Exploration of the Causal Association Between Behavioral Risk Factors and Gallstone Disease Development in Two European Ancestry Populations

Introduction Risk factors for developing gallstones are related to disturbances in either cholesterol or bilirubin metabolism in the biliary tract. The risk of forming gallstones can be associated with chronic illnesses, dietary habits, reduced gallbladder motility, and medications. Our study aims to explore the causal relationship between multiple risk factors, including nutritional habits (cheese intake, salad intake, processed meat intake, coffee drinking), smoking behavior, overall obesity measured by body mass index (BMI), lipid biomarkers, total bilirubin and maternal diabetes mellitus (DM) and the development of gallstone disease in two different populations of European ancestry (United Kingdom Biobank (UKB) and FinnGen). Materials and methods Using publicly available genome-wide association studies (GWAS) data, we performed a two-sample Mendelian randomization (MR) to examine the association between risk factors and gallstone development. Exposures used in this study included age of smoking initiation, smoking intensity, coffee intake, cheese intake, salad intake, processed meat intake, BMI, and lipid biomarkers (cholesterol, low-density lipoproteins (LDL), triglycerides (TG), and high-density lipoproteins (HDL)). Current analyses were based on 93 single nucleotide polymorphisms (SNPs) for smoking initiation, four SNPs for smoking intensity, 65 SNPs for cheese intake, three SNPs for coffee intake, 22 SNPs for salad intake, 23 SNPs for processed meat intake, 79 SNPs for BMI, 26 SNPs for maternal DM, 89 SNPs for total bilirubin, 46 SNPs for cholesterol, 41 SNPs for LDL, 55 SNPs for TG, and 89 SNPs for HDL. The outcome in this study is gallstones/cholelithiasis. To evaluate the causal relationships between these risk factors and gallstones, two-sample MR methods were used. TwoSampleMR package in R software version 4.0.5 (R Foundation for Statistical Computing, Vienna, Austria) was used to obtain MR analyses and sensitivity analyses. Results In the UKB, genetic predispositions to smoking initiation, BMI, and total bilirubin were significantly associated with an increased risk of gallstones. The odds of gallstones would increase per 1-SD increase of genetically estimated smoking initiation (OR: 1.004, P=0.008), BMI (OR: 1.02, P<0.001), and total bilirubin (OR: 1.0001, P=0.025). Conversely, genetic predispositions to cheese intake, coffee intake, cholesterol, LDL, and TG were statistically significantly associated with a decreased risk of gallstones (OR=0.99, P=0.014; OR=0.97, P=0.009; OR=0.99, P=0.006; OR=0.99, P=0.01; and OR=0.99, P<0.001, respectively). In FinnGen, genetic predispositions to BMI and total bilirubin were significantly associated with an increased risk of gallstones. The odds of gallstones would increase per 1-SD increase of genetically estimated BMI (OR: 1.7, P<0.001) and total bilirubin (OR: 1.02, P=0.002). Conversely, genetic predispositions to cheese intake, coffee intake, cholesterol, LDL, and TG were statistically significantly associated with a decreased risk of gallstones (OR=0.23, P=0.006; OR=0.42, P=0.041; OR=0.77, P=0.034; OR=0.88, P=0.008; and OR=0.70, P=0.005, respectively). Conclusion Genetically estimated BMI and total bilirubin levels were associated with increased risk of gallstones among the two populations while genetically estimated cheese intake, coffee intake, and cholesterol, LDL, and TG levels factors were consistently associated with reduced risk of gallstones among the two populations.