Circulating YKL-40 levels but not CHI3L1 or TRIB1 gene variants predict long-term outcomes in patients with angiographically confirmed multivessel coronary artery disease

YKL-40 is significantly associated with the prevalence and severity of coronary artery disease (CAD). YKL-40 levels are significantly associated with variations in the CHI3L1 and TRIB1 genes. We investigated candidate genes for YKL-40 levels and evaluated the prognostic value of this biomarker and corresponding variants for long-term outcomes in patients with CAD. We included 4664 and 521 participants from the Taiwan Biobank (TWB) and CAD cohorts, respectively. Candidate variants for circulating YKL-40 levels were investigated using genome-wide association study (GWAS) data from the TWB cohort, and the results were validated in the CAD cohort. The primary endpoint was all-cause mortality. The secondary endpoint was major adverse cardiac events (MACEs), which included the composite endpoints of all-cause mortality, nonfatal acute coronary syndrome, hospitalization for heart failure, and nonfatal stroke. According to the GWAS data from the TWB cohort, three CHI3L1 variants (rs4950928, rs10399931, and rs872129) and one TRIB1 variant (rs6982502) were independently associated with YKL-40 levels. These findings were validated in the CAD cohort. The combined CHI3L1 and TRIB1 weighted genetic risk scores (WGRSs) were not associated with the long-term outcomes (median follow-up period of 3.7 years) in patients with CAD. Conversely, patients with YKL-40 levels in the upper tertile had the highest rates of all-cause mortality and MACEs (log-rank p = 9.58 × 10^-8 for all-cause mortality and 1.34 × 10^-7 for MACEs). Furthermore, YKL-40 levels predicted poor clinical outcomes only in patients with multivessel CAD (log-rank p = 3.0 × 10^-6 for all-cause mortality and 1.10 × 10^-5 for MACEs) and not in patients with single-vessel CAD. This study revealed that YKL-40 levels but not the combined CHI3L1 and TRIB1 WGRSs were found to be independent predictors of poor clinical outcomes in patients with multivessel CAD.