finding of variable absolute risks in different settings but comparable relative risks. 38 Our study also suggests that relative risk may be a better reflection of the biological effect (pathogenicity) of the rare variants and represent a better parameter to classify high- and low-penetrance variants/gene compared to the absolute risk. However, this may not be true for all monogenic diseases.…”

Heart failure risk is accurately predicted by certain serum proteins

“…Other predictors include PKN1 and TIMP4 in the HFpEF predictor panel and TNNI3 in the HFrEF predictor panel. PKN1 deficiency has been linked to systolic and diastolic dysfunction with preserved ejection fraction in a global ischaemia and reperfusion mouse model 50 , whereas pathogenic DNA sequence variants in the TNNI3 are well-established causes of restricted cardiomyopathies 51,52 . The metalloproteinase inhibitor TIMP4 has been linked to heart tissue remodeling and heart failure in rodent models with higher levels of the protein associated with better outcomes 53 .…”