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Identification of novel drug targets for diabetic retinopathy:proteome-wide mendelian randomization and colocalization analyses

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Eye Science 2024年第1期1卷 26-44页

作者：杨少鹏朱梓瑜刘日乾黄文勇王伟 State Key Laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangdong Provincial Key Laboratory of Ophthalmology and Visual ScienceGuangdong Provincial Clinical Research Center for Ocular DiseasesGuangzhou 510060China Hainan Eye Hospital and Key Laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen UniversityHaikou 570100China

Background:Diabetic retinopathy(DR)urgently needs novel and effective therapeutic *** analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel targets for diseases,but no systematic screening for DR has been ***:Summary statistics of plasma protein quantitative trait loci(pQTL)were derived from two extensive genome-wide analysis study(GWAS)datasets and one systematic review,with over 100 thousand participants covering thousands of plasma *** data were sourced from the largest FinnGen study,comprising 10,413 DR cases and 308,633 European *** instrumental variables were identified using multiple *** the two-sample MR analysis,Wald ratio and inverse variance-weighted(IVW)MR were utilized to investigate the causality of plasma proteins with *** MR,Bayesian Co-localization,and phenotype scanning were employed to test for potential reverse causality and confounding factors in the main MR *** systemically searching druggable gene lists,the ChEMBL database,DrugBank,and Gene Ontology database,the druggability and relevant functional pathways of the identified proteins were systematically ***:Genetically predicted levels of 24 proteins were significantly associated with DR risk at a false discovery rate<0.05 including 11 with positive associations and 13 with negative *** each standard deviation increase in plasm protein levels,the odds ratios(ORs)for DR varied from 0.51(95%CI:0.36-0.73;P=2.22×10-5)for tubulin polymerization-promoting protein family member 3(TPPP3)to 2.02(95%CI:1.44-2.83;P=5.01×10-5)for olfactomedin like 3(OLFML3).Bidirectional MR indicated there was no reverse causality that interfered with the results of the main MR *** proteins exhibited strong co-localization evidence(PH4≥0.8):cytoplasmic tRNA synthetase(WARS),acrosin binding protein(ACRBP),and intercellular adhesion molecule 1(ICAM1)wer

关键词： plasma proteome mendelian randomization therapeutic targets genome-wide analysis study colocalization analysis diabetic retinopathy

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