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. 2024 Apr 15:15:1379607.
doi: 10.3389/fendo.2024.1379607. eCollection 2024.

Protective effect of higher free thyroxine levels within the reference range on biliary tract cancer risk: a multivariable mendelian randomization and mediation analysis

Yuxian Chen #  1 , Hao Dong #  1 , Baozhen Qu #  2 , Xuezhen Ma  3 , LinLin Lu  2
Affiliations

Protective effect of higher free thyroxine levels within the reference range on biliary tract cancer risk: a multivariable mendelian randomization and mediation analysis

Yuxian Chen et al. Front Endocrinol (Lausanne). .

Abstract

Background: Hepatobiliary cancer (HBC), including hepatocellular carcinoma (HCC) and biliary tract cancer (BTC), is currently one of the malignant tumors that mainly cause human death. Many HBCs are diagnosed in the late stage, which increases the disease burden, indicating that effective prevention strategies and identification of risk factors are urgent. Many studies have reported the role of thyroid hormones on HBC. Our research aims to assess the causal effects and investigate the mediation effects between thyroid function and HBC.

Methods: Utilizing the Mendelian randomization (MR) approach, the study employs single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) to explore causal links between thyroid function [free thyroxine (FT4), thyroid stimulating hormone (TSH), hyperthyroidism and hypothyroidism] and HBC. Data were sourced from the ThyroidOmic consortium and FinnGen consortium. The analysis included univariable and multivariable MR analysis, followed by mediation analysis.

Results: The study found a significant causal association between high FT4 levels and the reduced risk of BTC, but not HCC. However, TSH, hyperthyroidism and hypothyroidism had no causal associations with the risk of HBC. Notably, we also demonstrated that only higher FT4 levels with the reference range (FT4-RR) could reduce the risk of BTC because this protective effect no longer existed under the conditions of hyperthyroidism or hypothyroidism. Finally, we found that the protective effect of FT4-RR on BTC was mediated partially by decreasing the risk of metabolic syndrome (MetS) and reducing the waist circumference (WC).

Conclusion: The findings suggest that higher FT4-RR may have a protective effect against BTC, which is partially mediated by decreased risk of MetS and a reduction in WC. This study highlights the potential role of FT4 in the pathogenesis of BTC and underscores that MetS and WC may play mediation effects as two mediators in this process.

Keywords: Mendelian randomization; free thyroxine; hepatobiliary cancer; metabolic syndrome; thyroid function; waist circumference.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Design of the present study. (A) Schematic diagram of MR analysis satisfying three key assumptions. SNP, Single nucleotide polymorphism. (B) Two-step MR analysis framework. Step 1 estimated the causal effect of the exposure on the potential mediators, and step 2 assessed the causal effect of the mediators on BTC risk.
Figure 2
Figure 2
MR analysis results between thyroid function and risk of hepatobiliary carcinoma. (A) The forest plot existing causal effect of thyroid function on HCC. (B) The forest plot existing causal effect of thyroid function on BTC.
Figure 3
Figure 3
Scatter plots of SNP effects on FT4 level and BTC risk. X axes represent SNP effects on FT4 level. Y axes represent SNP effects on BTC risk.
See this image and copyright information in PMC

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