Genetic insights into therapeutic targets for gout: evidence from a multi-omics mendelian randomization study.

IF 2.7 3区生物学

Hereditas Pub Date : 2024-12-30 DOI:10.1186/s41065-024-00362-8

Mingyuan Fan, Zhangjun Yun, Jiushu Yuan, Sai Zhang, Hongyan Xie, Dingyi Lu, Haipo Yuan, Hong Gao

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引用次数: 0

Abstract

Background: Considering that the treatment of gout is poor, we performed a Mendelian randomization (MR) study to identify candidate biomarkers and therapeutic targets for gout.

Methods: A drug-targeted MR study was performed for gout by integrating the gout genome-wide association studies (GWAS) summary data and cis expression quantitative trait loci of 2,633 druggable genes from multiple cohorts. Summary data-based Mendelian randomization (SMR) analyses based on transcript and protein levels were further implemented to validate the reliability of the identified potential therapeutic targets for gout. Phenome-wide MR (Phe-MR) analysis was conducted in 1403 diseases to investigate incidental side effects of potential therapeutic targets for gout.

Results: Eight potential therapeutic targets (ALDH3B1, FCGR2B, IL2RB, NRBP1, RCE1, SLC7A7, SUMF1, THBS3) for gout were identified in the discovery cohort using MR analysis. Replication analysis and meta-analysis implemented in the replication cohort validated the robustness of the MR findings (P < 0.05). Evidence from the SMR analysis (P < 0.05) further strengthened the reliability of the 8 potential therapeutic targets for gout also revealed that high levels of ALDH3B1 reduced the gout risk possibly modified by the methylation site cg25402137. SMR analysis (P < 0.05) at the protein level added emphasis on the impact of the risk genes NRBP1 and SUMF1 on gout. Phe-MR analysis indicated significant causality between 7 gout causal genes and 45 diseases.

Conclusion: This study identified several biomarkers associated with gout risk, providing new insights into the etiology of gout and promising targets for the development of therapeutic agents.

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痛风治疗靶点的遗传洞察：来自多组学孟德尔随机化研究的证据。

背景：考虑到痛风的治疗效果不佳，我们进行了一项孟德尔随机化（MR）研究，以确定痛风的候选生物标志物和治疗靶点。方法：通过整合来自多个队列的2633个可用药基因的痛风全基因组关联研究（GWAS）汇总数据和顺式表达数量性状位点，对痛风进行药物靶向MR研究。基于转录物和蛋白质水平的孟德尔随机化（SMR）分析进一步验证了确定的痛风潜在治疗靶点的可靠性。对1403例疾病进行全现象MR （Phe-MR）分析，探讨痛风潜在治疗靶点的附带副作用。结果：通过MR分析，在发现队列中确定了8个痛风潜在治疗靶点（ALDH3B1、FCGR2B、IL2RB、NRBP1、RCE1、SLC7A7、SUMF1、THBS3）。在复制队列中实施的复制分析和荟萃分析验证了MR结果的稳健性(P结论：本研究确定了与痛风风险相关的几种生物标志物，为痛风的病因学提供了新的见解，并为治疗剂的开发提供了有希望的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Hereditas Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

3.80

自引率

3.70%

发文量

期刊介绍： For almost a century, Hereditas has published original cutting-edge research and reviews. As the Official journal of the Mendelian Society of Lund, the journal welcomes research from across all areas of genetics and genomics. Topics of interest include human and medical genetics, animal and plant genetics, microbial genetics, agriculture and bioinformatics.