Synergistic Effects of Weighted Genetic Risk Scores and Resistin and sST2 Levels on the Prognostication of Long-Term Outcomes in Patients with Coronary Artery Disease.

Resistin and soluble suppression of tumorigenicity 2 (sST2) are useful predictors in patients with coronary artery disease (CAD). Their serum levels are significantly attributed to variations in and loci. We investigated candidate variants in the for resistin levels and those in the locus for sST2 levels and evaluated the prognostication of these two biomarkers and the corresponding variants for long-term outcomes in the patients with CAD. We included 4652, 557, and 512 Chinese participants from the Taiwan Biobank (TWB), cardiovascular health examination (CH), and CAD cohorts, respectively. Candidate variants in and were investigated using whole-genome sequence (WGS) and genome-wide association study (GWAS) data in the TWB cohort. The weighted genetic risk scores (WGRS) of and with resistin and sST2 levels were calculated. Kaplan-Meier curves were used to analyze the prognostication of resistin and sST2 levels, WGRS of and , and their combinations. Three variants (rs3219175, rs370006313, and rs3745368) and two variants (rs10183388 and rs4142132) were independently associated with resistin and sST2 levels as per the WGS and GWAS data in the TWB cohort and were further validated in the CH and CAD cohorts. In combination, these variants explained 53.7% and 28.0% of the variation in resistin and sST2 levels, respectively. In the CAD cohort, higher resistin and sST2 levels predicted higher rates of all-cause mortality and major adverse cardiac events (MACEs) during long-term follow-up, but WGRS of and variants had no impact on these outcomes. A synergistic effect of certain combinations of biomarkers with and variants was found on the prognostication of long-term outcomes: Patients with high resistin levels/low WGRS and those with high sST2 levels/low WGRS had significantly higher all-cause mortality and MACEs rates, and those with both these combinations had the poorest outcomes. Both higher resistin and sST2 levels, but not and variants, predict poor long-term outcomes in patients with CAD. Furthermore, combining resistin and sST2 levels with the WGRS of and genotyping exerts a synergistic effect on the prognostication of CAD outcomes. Future studies including a large sample size of participants with different ethnic populations are needed to verify this finding.