Risk associated circulating biomarkers S100A3 identified in congenital heart disease-associated pulmonary arterial hypertension.

With improved survival rates among congenital heart disease (CHD) patients, pulmonary arterial hypertension (PAH) linked to CHD becomes more prevalent in both children and adults. PAH remains a significant contributor to morbidity and mortality in this population. Although genome-wide association studies (GWAS) have identified potential genetic variants with PAH risk and prognosis, the identification of circulating biomarkers with causal roles in CHD-PAH remains unclear. We employed the summary data-based Mendelian randomization (SMR) method, integrating expression profile data from the Gene Expression Omnibus (GEO) database related to CHD-PAH. This approach aimed to pinpoint genes causally associated with risk of CHD-PAH. We used a two-sample Mendelian randomization (MR) approach to efficiently screen for circulating proteins affecting CHD-PAH, leveraging publicly available genetic data from the UK biobank Pharma Proteomics Project (UKB-PPP) (54,219 UKB participants). Genetic determinants (cis-SNPs) of circulating proteins were used as instruments, and MR analyses assessed the influence of these proteins on CHD-PAH susceptibility in the largest PAH GWAS (2085 cases and 9659 controls). We conducted colocalization analyses to ensure shared genetic signals between circulating proteins and PAH and performed immune cell infiltration analysis to understand immune regulatory mechanisms in CHD-PAH. We found that a 1 SD increase in circulating S100 calcium binding protein A3 (S100A3) levels correlated with a reduced PAH risk (OR: 0.073, 95% CI: 0.020-0.267;