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

作　　者：杨少鹏 朱梓瑜 刘日乾 黄文勇 王伟 Shaopeng Yang;Ziyu Zhu;Riqian Liu;Wenyong Huang;Wei Wang(State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangdong Provincial Clinical Research Center for Ocular Diseases,Guangzhou 510060,China;Hainan Eye Hospital and Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Haikou 570100,China)

机构地区：[1]State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangdong Provincial Clinical Research Center for Ocular Diseases,Guangzhou 510060,China [2]Hainan Eye Hospital and Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Haikou 570100,China

出　　处：《Eye Science》2024年第1期26-44,共19页眼科学报（英文版）

基　　金：funded by the Hainan Province Clinical Medical Center(82171084);the National Natural Science Foundation of China(82371086).

摘　　要：Background:Diabetic retinopathy(DR)urgently needs novel and effective therapeutic targets.Integrated 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 performed.Methods: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 proteins.DR data were sourced from the largest FinnGen study,comprising 10,413 DR cases and 308,633 European controls.Genetic instrumental variables were identified using multiple filters.In the two-sample MR analysis,Wald ratio and inverse variance-weighted(IVW)MR were utilized to investigate the causality of plasma proteins with DR.Bidirectional MR,Bayesian Co-localization,and phenotype scanning were employed to test for potential reverse causality and confounding factors in the main MR analyses.By 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 evaluated.Results: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 associations.For 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 analyses.Four proteins exhibited strong co-localization evidence(PH4≥0.8):cytoplasmic tRNA synthetase(WARS),acrosin binding protein(ACRBP),and intercellular adhesion molecule 1(ICAM1)were negatively associated with DR risk,while n

关 键 词：plasma proteome mendelian randomization therapeutic targets genome-wide analysis study colocalization analysis diabetic retinopathy 

分 类 号：R587.2[医药卫生—内分泌] R774.1[医药卫生—内科学]