Clinical impact of cardiomyopathy-associated rare variants and cardiovascular comorbidities in multi-ancestry populations

Background Recent studies highlight the adverse clinical impact of rare cardiomyopathy (CMP) gene variants at a population level, supporting the increased utilization of genetic screening in clinical care. However, most discovery and clinical association studies of pathogenic CMP gene variants have focused on individuals of European (EUR) genetic ancestry and do not consider the impact modifiable cardiovascular comorbidities on penetrance. Purpose To assess the clinical impact of established rare CMP gene variants and cardiovascular comorbidities in diverse multi-ancestry cohorts using large-scale genomic and phenotypic data from the UKB Biobank (UKB), All of Us Research Program (AllofUs), and Million Veteran Program (MVP). Methods Genetic sequencing data was used to identify carriers of disease-causing CMP gene variants in each dataset. This analysis focused on ClinVar pathogenic or likely pathogenic variants in genes with strong evidence for dilated, hypertrophic or arrhythmogenic right-ventricular cardiomyopathy, and truncating variants with an established gene-disease mechanism. Multi-variable time-to-event analyses were used to compare the clinical impact of CMP gene variants and cardiovascular comorbidities – type 2 diabetes mellitus, hypertension, chronic kidney disease, and obesity - among European (EUR) and non-European (NEUR) ancestry participants. Results A total of 392,224 UKB participants (mean age 57 years; 94% EUR) 283,612 AllofUs participants (mean age 55 years; 53% EUR), and 101,571 MVP participants (mean age 66 years; 70% European) were included. Pooled fixed-effect meta-analysis showed that CMP gene variant carriers (CMPgeno+) in all datasets had a significantly higher risk of a composite cardiovascular outcome – including heart failure, non-ischemic cardiomyopathy, atrial fibrillation, and ventricular tachycardia – compared to non-carriers: EUR (HR: 1.72 [1.63 – 1.81], p = 0.0003) and NEUR (HR: 1.88 [1.71 – 2.08], p = 0.0009) (Figure 1). CMPgeno+ participants with ≥ 2 cardiovascular comorbidities had between a ~1.5-3.4-fold higher risk of a cardiovascular composite outcome compared to those with none across UKB, AllofUs, and MVP – for example in AllofUs: EUR (HR 2.88 [ 2.37 – 3.52], p <2E-16 vs. HR 4.61 [4.01 – 5.31], p <2E-16) and NEUR (HR 3.39 [2.25 – 5.09], p <2E-16 vs. HR 11.44 [9.51 – 13.76], p < 2E-16) (Figure 2A-F). In multi-variable analysis, hypertension was most consistently associated with increased risk of a cardiovascular composite outcome. Conclusion In large multi-ancestry population-based cohorts, both EUR and NEUR ancestry CMP gene variant carriers demonstrated an elevated risk of adverse cardiovascular outcomes. The presence of common cardiovascular comorbidities – in particular hypertension – was consistently shown to moderate this risk. These findings support the clinical utility of genetic testing and highlight the importance of addressing comorbidities to prevent adverse events.