Gallstone disease, diabetes, calcium, triglycerides, smoking and alcohol consumption and pancreatitis risk: Mendelian randomization study

Abstract

We conducted a Mendelian randomization study to determine the potential causal associations of gallstone disease, diabetes, serum calcium, triglyceride levels, smoking and alcohol consumption with acute and chronic pancreatitis. Genetic variants associated with the exposures at p < 5 × 10^-8 were selected from corresponding genome-wide association studies. Summary-level data for pancreatitis were obtained from the FinnGen consortium and UK Biobank. Univariable and multivariable Mendelian randomization analyses were performed and results from FinnGen and UK Biobank were combined using the fixed-effects meta-analysis method. Genetic predisposition to gallstone disease, type 2 diabetes and smoking initiation was associated with an increased risk of acute pancreatitis. The combined odds ratios (ORs) were 1.74 (95% confidence interval (CI), 1.57, 1.93) for gallstone disease, 1.14 (95% CI, 1.06, 1.21) for type 2 diabetes and 1.56 (95% CI, 1.32, 1.83) for smoking initiation. The association for type 2 diabetes attenuated after adjustment for gallstone disease. Genetic predisposition to gallstone disease and smoking initiation as well as higher genetically predicted serum calcium and triglyceride levels were associated with an increased risk of chronic pancreatitis. The combined ORs of chronic pancreatitis were 1.27 (95% CI, 1.08, 1.50) for gallstone disease, 1.86 (95% CI, 1.43, 2.43) for smoking initiation, 2.20 (95% CI, 1.30, 3.72) for calcium and 1.47 (95% CI, 1.23, 1.76) for triglycerides. This study provides evidence in support that gallstone disease, type 2 diabetes, smoking and elevated calcium and triglyceride levels are causally associated with the risk of acute or chronic pancreatitis.

Fig. 1. Combined effect^a of risk factors on acute pancreatitis in the FinnGen consortium and UK Biobank study.

CI indicates confidence interval; OR odds ratio, UKBB UK Biobank. ^aEstimates were based on the fixed-effect meta-analysis of odds ratio derived from the inverse-variance weighted method with random-effects.

Fig. 2. Combined effect^a of risk factors on acute pancreatitis after adjustment of gallstone disease in the FinnGen consortium and UK Biobank study.

CI indicates confidence interval; OR odds ratio, UKBB UK Biobank. ^aEstimates were based on the fixed-effect meta-analysis of odds ratio derived from the inverse-variance weighted method with random-effects adjusting for gallstone disease.

Fig. 3. Combined effect^a of risk factors on chronic pancreatitis in the FinnGen consortium and UK Biobank study.

CI indicates confidence interval; OR odds ratio, UKBB UK Biobank. ^aEstimates were based on the fixed-effect meta-analysis of odds ratio derived from the inverse-variance weighted method with random-effects.

Fig. 4. Combined effect^a of risk factors on chronic pancreatitis after adjustment of gallstone disease in the FinnGen consortium and UK Biobank study.

CI indicates confidence interval; OR odds ratio, UKBB UK Biobank. ^aEstimates were based on the fixed-effect meta-analysis of odds ratio derived from the inverse-variance weighted method with random-effects adjusting for gallstone disease.

Fig. 5. Study design overview and assumptions of the Mendelian randomization framework.

IVW inverse-variance weighted, LD linkage disequilibrium, SNPs single-nucleotide polymorphisms, T2DM type 2 diabetes mellitus. Assumption 1 indicates that the genetic variants proposed as instrumental variables should be robustly associated with the risk factor of interest; assumption 2 indicates that the used genetic variants should not be associated with potential confounders, and assumption 3 indicates that the selected genetic variants should affect the risk of the outcome merely through the risk factor, not via alternative pathways.