Rare Genetic Variants Associated With Myocardial Fibrosis: Multi-Ethnic Study of Atherosclerosis

Abstract

BackgroundRare pathogenic variants in cardiomyopathy (CM) genes can predispose to cardiac remodeling or fibrosis. We studied the carrier status for such variants in adults without clinical cardiovascular disease (CVD) in whom cardiac MRI (CMR)-derived measures of myocardial fibrosis were obtained in the Multi-Ethnic Study of Atherosclerosis (MESA).ObjectivesTo identify CM-associated pathogenic variants and assess their relative prevalence in participants with extensive myocardial fibrosis by CMR.MethodsMESA whole-genome sequencing data was evaluated to capture variants in CM-associated genes (n = 82). Coding variants with a frequency of <0.1% in gnomAD and 1,000 Genomes Project databases and damaging/deleterious effects based on in-silico scoring tools were assessed by ClinVar database and ACMG curation guidelines for evidence of pathogenicity. Cases were participants with high myocardial fibrosis defined as highest quartile of extracellular volume (ECV) or native T1 time in T1-mapping CMR and controls were the remainder of participants.ResultsA total of 1,135 MESA participants had available genetic data and phenotypic measures and were free of clinical CVD at the time of CMR. We identified 6,349 rare variants in CM-associated genes in the overall MESA population, of which six pathogenic/likely pathogenic (P/LP) variants were present in the phenotyped subpopulation. The genes harboring P/LP variants in the case group were MYH7, CRYAB, and SCN5A. The prevalence of P/LP rare variants in cases was higher than controls (5 in 420 [1.1%] vs. 1 in 715 [0.1%], p = 0.03). We identified two MYBPC3 Variants of Unknown Significance (VUS)s with borderline pathogenicity in the case group. The left ventricle (LV) volume, mass, ejection fraction (EF), and longitudinal and circumferential strain in participants with the variants were not different compared to the overall cohort.ConclusionsWe observed a higher prevalence of rare potentially pathogenic CM associated genetic variants in participants with significant myocardial fibrosis quantified in CMR as compared to controls without significant fibrosis. No cardiac structural or functional differences were found between participants with or without P/LP variants.

Myocardial Fibrosis and Cardiomyopathy Risk: A Genetic Link in the MESA

“…7,8 MF can be a subclinical finding in HCM or sometimes it is the only pathophysiological manifestation as reflected by increased serum C-terminal propeptide of type I procollagen levels in HCM mutation carriers who do not yet have imaging evidence of hypertrophy. 7,8 We have also previously demonstrated that carrier status of rare pathogenic variants in 26 Although the prognostic role of MF has been well established in DCM, 27 its role in the risk for DCM has not been defined. The alternate alleles of the rs2186370 intronic variant identified in our study, A and G, are risk alleles for HCM and DCM, respectively.…”

“…7,8 We have also previously demonstrated that carrier status of rare pathogenic variants in cardiomyopathy-related genes in the MESA cohort who have not yet developed cardiomyopathies is more prevalent in individuals with CMR-detectable MF as compared with individuals with lower MF. 26 Although the prognostic role of MF has been well established in DCM, 27 its role in the risk for DCM has not been defined.…”

Rare Genetic Variants Associated with Sudden Cardiac Arrest in the Young: A Prospective, Population-Based Study

“…Although variants in cardiomyopathy-related genes are usually present in SCD cases due to inherited cardiomyopathies, such variants have also been associated with nonspecific subtle structural alterations ( e.g . myocardial fibrosis) 36, 44, 45 , and structurally normal hearts 46 . It has been hypothesized that variants in cardiomyopathy-related genes may contribute to SCA even without overt clinical signs of inherited cardiomyopathy, thus representing “concealed cardiomyopathy”.…”

Association of cardiac troponin T and growth differentiation factor 15 with replacement and interstitial cardiac fibrosis in community dwelling adults: The multi-ethnic study of atherosclerosis

“…ECV may also be sensitive to myocardial edema and inflammation, but such effects should be minimal because of the chronicity of alterations and the fact that it is a population of community dwellers, not patients. Additionally, our definition of interstitial fibrosis was somewhat arbitrary as the highest quartile since ECV is a continuous variable but is consistent with prior definitions used in MESA (30). Changing this definition could change the odds ratios but shouldn't qualitatively impact the differences between hs-cTnT and GDF-15 with ECV.…”