Fan Mingyuan, Yun Zhangjun, Yuan Jiushu, Zhang Sai, Xie Hongyan, Lu Dingyi, Yuan Haipo, Gao Hong
Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
Dongzhimen Hospital, Beijing University of Chinese Medicine (BUCM), Beijing, China.
Hereditas. 2024 Dec 30;161(1):56. doi: 10.1186/s41065-024-00362-8.
Considering that the treatment of gout is poor, we performed a Mendelian randomization (MR) study to identify candidate biomarkers and therapeutic targets for gout.
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.
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.
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.
鉴于痛风的治疗效果不佳，我们开展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。
通过整合痛风全基因组关联研究（GWAS）汇总数据以及来自多个队列的2633个可成药基因的顺式表达定量性状位点，对痛风进行了药物靶向MR研究。基于转录本和蛋白质水平进一步开展基于汇总数据的孟德尔随机化（SMR）分析，以验证所确定的痛风潜在治疗靶点的可靠性。在1403种疾病中进行全表型孟德尔随机化（Phe-MR）分析，以研究痛风潜在治疗靶点的偶然副作用。
在发现队列中使用MR分析确定了8个痛风潜在治疗靶点（醛脱氢酶3B1、Fc段γ受体ⅡB、白细胞介素2受体β链、核受体结合蛋白1、Ras转化酶1、溶质载体家族7成员7、硫酸酯酶修饰因子1、血小板反应蛋白3）。在复制队列中进行的重复分析和荟萃分析验证了MR结果的稳健性（P < 0.05）。SMR分析的证据（P < 0.05）进一步强化了这8个痛风潜在治疗靶点的可靠性，还显示醛脱氢酶3B1水平升高降低了可能由甲基化位点cg25402137改变的痛风风险。蛋白质水平的SMR分析（P < 0.05）进一步强调了风险基因核受体结合蛋白1和硫酸酯酶修饰因子1对痛风的影响。Phe-MR分析表明7个痛风因果基因与45种疾病之间存在显著因果关系。
本研究确定了几种与痛风风险相关的生物标志物，为痛风的病因学提供了新见解，并为治疗药物的开发提供了有前景的靶点。
