Abstract
Introduction: Only a subset of patients with hypertrophic cardiomyopathy (HCM) have positive genotype. Although genotype-positive patients with HCM are known to have worse prognosis than genotype-negative patients, the underlying mechanism is unclear. Hypothesis/Aims: To test the hypothesis that plasma proteomics profiling identifies signaling pathways that are dysregulated in genotype-positive patients with HCM compared with those with negative genotype. Methods: In this multi-center study, we conducted plasma proteomics profiling of 4986 proteins in patients with HCM who underwent genetic testing. The outcome measure was positive genotype, defined as having a mutation that is pathogenic or likely pathogenic for HCM. We identified plasma proteins with significant (univariable P<0.05) differences in concentration between patients with positive and negative genotype in HCM using the Mann-Whitney-Wilcoxon test. Using these proteins, we performed pathway analysis to determine dysregulated pathways with false discovery rate <0.05. Results: A total of 340 patients with HCM underwent genotyping and 103 patients (30%) had positive genotype for HCM. Among the 4986 proteins, 844 (17%) had significant differences between patients with positive and negative genotypes - a larger percentage than what is expected by chance. Pathway analysis exhibited that both pathways known to be associated with poor prognosis (e.g., TGF-β, metabolic, and inflammation) and novel pathways (e.g., Ras-MAPK and associated pathways such as Pl3K-Akt and JAK-STAT) were dysregulated in genotype-positive patients with HCM compared to those who were genotype-negative ( Figure ). Conclusions: This study serves as the first to apply comprehensive proteomics profiling to identify signaling pathways that are differentially regulated in patients with positive genotype in the HCM population, elucidating dysregulation of both known (e.g., TGF-β) and novel (e.g., Ras-MAPK) pathways.
Published Version
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