Author:
Zhang Li,Zhang Wenqiang,He Lin,Cui Huijie,Wang Yutong,Wu Xueyao,Zhao Xunying,Yan Peijing,Yang Chao,Xiao Changfeng,Tang Mingshuang,Chen Lin,Xiao Chenghan,Zou Yanqiu,Liu Yunjie,Yang Yanfang,Zhang Ling,Yao Yuqin,Li Jiayuan,Liu Zhenmi,Yang Chunxia,Jiang Xia,Zhang Ben
Abstract
Abstract
Background
Despite 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).
Methods
We 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).
Results
An 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 ($${r}_{g}$$
r
g
=0.16, P = 6.00 × 10–4) and CAD ($${r}_{g}$$
r
g
=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.
Conclusions
Our 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.
Funder
National Key R&D Program of China
National Natural Science Foundation of China
the Recruitment Program for Young Professionals of China
Publisher
Springer Science and Business Media LLC