Integrative plasma proteomic and Mendelian randomization analyses prioritize an SH2B3-centered immunogenetic signal in coronary heart disease

Background Coronary atherosclerosis is shaped by immune, vascular, and metabolic interactions, but genetic links between circulating protein networks and immune-regulatory mechanisms remain incompletely resolved. Methods In an exploratory MR screen using a suggestive instrument threshold, we screened 2,821 genetically proxied plasma protein ratios for association with coronary heart disease (CHD) and evaluated the leading signal using bidirectional Mendelian randomization, two-step mediation analysis, Bayesian colocalization, expression quantitative trait locus colocalization, regulatory annotation, and plasma-based phenotypic evaluation in a case-control cohort. Results A higher genetically predicted MED18/SH2B3 ratio was associated with CHD after Bonferroni correction (inverse-variance weighted odds ratio = 1.13, 95% confidence interval 1.07-1.18; P = 4.93 × 10 -6 ). The ratio rQTL and SH2B3 protein signal colocalized with CHD at the chromosome 12 SH2B3 locus (PP.H4 = 0.984 and 0.985, respectively). SH2B3 eQTLs also colocalized with CHD in Whole Blood (PP.H4 = 0.937) and EBV-transformed lymphocytes (PP.H4 = 0.932), supporting a blood and lymphocyte context. In 168 clinical participants, the highest ratio tertile remained associated with CHD after multivariable adjustment (odds ratio = 2.81, 95% confidence interval 1.16-7.09). Adding the continuous ratio to clinical covariates increased the AUC from 0.696 to 0.785 (paired DeLong P = 0.013), whereas either protein alone did not significantly improve discrimination. Post hoc subtype-versus-control analyses showed an association for CCS, whereas the AMI estimates were imprecise. Exploratory profiling further identified ratio-group differences in selected hematological indices and circulating inflammatory cytokines. Conclusion These convergent genetic, transcript-level, and clinical findings prioritize an SH2B3-centered immunogenetic signal in CHD. They do not establish a cell-specific immune mechanism and require external and functional validation.