Abstract
OBJECTIVE: To investigate the relationship between function of thyroid, lipids, and cholelithiasis and to identify whether lipids mediate the causal relationship between function of thyroid and cholelithiasis. METHODS: A Mendelian randomization (MR) study of two samples was performed to determine the association of thyroid function with cholelithiasis. A two-step MR was also performed to identify whether lipid metabolism traits mediate the effects of thyroid function on cholelithiasis. A method of inverse variance weighted (IVW), weighted median method, maximum likelihood, MR-Egger, MR-robust adjusted profile score (MR-RAPS) method, and MR pleiotropy residual sum and outlier test (MR-PRESSO) methods were utilized to obtain MR estimates. RESULTS: The IVW method revealed that FT4 levels were correlated with an elevated risk of cholelithiasis (OR: 1.149, 95% CI: 1.082-1.283, P = 0.014). Apolipoprotein B (OR: 1.255, 95% CI: 1.027-1.535, P = 0.027) and low-density lipoprotein cholesterol (LDL-C) (OR: 1.354, 95% CI: 1.060-1.731, P = 0.016) were also correlated with an elevated risk of cholelithiasis. The IVW method demonstrated that FT4 levels were correlated with the elevated risk of apolipoprotein B (OR: 1.087, 95% CI: 1.019-1.159, P = 0.015) and LDL-C (OR: 1.084, 95% CI: 1.018-1.153, P = 0.012). Thyroid function and the risk of cholelithiasis are mediated by LDL-C and apolipoprotein B. LDL-C and apolipoprotein B had 17.4% and 13.5% of the mediatory effects, respectively. CONCLUSIONS: We demonstrated that FT4, LDL-C, and apolipoprotein B had significant causal effects on cholelithiasis, with evidence that LDL-C and apolipoprotein B mediated the effects of FT4 on cholelithiasis risk. Patients with high FT4 levels should be given special attention because they may delay or limit the long-term impact on cholelithiasis risk.