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We conducted an exploratory Mendelian randomization (MR) analysis to assess whether circulating plasma proteins show evidence consistent with potential causal effects on gout risk, integrating GWAS with pQTL data to prioritize proteins and pathways for follow-up.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>We applied an integrated genetics framework combining proteome-wide MR, reverse MR, Bayesian colocalization, and sensitivity analyses. Plasma pQTL datasets were obtained from Zheng et al. and deCODE Genetics; gout GWAS were from UK Biobank and the FinnGen R12 study. Primary inference used inverse-variance weighting (IVW) with MR-Egger and complementary sensitivity tests. Colocalization used Bayesian methods; reverse MR evaluated potential reverse causation. Where available, findings were checked in external datasets. Analyses followed STROBE-MR guidance and were implemented in R with standard MR\/colocalization packages.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>Five circulating proteins (FN1, PLAU, CPQ, SPOCK2, and FAM213A) met the predefined discovery threshold. Reverse Mendelian randomization provided no evidence supporting reverse causality from gout to protein levels, while Steiger directionality tests supported the protein-to-gout causal orientation. Bayesian colocalization indicated moderate to strong evidence of shared genetic signals for PLAU, FAM213A, and FN1, whereas the evidence for CPQ and SPOCK2 was comparatively weak. In the independent replication analysis, genetically predicted higher levels of PLAU and CPQ were directionally associated with an increased risk of gout, while higher FN1 levels showed a consistent protective association. Nevertheless, effect estimates and precision varied across datasets, and the overall findings should be interpreted as exploratory rather than confirmatory.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>This exploratory, assumption-dependent MR work nominates five circulating proteins as hypothesis-generating candidates for gout risk and potential therapeutic targeting. Given method assumptions and cross-dataset heterogeneity, functional validation and independent replication are required to clarify mechanisms, confirm targetability, and assess translational relevance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/03946320261428859","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T11:51:27Z","timestamp":1774525887000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Mendelian randomization implicates circulating plasma proteins in gout risk and identifies candidate therapeutic targets"],"prefix":"10.1177","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5689-9977","authenticated-orcid":false,"given":"Han","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixian","family":"Dang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pixue","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Qingdao Eighth People\u2019s Hospital, Qingdao, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"GuanHong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shanxian Central Hospital, Heze, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingze","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China"},{"name":"Department of Orthopedics, The Third Hospital of Hebei Medical University, Shijiazhuang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianrui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengbo","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Qingdao Municipal Hospital, Qingdao, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7537-9727","authenticated-orcid":false,"given":"Yongtao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Weifang People\u2019s Hospital, Weifang, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00569-9"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2017.155"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2015.91"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204463"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/762820"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/eci.13937"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keab539"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-023-01506-2"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpcardiol.2022.101437"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.2196\/45943"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-022-00844-x"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.3390\/foods13081269"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2016-014928"},{"issue":"12","key":"e_1_3_3_15_2","article-title":"Non-steroidal anti-inflammatory drugs for acute gout","volume":"12","author":"van Durme CM","year":"2021","unstructured":"van Durme CM, Wechalekar MD, Landewe RB, et al. 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