Integrated Proteogenomics and Single-Cell Transcriptomics Prioritize Putative Protective Plasma Proteins for...

Translating hidradenitis suppurativa (HS) genetic susceptibility into actionable targets remains challenging, as most genome-wide association study loci lie in non-coding regions and tissue-level transcriptomics cannot easily distinguish causal drivers from secondary inflammation. In this study, we aimed to prioritize plasma proteins whose genetically predicted levels are causally associated with HS risk and to localize them within human skin at single-cell resolution. We performed two-sample Mendelian randomization (MR) using cis-pQTL instruments for 2923 plasma proteins from the UK Biobank Pharma Proteomics Project against HS summary statistics from FinnGen R12. Following multiple-testing correction and Bayesian colocalization with a prior-sensitivity grid, the intersection of false-discovery rate (FDR)-significant MR with colocalization evidence (PP.H₄ ≥ 0.5) yielded three putative protective candidates: TNFRSF6B (OR = 0.748, 95% CI 0.666-0.840; PP.H₄ = 0.648), FCRL2 (OR = 0.896, 95% CI 0.819-0.979; PP.H₄ = 0.550), and APOD (OR = 0.789, 95% CI 0.647-0.963; PP.H₄ = 0.503). All sensitivity MR tests were concordant. Single-cell transcriptomic analysis localized FCRL2 and APOD to specific cell populations. FCRL2 was predominantly expressed in B cells and NK cells, while APOD showed multi-cellular expression across cornified keratinocytes, macrophages, and dendritic cells. Furthermore, TNFRSF6B was below the skin detection threshold, supporting its biological role as a circulating decoy receptor. Together, our integrated proteogenomic and single-cell approach prioritizes TNFRSF6B, FCRL2, and APOD as putative protective plasma proteins for HS, with TNFRSF6B emerging as the most genetically robust candidate for future translational follow-up.