阿司匹林与全表型疾病的因果关联:一项药物靶点孟德尔随机化研究

doi:10.6040/j.issn.1671-7554.0.2025.1060

摘要/Abstract

摘要： 目的采用药物靶点孟德尔随机化(mendelian randomization, MR)以及多基因评分方法,系统探讨遗传代理的阿司匹林与全表型疾病之间的因果关联。方法暴露数据来源于eQTLGen联盟(31 684名健康个体的外周血样本),筛选与阿司匹林作用靶点相关的顺式基因表达数量性状位点(cis-expression quantitative trait locus, cis-eQTL)作为工具变量;疾病结局数据来源于FinnGen数据库R12版本(500 348名芬兰裔参与者,2 502个疾病终点),纳入病例数≥1 000的1 265种疾病进行分析。采用逆方差加权法(inverse variance weighted, IVW)作为主要分析方法,加权中位数法、MR-Egger回归、简单模式法和加权模式法进行验证;通过Cochrans Q检验、MR-Egger 回归的截距项检验和留一法分别评估异质性和水平多效性。基于9个阿司匹林作用相关基因构建多基因评分,在英国生物银行队列(402 700人)中验证显著关联。结果共筛选出27个SNP作为工具变量。经多重检验校正后,IVW分析显示遗传代理的阿司匹林暴露与34种疾病存在显著因果关联,其中13种疾病的因果关联得到至少3种补充MR方法的支持(重复验证)。具体而言:胎儿生长受限(OR=0.471,95%CI:0.348~0.636,P<0.001)、其他栓塞和血栓(OR=0.665,95%CI:0.495~0.894,P=0.007)、未特指风湿病(OR=0.651,95%CI:0.489~0.867,P=0.003)、小肠良性肿瘤(OR=0.449,95%CI:0.251~0.802,P=0.003)、老年性白内障(OR=0.840,95%CI:0.760~0.929,P=0.001)风险降低;慢性溃疡性回肠结肠炎(OR=2.427,95%CI:1.363~4.320,P=0.003)、大肠克罗恩病(OR=1.843,95%CI:1.156~2.938,P=0.003)风险增加。多基因评分分析显示,阿司匹林与老年性白内障风险呈负相关(OR=0.985,95%CI:0.974~0.996,P=0.007)。结论阿司匹林在全表型层面表现出多系统效应,其对血栓栓塞、胎儿生长受限、风湿性疾病及小肠良性肿瘤具有保护作用,但可能增加炎症性肠病风险。本研究为阿司匹林的临床合理应用与药物再定位提供了遗传学依据。

关键词: 阿司匹林, 全表型疾病, 药物靶点孟德尔随机化, 因果关联

Abstract: Objective To systematically investigate the causal effects of genetically proxied aspirin exposure on a broad range of phenotypes using drug-target Mendelian randomization(MR)and polygenic score analysis. Methods Exposure data were obtained from the eQTLGen consortium(31,684 healthy European individuals). Cis-expression quantitative trait loci(cis-eQTL)significantly associated with aspirin target genes were selected as instrumental variables(IVs). Outcome data were derived from the FinnGen study R12 release(500,348 Finnish participants, 2,502 disease endpoints), with 1,265 diseases(case count ≥1,000)included for analysis. The inverse variance weighted(IVW)method was used as the primary MR analysis, complemented by weighted median, MR-Egger regression, simple mode, and weighted mode methods for verification. Heterogeneity and pleiotropy were assessed using Cochrans Q test, MR-Egger intercept test, and leave-one-out analysis. A polygenic score was constructed based on nine aspirin-related genes and tested for associations with disease outcomes in the UK Biobank cohort(402,700 participants). Results A total of 27 SNPs were selected as instrumental variables. After multiple testing correction, the IVW analysis showed that genetically proxied aspirin exposure was significantly causally associated with 34 diseases, among which 13 associations were supported by at least three complementary MR methods(replication evidence). Specifically, reduced risks were observed for fetal growth restriction(OR=0.471, 95%CI: 0.348-0.636, P<0.001), other embolism and thrombosis(OR=0.665, 95%CI: 0.495-0.894, P=0.007), unspecified rheumatic disease(OR=0.651, 95% CI: 0.489-0.867, P=0.003), benign neoplasm of the small intestine(OR=0.449, 95%CI: 0.251-0.802, P=0.003), and senile cataract(OR=0.840, 95%CI: 0.760-0.929, P=0.001).In contrast, increased risks were observed for chronic ulcerative ileocolitis(OR=2.427, 95%CI: 1.363-4.320, P=0.003)and Crohns disease of the large intestine(OR=1.843, 95%CI: 1.156-2.938, P=0.003). Polygenic risk score analysis further indicated a negative association between aspirin use and the risk of senile cataract(OR=0.985, 95% CI: 0.974-0.996, P=0.007). Conclusion Aspirin exhibits pleiotropic effects across multiple disease systems, with protective effects against thromboembolism, fetal growth restriction, rheumatic diseases, and benign small intestinal tumors, but potential risks for inflammatory bowel diseases. This study provides genetic evidence to inform clinical application and drug repurposing of aspirin.

Key words: Aspirin, Phenome-wide Diseases, Drug target Mendelian randomization, Causal association

中图分类号:

R969.4

张秀美, 陈昌海, 袁中尚, 王淑康. 阿司匹林与全表型疾病的因果关联:一项药物靶点孟德尔随机化研究[J]. 山东大学学报 (医学版), 2026, 64(9): 50-59.

ZHANG Xiumei, CHEN Changhai, YUAN Zhongshang, WANG Shukang. Causal effects of aspirin on phenome-wide diseases: a drug target Mendelian randomization study[J]. Journal of Shandong University (Health Sciences), 2026, 64(9): 50-59.

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