In a recent study published in the journal Dr Scientific reportResearchers performed a Mendelian randomization (MR) analysis to assess the causal relationship between gallstone disease (GSD) and coronary heart disease (CHD) or acute myocardial infarction (AMI) risk.
Study: Causal effect of gallbladder 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 gastrointestinal condition, has been linked to CHD and AMI, a type of CHD characterized by irreversible cardiac myocyte necrosis due to sudden ischemia.
The association between GSD, CHD and AMI is unknown; However, some studies indicate that abnormal cholesterol metabolism contributes to atherosclerosis. Although evidence of a positive relationship exists, the mechanism of the association remains unknown due to limited research.
About the study
In the current study, researchers investigated whether gallbladder disease is associated with CHD or AMI and explored the genetic loci driving causation.
Data from publicly accessible genome-wide association studies (GWAS) were evaluated at the summary level. Pooled GSD data were collected from Japan Biobank (461,431 controls and 26,122 cases in East Asian individuals) and Fingen Biobank (301,383 controls and 32,894 cases of European ancestry).
Data were pooled from 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).
In addition, information on AMI risk variables at the summary level was collected from the IEU OpenGWAS database. International Classification of Diseases, Tenth Revision (ICD-10) codes were used to diagnose GSD and CHD.
AMI diagnosis is based on presence of persistent chest discomfort, development of ischemia signal on electrocardiogram (ECG) and elevated expression of infarct-related biomarkers. AMI risk variables established to investigate were low-density lipoprotein cholesterol (LDL-C), hypertension, and smoking status.
The researchers extracted instrumental variable (IV) variants significantly associated with gallbladder disease and deleted those associated with AMI or CHD from their respective GWAS databases. Subsequently, unfit instrumental variables (cut-off: 10,000-kb window size and r2 0.001) to ensure that all IVs met the assumption of independence. The 1000 Genomes Project found R2 Thresholds for European populations.
The researchers removed all palindromic and duplicate single-nucleotide polymorphisms (SNPs) and incomplete data throughout the study. Furthermore, SNPs associated with parameters associated with GSD, AMI, or CHD (eg, total cholesterol, body mass index, and diabetes mellitus) were excluded.
The following analyzes were performed: MR-Egar, inverse variance weighting (IVW), maximum likelihood and weighted mean. MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) was used to correct outliers as a corrective treatment for IV heterogeneity in IV-weighted linear regression models. Furthermore, “leave-one-out” and co-localization studies were performed.
After elimination of confounders and outliers, 64 SNPs were included in the analysis to explore the causal effect of gallstone disease on acute myocardial infarction risk. All four Mendelian randomization strategies revealed significantly negative causality, as did the MR-PRESSO analysis.
The same strategy was used to assess the causal link between gallbladder disease and coronary heart disease risk with 65 SNPs. The results of the Mendelian randomization analysis showed that gallbladder disease may have a small negative effect on CHD risk; However, this causal association was not statistically significant.
Sensitivity analyzes indicated that preliminary results were robust. Results from MR investigations indicated that GSD patients had a significantly lower AMI risk but not CHD risk.
A contrast MR analysis was also performed to rule out the possibility that contrast performance would influence the negative effect of gallstone disease on acute myocardial infarction risk. The study included 54 single-nucleotide polymorphisms for AMI and 74 single-nucleotide polymorphisms for CHD as study outcomes for study exposure and gallstone disease, respectively.
However, neither CHD nor AMI was found to be a major cause of GSD, and each MR procedure yielded similar results.
To strengthen the generalizability of the results, the researchers investigated whether the negative effect of gallbladder disease on AMI risk persists in ethnicities other than Finnish individuals. For externally validated MR analysis, another gallbladder disease database included East Asian (mostly Japanese) individuals.
In investigating the causal effect of gallstone disease on acute myocardial infarction risk, MR analysis revealed a significant and negative causal association. Similarly, no significant causal link was detected between gallstone disease and coronary heart disease in novel GWAS, similar to findings in Finnish individuals.
Consistent results reaching external validity support the study’s findings and imply that they may be applicable to a larger population. Neither LDL-C, smoking, nor hypertension mediated the link between GSD and lower AMI risk.
The team found rs4245791 as the key locus that may mediate the negative effect of gallstone disease on AMI in co-localization analysis, providing strong evidence for an etiological explanation of the low incidence of AMI in GSD patients. ABCG8 protein, regulated by rs4245791, may explain the negative causal effect of GSD on AMI risk.
Overall, the study results indicate that genetic predisposition to GSD has a protective causative effect on AMI, implying that the risk is reduced in GSD patients. In addition, rs4245791 and its regulation of ATP-cassette binding proteins G5 and G8 (ABCG5/8) proteins are thought to be crucial for producing this causal effect.
The results provide important insights into AMI etiology and prevention in GSD patients. However, further studies are needed to investigate the mechanisms underlying the association between gallstone disease and AMI and the potential therapeutic benefits of targeting ABCG5/8.