Circulating Quiescin Sulfhydryl Oxidase and Risk of Cardiovascular Disease: A Mendelian Randomization and Post-GWAS Analysis.

BACKGROUND: To systematically evaluate the causal associations between circulating quiescin sulfhydryl oxidase (QSOX) family enzymes and cardiovascular diseases (CVDs) using Mendelian randomization (MR) and post-Genome-Wide Association Study (post-GWAS) analyses. METHODS: The authors integrated protein quantitative trait locus (pQTL) data for plasma QSOX from the INTERVAL and deCODE studies with CVD GWAS summary statistics from large‑scale biobank datasets and disease‑specific consortia. Discovery MR analyses were followed by meta-analysis and independent replication. Post-GWAS annotation using the FUMA platform was performed to delineate the pQTL architecture of circulating QSOX2 and to prioritize likely causal variants. Summary-data-based Mendelian randomization (SMR) was applied to confirm direct effects of QSOX2 on CVDs and to characterize its regulatory networks at individual cis and trans pQTLs. RESULTS: Initial pan-MR analyses suggested risk-increasing associations of circulating QSOX2 with several CVDs, but showed substantial SNP-level heterogeneity. Regional and functional annotation identified pleiotropic signals originating from distal and trans regions, and prioritized the missense variant rs12380852 as the leading causal candidate, predicted to impair QSOX2 structural stability and enzymatic activity. Notably, cis-MR and SMR analyses restricted to the QSOX2 locus revealed consistent protective effects against atrial fibrillation (AF) and heart failure (HF). Summary‑data-based Mendelian randomization on trans pQTL rs3184504 (a SH2B3 missense variant) linked SH2B3‑mediated inflammatory pathways to QSOX2 trans regulation. CONCLUSION: The authors' findings suggest a protective role of circulating QSOX2 in AF and HF. The prioritized causal variants and identified trans-regulatory pathways may serve as targets for future functional validation and druggable design. #Xinyu Che, Ao Chen, and Yan Xia contributed equally to this work.