Integrative plasma proteomic and Mendelian randomization analyses prioritize an SH2B3-centered immunogenetic signal in coronary heart disease
Abstract
BackgroundCoronary atherosclerosis is shaped by immune, vascular, and metabolic interactions, but genetic links between circulating protein networks and immune-regulatory mechanisms remain incompletely resolved.MethodsIn 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.ResultsA 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.ConclusionThese 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.
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BibTeX
@article{lin2026integrative,
title = {{Integrative plasma proteomic and Mendelian randomization analyses prioritize an SH2B3-centered immunogenetic signal in coronary heart disease}},
author = {Xin Lin and Yajuan Ren and Qin Luo and Rui Bai and Yang Feng and Yao Zhao and Jiani Xiong and Yunfei Bian},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1949795},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1949795},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Integrative plasma proteomic and Mendelian randomization analyses prioritize an SH2B3-centered immunogenetic signal in coronary heart disease
AU - Xin Lin
AU - Yajuan Ren
AU - Qin Luo
AU - Rui Bai
AU - Yang Feng
AU - Yao Zhao
AU - Jiani Xiong
AU - Yunfei Bian
PY - 2026
DA - 2026/11/09
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1949795
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1949795
AB - BackgroundCoronary atherosclerosis is shaped by immune, vascular, and metabolic interactions, but genetic links between circulating protein networks and immune-regulatory mechanisms remain incompletely resolved.MethodsIn 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.ResultsA 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.ConclusionThese 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.
SN - 1664-3224
ER -