{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:58:24Z","timestamp":1785412704438,"version":"3.56.0"},"reference-count":32,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Beijing You\u2019an Hospital, Capital Medical University","award":["BJYAYY-YN2026-13"],"award-info":[{"award-number":["BJYAYY-YN2026-13"]}]},{"award":["BJYAYY-YN2026-13"],"award-info":[{"award-number":["BJYAYY-YN2026-13"]}],"id":[{"id":"https:\/\/ror.org\/013xs5b60","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Infection susceptibility and systemic infection severity arise from distinct tissue barriers and host-response compartments, but plasma-protein genetic studies often treat infection as a broad phenotype. We aimed to define a site-resolved host plasma-protein architecture of infection susceptibility across urinary, lower-respiratory, systemic, and skin\/soft-tissue infection outcomes. Methods: We performed proteome-wide two-sample cis-protein quantitative trait locus (cis-pQTL) Mendelian randomization (MR) using UK Biobank Pharma Proteomics Project (UKB-PPP) instruments and registry-derived FinnGen R13 infection endpoints. Prioritized protein\u2013outcome pairs underwent regional colocalization, prior-sensitivity analysis, Steiger-like directionality sensitivity, Finnish and broader European reference-panel linkage disequilibrium (LD) assessment, candidate-level deCODE pQTL-source follow-up where feasible, and druggability and safety-domain annotation. Results: Across 18,766 harmonized tests, evidence was strongly site-resolved. PSCA emerged as the principal novel cystitis-specific candidate (OR 0.977, 95% CI 0.967\u20130.987), with strong colocalization and high Finnish reference-panel linkage disequilibrium between the MR instrument and the top colocalization single-nucleotide polymorphism (SNP) (r2 = 0.980). UMOD anchored urinary host-defense coherence. APOE showed strong evidence for the registry-derived implicit sepsis endpoint but was interpreted as a pleiotropy-prone broad host-response or severity-associated locus. TNFSF8 retained a robust pneumonia MR signal, but colocalization was moderate (PP.H4 = 0.544) and became weak under stringent priors (PP.H4 = 0.107), despite high-LD deCODE proxy-instrument follow-up. Skin\/soft-tissue infection lacked a convergent lead. Conclusions: This study supports a site-resolved architecture of genetically anchored plasma-protein candidates for infection susceptibility. PSCA and UMOD define complementary urinary signals, whereas APOE and TNFSF8 require cautious interpretation as broad host-response and lower-respiratory follow-up hypotheses rather than established therapeutic targets.<\/jats:p>","DOI":"10.3390\/genes17080887","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:45:14Z","timestamp":1785325514000},"page":"887","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Site-Resolved Plasma-Protein Architecture of Infection Susceptibility: A Cis-pQTL Mendelian Randomization and Colocalization Study"],"prefix":"10.3390","volume":"17","author":[{"given":"Shan","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Beijing You\u2019an Hospital, Capital Medical University, Beijing 100071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongzeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Beijing You\u2019an Hospital, Capital Medical University, Beijing 100071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00281-017-0639-8","article-title":"Cytokine storm and sepsis disease pathogenesis","volume":"39","author":"Chousterman","year":"2017","journal-title":"Semin. 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