• Li Zhang, Wenqiang Zhang, Lin He, Huijie Cui, Yutong Wang, Xueyao Wu, Xunying Zhao, Peijing Yan, Chao Yang, Changfeng Xiao, Mingshuang Tang, Lin Chen, Chenghan Xiao, Yanqiu Zou, Yunjie Liu, Yanfang Yang, Ling Zhang, Yuqin Yao, Jiayuan Li, Zhenmi Liu, Chunxia Yang, Xia Jiang, and Ben Zhang.
• Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China.
• Bmc Med. 2023 Sep 13; 21 (1): 353353.

BackgroundDespite epidemiological evidence associating gallstone disease (GSD) with cardiovascular disease (CVD), a dilemma remains on the role of cholecystectomy in modifying the risk of CVD. We aimed to characterize the phenotypic and genetic relationships between GSD and two CVD events - stroke and coronary artery disease (CAD).MethodsWe first performed a meta-analysis of cohort studies to quantify an overall phenotypic association between GSD and CVD. We then investigated the genetic relationship leveraging the largest genome-wide genetic summary statistics. We finally examined the phenotypic association using the comprehensive data from UK Biobank (UKB).ResultsAn overall significant effect of GSD on CVD was found in meta-analysis (relative risk [RR] = 1.26, 95% confidence interval [CI] = 1.19-1.34). Genetically, a positive shared genetic basis was observed for GSD with stroke ([Formula: see text]=0.16, P = 6.00 × 10-4) and CAD ([Formula: see text]=0.27, P = 2.27 × 10-15), corroborated by local signals. The shared genetic architecture was largely explained by the multiple pleiotropic loci identified in cross-phenotype association study and the shared gene-tissue pairs detected by transcriptome-wide association study, but not a causal relationship (GSD to CVD) examined through Mendelian randomization (MR) (GSD-stroke: odds ratio [OR] = 1.00, 95%CI = 0.97-1.03; GSD-CAD: OR = 1.01, 95%CI = 0.98-1.04). After a careful adjustment of confounders or considering lag time using UKB data, no significant phenotypic effect of GSD on CVD was detected (GSD-stroke: hazard ratio [HR] = 0.95, 95%CI = 0.83-1.09; GSD-CAD: HR = 0.98, 95%CI = 0.91-1.06), further supporting MR findings.ConclusionsOur work demonstrates a phenotypic and genetic relationship between GSD and CVD, highlighting a shared biological mechanism rather than a direct causal effect. These findings may provide insight into clinical and public health applications.© 2023. BioMed Central Ltd., part of Springer Nature.

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