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In this study, we integrated the data from the largest genome-wide association study (GWAS; N = 898 130) of T2DM with human plasma protein quantitative trait locus (pQTL; N = 53 022) data to conduct the first proteome-wide association study (PWAS) of T2DM. Following Mendelian randomization and colocalization analyses, we identified 9 independent putatively causal proteins. Among these, 3 were successfully replicated in other independent pQTL datasets, including 2 (HYOU1 and FLT3) that were novel and not identified in the original GWAS. Further integration with expression quantitative trait locus (eQTL) data from 3 diabetes-related tissues (blood, adipose tissue, and pancreas) revealed that 5 of the causal proteins also showed significant associations with T2DM at their cis-regulatory mRNA levels. Subsequent functional annotation supported potential pathogenic roles of the causal proteins. Notably, drug repurposing analysis identified 29 candidate drugs for T2DM treatment by targeting 4 causal proteins. In conclusion, our findings provide new insights into the pathogenesis of T2DM and highlight promising targets for future mechanistic and therapeutic investigations.<\/jats:p>","DOI":"10.1210\/clinem\/dgaf462","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T11:37:58Z","timestamp":1754998678000},"page":"591-601","source":"Crossref","is-referenced-by-count":5,"title":["Blood Plasma Proteome-Wide Association Study Implicates New Proteins in Type 2 Diabetes Mellitus Pathogenesis"],"prefix":"10.1210","volume":"111","author":[{"given":"Yang","family":"Yang","sequence":"first","affiliation":[{"name":"Clinical Laboratory, the First Affiliated Hospital, Xi\u2019an Jiaotong University , Xi\u2019an, Shaanxi 710061 ,","place":["P. R. 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