Smith, J Gustav

BACKGROUND: This study aimed to evaluate the prevalence of pathogenic/likely pathogenic cardiomyopathy variant carriers in a multiancestry US population and examine the risk of adverse clinical outcomes. METHODS: This retrospective cohort study included multiancestry US adults aged ≥18 years with sequencing data from the All of Us Research Program. Pathogenic/likely pathogenic variants in cardiomyopathy genes were identified using the ClinVar database. The primary outcome was heart failure. Secondary outcomes included cardiomyopathy and arrhythmia. Outcomes were identified from electronic health records. Interval-censored Cox models, taking age on the timescale, were used to assess the risk of outcomes in pathogenic/likely pathogenic variant carriers with noncarriers as the reference group. RESULTS: Among 167 435 individuals (median age, 55.2 [39.5–66.3] years; 61.7% female; 40.7% non-European ancestry) included, the prevalence of pathogenic/likely pathogenic cardiomyopathy variant carriers was 0.7% in the overall population and 0.8%, 0.8%, 0.5%, and 1.2% among European, African, East Asian, and South Asian ancestry individuals, respectively. Over their lifetime, there were 12 867 heart failure events (205 in carriers and 12 662 in noncarriers), with an incidence rate of 3.05 (95% CI, 2.66–3.49) per 1000 person-years in carriers and 1.37 (95% CI, 1.35–1.40) in noncarriers (adjusted hazard ratio, 2.30 [95% CI, 2.04–2.60]). Cardiomyopathy occurred in 5164 (161 in carriers and 5003 in noncarriers), with an incidence rate of 2.38 (95% CI, 2.04–2.78) per 1000 person-years among carriers and 0.54 (95% CI, 0.53–0.56) in noncarriers (adjusted hazard ratio, 4.31 [95% CI, 3.73–4.97]). There were 19 405 arrhythmia events (263 in carriers and 19 142 in noncarriers), with an incidence rate of 3.93 (95% CI, 3.48–4.44) per 1000 person-years among carriers and 2.09 (95% CI, 2.06–2.12) in noncarriers (adjusted hazard ratio, 2.12 [95% CI, 1.78–2.53]). CONCLUSIONS: Pathogenic/likely pathogenic cardiomyopathy variant carriers have an increased risk of heart failure, cardiomyopathy, and arrhythmias. Despite the modest overall prevalence, the associated risks suggest potential benefits of targeted genetic screening for early detection and management.

Background: Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a “virtual proteomic” approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals. Methods: We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmö Diet and Cancer Study; n=651). Results: In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-β predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08–1.58; P =0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66–0.94; P =0.008) per 1-SD increment in platelet-derived growth factor receptor-β. Conclusions: We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases.