Impact of gallstone disease on the risk of stroke and coronary artery disease: evidence from prospective observational studies and genetic analyses

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 ([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.

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.

Keywords: Cardiovascular disease; Gallstone disease; Genetic correlation; Mendelian randomization; Phenotypic association.

Fig. 1

Flowchart on the overall study design. Gallstone disease was set as exposure, and two CVD phenotypes (stroke and coronary artery disease) were included as outcomes. We first updated the epidemiological evidence between GSD and CVD. We then performed a comprehensive genome-wide cross-trait analysis to investigate the shared genetic architecture underlying both traits and dissected such shared genetic basis into pleiotropy and causality. Lastly, we used UK Biobank (UKB) data to explore the phenotypic association

Fig. 2

Forest plot of pooled relative risk of incident cardiovascular disease in participants with gallstone disease. Square represents the estimate of relative risk for each study; the horizontal line represents the 95% confidence intervals, and the diamond represents the overall estimate and its 95% confidence intervals. RR, relative risk. GSD, gallstone disease; cardiovascular disease (CVD)

Fig. 3

Local genetic correlation between gallstone disease and cardiovascular diseases. Manhattan plot presenting region-specific P-values for local genetic correlation between (A) gallstone disease and stroke and (B) gallstone disease and coronary artery disease. Red dots represent loci showing significant local genetic correlation after multiple testing adjustments (P < 0.05/2,353)

Fig. 4

Cross-trait meta-analysis between gallstone disease and cardiovascular diseases. In each circular Manhattan plot, the outermost circle shows the cross-trait meta-analysis results between (A) gallstone disease and stroke and (B) gallstone disease and coronary artery disease; from the periphery to the center, each circle shows the GWAS results on gallstone disease and cardiovascular diseases, respectively. Light blue indicates variants with genome-wide significance (P < 5 × 10^–8) while dark blue indicates variants with P ≥ 5 × 10^–8. According to their single-trait and cross-trait characteristics, SNPs are divided into two different types named “Known associated SNP” and “Novel shared SNP”,which are presented in grey and red, respectively. RSIDs of them are listed. The bar plot presents the numbers of two types of SNPs detected in the cross-trait meta-analysis between (C) gallstone disease and stroke and (D) gallstone disease and coronary artery disease

Fig. 5

The estimated causal association between gallstone disease and cardiovascular diseases using two-sample Mendelian randomization. Boxes denote the point estimate of the causal effects between (A) gallstone disease and stroke and (B) gallstone disease and coronary artery disease. Error bars denote 95% confidence intervals. GSD, gallstone disease; CAD, coronary artery disease