{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T09:17:24Z","timestamp":1783070244271,"version":"3.54.6"},"reference-count":44,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":183,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170910"],"award-info":[{"award-number":["82170910"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Diabetes Research"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Lactylation is a posttranslational modification involved in cellular metabolic and immune processes. Although dysregulated lactate metabolism has been implicated in type 1 diabetes (T1D), the genetic relevance of lactylation\u2010related molecular traits remains poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Summary\u2010data\u2013based Mendelian randomization (SMR) was applied to integrate blood\u2010derived methylation\/expression\/protein quantitative trait loci (mQTLs\/eQTLs\/pQTLs) for 353 lactylation\u2010related genes with a T1D genome\u2010wide association study (7467 cases and 10,218 controls). The HEIDI test evaluated heterogeneity. Shared genetic signals were assessed by Bayesian colocalization. Associations identified in the discovery analysis were replicated in the FinnGen_R12_T1D and FinnGen_R9_E4_DM1NEU cohorts. mQTL\u2010eQTL SMR analysis evaluated methylation\u2013expression regulatory relationships. Steiger directionality testing and GTEx tissue eQTL analyses were performed for prioritized genes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SMR prioritized\n                      <jats:italic>PDAP1<\/jats:italic>\n                      ,\n                      <jats:italic>PNKD<\/jats:italic>\n                      , and\n                      <jats:italic>HMGB1<\/jats:italic>\n                      as candidate genes associated with T1D. At the DNA methylation level, methylation at cg05715492 (\n                      <jats:italic>PDAP1<\/jats:italic>\n                      ) was positively associated with T1D risk (OR = 1.29, 95% CI: 1.09\u20131.53), whereas cg05991184 (\n                      <jats:italic>PNKD<\/jats:italic>\n                      ) showed an inverse association (OR = 0.73, 95% CI: 0.59\u20130.90). cg22712983, cg26786924, and cg04880052 in\n                      <jats:italic>PNKD<\/jats:italic>\n                      exhibited positive associations. cg25251738 (\n                      <jats:italic>HMGB1<\/jats:italic>\n                      ) methylation was inversely associated with risk (OR = 0.85, 95% CI: 0.75\u20130.97). At the expression level, genetically predicted\n                      <jats:italic>PDAP1<\/jats:italic>\n                      (OR = 0.26, 95% CI: 0.10\u20130.66) and\n                      <jats:italic>HMGB1<\/jats:italic>\n                      (OR = 0.45, 95% CI: 0.22\u20130.91) expressions were inversely associated with T1D risk, whereas\n                      <jats:italic>PNKD<\/jats:italic>\n                      expression was positively associated (OR = 1.13, 95% CI: 1.04\u20131.23). mQTL\u2010eQTL SMR analyses demonstrated significant methylation\u2013expression associations at\n                      <jats:italic>PDAP1<\/jats:italic>\n                      ,\n                      <jats:italic>PNKD<\/jats:italic>\n                      , and\n                      <jats:italic>HMGB1<\/jats:italic>\n                      loci. Steiger directionality testing supported the observed associations. In GTEx datasets, higher\n                      <jats:italic>PNKD<\/jats:italic>\n                      expression was associated with increased T1D risk in both whole blood and spleen.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>PNKD<\/jats:italic>\n                      ,\n                      <jats:italic>PDAP1<\/jats:italic>\n                      , and\n                      <jats:italic>HMGB1<\/jats:italic>\n                      were prioritized as lactylation\u2010related candidate genes associated with T1D risk through integrated genetic analyses. This finding generates hypothesis for future investigations into the potential involvement of lactylation\u2010related pathways in T1D pathogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/jdr\/9544974","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T08:33:22Z","timestamp":1783067602000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multiomics Mendelian Randomization Identifies Lactylation\u2010Related Molecular Traits in Type 1 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