Genetic twist in gallstone disease may shield against heart attacks

By Pooja Toshniwal PahariaNov 5 2023Reviewed by Sophia Coveney

In a recent study published in the journal Scientific Reports, researchers performed a Mendelian randomization (MR) analysis to evaluate the causal association between gallstone disease (GSD) and coronary heart disease (CHD) or acute myocardial infarction (AMI) risk.

Study: Causal effect of gallstone disease on the risk of coronary heart disease or acute myocardial infarction: a Mendelian randomization study. Image Credit: Kateryna Kon/Shutterstock.com

GSD, a common digestive system condition, has been linked to CHD and AMI, a type of CHD characterized by irreversible cardiac myocyte necrosis due to abrupt ischemia.

The link between GSD, CHD and AMI is unknown; however, a few studies indicate abnormal cholesterol metabolism contributes to atherosclerosis. Although evidence of a positive correlation exists, the mechanism of the association remains unknown due to limited studies.

About the study

In the present study, researchers investigated whether gallstone disease is causally linked to CHD or AMI and searched for genetic loci driving causality.

Data from publicly accessible genome-wide association studies (GWAS) were evaluated at the summary level. Pooled GSD data were gathered from Japan’s Biobank (461,431 controls and 26,122 cases among East Asian individuals) and FinnGen Biobank (301,383 controls and 32,894 cases of European ancestry).

Data from the CARDIoGRAMplusC4D (43,676 AMI patients and 128,199 control cases) and the United Kingdom Biobank (UKBB) CardioMetabolic Consortium coronary heart disease working group (123,504 controls and 60,801 cases), were combined.

In addition, data on AMI risk variables at the summary level were gathered from the IEU OpenGWAS database. International Classification of Diseases, Tenth Revision (ICD-10) codes were used to diagnose GSD and CHD.

AMI diagnosis was based on the presence of persistent chest discomfort, the evolution of ischemia signals on the electrocardiogram (ECG), and elevated expression of infarct-associated biomarkers. Low-density lipoprotein cholesterol (LDL-C), hypertension, and smoking status were the established AMI risk variables for investigation.

The researchers extracted instrumental variable (IV) variants significantly linked with gallstone disease and deleted those related to AMI or CHD from their respective GWAS databases.  Subsequently, linkage disequilibrium (LD) was applied to eliminate unqualified instrumental variables (cut-offs: 10,000-kb window size and r² of 0.001) to ensure that all IVs fulfilled the independence assumption. The 1000 Genomes Project found the r² threshold for European populations.

The researchers deleted all palindromic and duplicate single-nucleotide polymorphisms (SNPs) and those with incomplete information throughout the study. Furthermore, SNPs belonging to parameters linked with GSD, AMI, or CHD (e.g., total cholesterol, body mass index, and diabetes mellitus) were excluded.

The following analyses were performed: MR-Egger, inverse variance weighting (IVW), maximum likelihood, and weighted median. MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) was used to correct outliers in the IV-weighted linear regression model as a corrective therapy for IV heterogeneity. Furthermore, "leave-one-out" and co-localization studies were performed.

Results

After eliminating confounders and outliers, the analysis included 64 SNPs to explore the causal influence of gallstone disease on acute myocardial infarction risk. All four Mendelian randomization techniques revealed significantly negative causality, as did the MR-PRESSO analyses.

The same strategy was used to evaluate the causal link between gallstone disease and coronary heart disease risk, with 65 SNPs. The Mendelian randomization analysis results showed that gallstone disease might have a slightly negative influence on CHD risk; however, this causal association was not statistically significant.

Sensitivity analyses indicated that the primary findings were robust. The MR investigation results indicated GSD patients have a considerably lower AMI risk but not CHD risk.

A reverse MR analysis was also undertaken to rule out the potential that reverse causality would influence the negative impact of gallstone disease on acute myocardial infarction risk. The investigation included 54 single-nucleotide polymorphisms for AMI and 74 single-nucleotide polymorphisms for CHD as study exposure and gallstone disease as the study outcome, respectively.

However, neither CHD nor AMI was found to be a major cause of GSD, and each MR approach produced similar results.

To strengthen the generalizability of the findings, the researchers investigated if the negative impact of gallstone disease on AMI risk continues in ethnicities other than Finnish individuals. For externally validated MR analysis, another gallstone disease database included East Asian (mostly Japanese) individuals.

In investigating the causative influence of gallstone disease on acute myocardial infarction risk, the MR analysis revealed a significant and negative causal association. Likewise, no significant causal link between gallstone disease and coronary heart disease was detected in novel GWAS information, which is similar to the findings among Finnish individuals.

The identical outcomes reached in the external validation support the study findings and imply that they may apply to a larger population. LDL-C, smoking, or hypertension did not mediate the link between GSD and a lower AMI risk.

The team found rs4245791 to be the core locus that may mediate the negative causative effect of gallstone disease on AMI in co-localization analysis, providing strong evidence for the etiological explanation of the lower incidence of AMI in GSD patients. The ABCG8 protein, controlled by rs4245791, might explain GSD's negative causative influence on AMI risk.

Conclusions

Overall, the study findings indicated that genetic predisposition to GSD has a protective causative impact on AMI, implying that GSD patients are at a reduced risk. In addition, rs4245791 and its regulated ATP-cassette binding proteins G5 and G8 (ABCG5/8) proteins were found to be crucial to producing this causal impact.

The findings offer important insights into AMI etiology and prevention in GSD patients. However, further research is required to investigate the mechanisms underlying the link between gallstone disease and AMI and the possible therapeutic advantages of targeting ABCG5/8.