The role of metabolic factors in the association between obesity and cholelithiasis: A two-step, two-sample multivariable mendelian randomization study.

Background and purpose: The extent to which the effects of BMI on cholelithiasis are mediated by metabolic factors (including blood pressure, blood lipids, body mass, and fasting blood glucose) is unclear. Therefore, in this study, the authors used genetic evidence to test the effects of these characteristics.

Methods: Summary-level data for exposures and main outcomes were extracted from GWAS consortia. The authors used a two-step, two-sample Multivariable Mendelian Randomization (MVMR) analysis to illustrate the effect of BMI on cholelithiasis and a stepwise test method to quantify the possible mediating effects of cardiometabolic factors on cholelithiasis.

Results: For each one-unit logarithmic increase in body mass index, the risk of cholelithiasis increased by 98 % (Odds Ratio [OR = 1.98], 95 % CI: 1.73 %‒2.28 %). After mediation analysis, the authors found that high-density lipoprotein and triglycerides were the main mediating factors, while the mediating effects of other metabolic factors were not significant. The total effect ratios of HDL and TG on cholelithiasis were 7.3 % (95 % CI: 8.51 %‒12.85 %) and 3.5 % (95 % CI: 3.59 %‒6.50 %), respectively. HDL and TG played a significant role in regulating cholelithiasis, but there was no evidence to show the regulatory effect of LDL on cholelithiasis. The total effects of BMI and triglycerides on cholelithiasis were 10.7 % and 5.0 %, respectively.

Conclusion: The authors found that among the metabolic factors evaluated, the decrease of HDL and the increase of TG mediated a high proportion of the effect of BMI on cholelithiasis. Therefore, intervention with these factors may reduce the increased risk of cholelithiasis in patients with high BMI.