{"title":"通过多队列血浆蛋白分析研究 IgA 肾病和膜性肾病的潜在药物靶点：基于 SMR 和共定位分析的孟德尔随机研究。","authors":"Xinyi Xu, Changhong Miao, Shirui Yang, Lu Xiao, Ying Gao, Fangying Wu, Jianbo Xu","doi":"10.1186/s13040-024-00405-w","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Membranous nephropathy (MN) and IgA nephropathy (IgAN) pose challenges in clinical treatment with existing therapies primarily focusing on symptom relief and often yielding unsatisfactory outcomes. The search for novel drug targets remains crucial to address the shortcomings in managing both kidney diseases.</p><p><strong>Methods: </strong>Utilizing GWAS data for MN (ncase = 2150, ncontrol = 5829) and IgAN (ncase = 15587, ncontrol = 462197), instrumental variables for plasma proteins were derived from recent GWAS. Sensitivity analysis involved bidirectional Mendelian randomization analysis, MR Steiger, Bayesian co-localization, and Phenotype scanning. The SMR analysis using eQTL data from the eQTLGen Consortium was conducted to assess the availability of selected protein targets. The PPI network was constructed to reveal potential associations with existing drug treatment targets.</p><p><strong>Results: </strong>The study, subjected to the stringent Bonferroni correction, revealed significant associations: four proteins with MN and three proteins with IgAN. In plasma protein cis-pQTL data from two cohorts, an increase in one standard deviation in PLA2R1 (OR = 2.01, 95%CI = 1.83-2.21), AIF1 (OR = 9.04, 95%CI = 4.69-17.41), MLN (OR = 3.79, 95%CI = 2.12-6.78), and NFKB1 (OR = 29.43, 95%CI = 7.73-112.0) was associated with an increased risk of MN. Additionally, in plasma protein cis-pQTL data, a standard deviation increase in FCGR3B (OR = 1.15, 95%CI = 1.09-1.22) and BTN3A1 (OR = 4.05, 95%CI = 2.65-6.19) correlated with elevated IgAN risk, while AIF1 (OR = 0.58, 95%CI = 0.46-0.73) exhibited IgAN protection. Bayesian co-localization indicated that PLA2R1 (coloc.abf-PPH4 = 0.695), NFKB1 (coloc.abf-PPH4 = 0.949), FCGR3B (coloc.abf-PPH4 = 0.909), and BTN3A1 (coloc.abf-PPH4 = 0.685) share the same variants associated with MN and IgAN. The SMR analysis indicated a causal link between NFKB1 and BTN3A1 plasma protein eQTL in both conditions, and BTN3A1 was validated externally.</p><p><strong>Conclusion: </strong>Genetically influenced plasma levels of PLA2R1 and NFKB1 impact MN risk, while FCGR3B and BTN3A1 levels are causally linked to IgAN risk, suggesting potential drug targets for further clinical exploration, notably BTN3A1 for IgAN.</p>","PeriodicalId":48947,"journal":{"name":"Biodata Mining","volume":"17 1","pages":"49"},"PeriodicalIF":4.0000,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11545554/pdf/","citationCount":"0","resultStr":"{\"title\":\"Investigating potential drug targets for IgA nephropathy and membranous nephropathy through multi-queue plasma protein analysis: a Mendelian randomization study based on SMR and co-localization analysis.\",\"authors\":\"Xinyi Xu, Changhong Miao, Shirui Yang, Lu Xiao, Ying Gao, Fangying Wu, Jianbo Xu\",\"doi\":\"10.1186/s13040-024-00405-w\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Membranous nephropathy (MN) and IgA nephropathy (IgAN) pose challenges in clinical treatment with existing therapies primarily focusing on symptom relief and often yielding unsatisfactory outcomes. The search for novel drug targets remains crucial to address the shortcomings in managing both kidney diseases.</p><p><strong>Methods: </strong>Utilizing GWAS data for MN (ncase = 2150, ncontrol = 5829) and IgAN (ncase = 15587, ncontrol = 462197), instrumental variables for plasma proteins were derived from recent GWAS. Sensitivity analysis involved bidirectional Mendelian randomization analysis, MR Steiger, Bayesian co-localization, and Phenotype scanning. The SMR analysis using eQTL data from the eQTLGen Consortium was conducted to assess the availability of selected protein targets. The PPI network was constructed to reveal potential associations with existing drug treatment targets.</p><p><strong>Results: </strong>The study, subjected to the stringent Bonferroni correction, revealed significant associations: four proteins with MN and three proteins with IgAN. In plasma protein cis-pQTL data from two cohorts, an increase in one standard deviation in PLA2R1 (OR = 2.01, 95%CI = 1.83-2.21), AIF1 (OR = 9.04, 95%CI = 4.69-17.41), MLN (OR = 3.79, 95%CI = 2.12-6.78), and NFKB1 (OR = 29.43, 95%CI = 7.73-112.0) was associated with an increased risk of MN. Additionally, in plasma protein cis-pQTL data, a standard deviation increase in FCGR3B (OR = 1.15, 95%CI = 1.09-1.22) and BTN3A1 (OR = 4.05, 95%CI = 2.65-6.19) correlated with elevated IgAN risk, while AIF1 (OR = 0.58, 95%CI = 0.46-0.73) exhibited IgAN protection. Bayesian co-localization indicated that PLA2R1 (coloc.abf-PPH4 = 0.695), NFKB1 (coloc.abf-PPH4 = 0.949), FCGR3B (coloc.abf-PPH4 = 0.909), and BTN3A1 (coloc.abf-PPH4 = 0.685) share the same variants associated with MN and IgAN. The SMR analysis indicated a causal link between NFKB1 and BTN3A1 plasma protein eQTL in both conditions, and BTN3A1 was validated externally.