Serum endostatin as a genetically-influenced biomarker in PAH

Endostatin (ES) is an angiostatic peptide encoded by Col18a1. Our group has shown that a single nucleotide polymorphism (SNP) resulting in a missense mutation in Col18a1 is associated with altered disease severity and survival in PAH. We hypothesized that associations would exist between circulating serum ES levels and 1) clinical metrics of PAH severity, including survival and 2) SNPs in Col18a1. Serum samples and clinical data were obtained from 2,017 adult subjects in the PAH Biobank. Serum ES was measured with an electrochemiluminescent immunosorbent assay. Statistical associations between ES and clinical variables were examined with regression models. Genotyping was performed for protein quantitative trait loci (pQTL) analysis. Each log-unit increase in ES was associated with higher right atrial pressure (1.8 mmHg, 95% CI 1.3-2.3), higher mean pulmonary arterial pressure (2.0 mmHg, 95% CI 0.7 to 3.2), higher pulmonary vascular resistance (1.0 Wood unit, 95% CI 0.4 to 1.5), and lower 6 minute walk distance (-53.5m, 95 % CI -70.7 to -36.2). Mortality doubled for each log-unit increase in ES (2.3, 95% CI 1.6 to 3.4). In pQTL analysis, 4 SNPs in Col18a1 were associated with differences in circulating ES levels (Figure). Increased ES levels are associated with disease severity and survival in PAH, and several SNPs in Col18a1 are associated with differences in circulating ES levels. ES is a genetically-influenced determinant of disease severity in PAH.