</p><p><strong>Conclusion: </strong>Genetically influenced plasma levels of PLA2R1 and NFKB1 impact MN risk, while FCGR3B and BTN3A1 levels are causally linked to IgAN risk, suggesting potential drug targets for further clinical exploration, notably BTN3A1 for IgAN.</p>\",\"PeriodicalId\":48947,\"journal\":{\"name\":\"Biodata Mining\",\"volume\":\"17 1\",\"pages\":\"49\"},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2024-11-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11545554/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biodata Mining\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1186/s13040-024-00405-w\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MATHEMATICAL & COMPUTATIONAL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biodata Mining","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s13040-024-00405-w","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MATHEMATICAL & COMPUTATIONAL BIOLOGY","Score":null,"Total":0}
Investigating potential drug targets for IgA nephropathy and membranous nephropathy through multi-queue plasma protein analysis: a Mendelian randomization study based on SMR and co-localization analysis.
Background: Membranous nephropathy (MN) and IgA nephropathy (IgAN) pose challenges in clinical treatment with existing therapies primarily focusing on symptom relief and often yielding unsatisfactory outcomes. The search for novel drug targets remains crucial to address the shortcomings in managing both kidney diseases.
Methods: Utilizing GWAS data for MN (ncase = 2150, ncontrol = 5829) and IgAN (ncase = 15587, ncontrol = 462197), instrumental variables for plasma proteins were derived from recent GWAS. Sensitivity analysis involved bidirectional Mendelian randomization analysis, MR Steiger, Bayesian co-localization, and Phenotype scanning. The SMR analysis using eQTL data from the eQTLGen Consortium was conducted to assess the availability of selected protein targets. The PPI network was constructed to reveal potential associations with existing drug treatment targets.
Results: The study, subjected to the stringent Bonferroni correction, revealed significant associations: four proteins with MN and three proteins with IgAN. In plasma protein cis-pQTL data from two cohorts, an increase in one standard deviation in PLA2R1 (OR = 2.01, 95%CI = 1.83-2.21), AIF1 (OR = 9.04, 95%CI = 4.69-17.41), MLN (OR = 3.79, 95%CI = 2.12-6.78), and NFKB1 (OR = 29.43, 95%CI = 7.73-112.0) was associated with an increased risk of MN. Additionally, in plasma protein cis-pQTL data, a standard deviation increase in FCGR3B (OR = 1.15, 95%CI = 1.09-1.22) and BTN3A1 (OR = 4.05, 95%CI = 2.65-6.19) correlated with elevated IgAN risk, while AIF1 (OR = 0.58, 95%CI = 0.46-0.73) exhibited IgAN protection. Bayesian co-localization indicated that PLA2R1 (coloc.abf-PPH4 = 0.695), NFKB1 (coloc.abf-PPH4 = 0.949), FCGR3B (coloc.abf-PPH4 = 0.909), and BTN3A1 (coloc.abf-PPH4 = 0.685) share the same variants associated with MN and IgAN. The SMR analysis indicated a causal link between NFKB1 and BTN3A1 plasma protein eQTL in both conditions, and BTN3A1 was validated externally.
Conclusion: Genetically influenced plasma levels of PLA2R1 and NFKB1 impact MN risk, while FCGR3B and BTN3A1 levels are causally linked to IgAN risk, suggesting potential drug targets for further clinical exploration, notably BTN3A1 for IgAN.
期刊介绍：
BioData Mining is an open access, open peer-reviewed journal encompassing research on all aspects of data mining applied to high-dimensional biological and biomedical data, focusing on computational aspects of knowledge discovery from large-scale genetic, transcriptomic, genomic, proteomic, and metabolomic data.
Topical areas include, but are not limited to:
-Development, evaluation, and application of novel data mining and machine learning algorithms.
-Adaptation, evaluation, and application of traditional data mining and machine learning algorithms.
-Open-source software for the application of data mining and machine learning algorithms.
-Design, development and integration of databases, software and web services for the storage, management, retrieval, and analysis of data from large scale studies.
-Pre-processing, post-processing, modeling, and interpretation of data mining and machine learning results for biological interpretation and knowledge discovery.
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