Bidirectional Mendelian randomization and mediation analysis of million-scale data reveal causal relationships between thyroid-related phenotypes, smoking, and lung cancer

Abstract

Emerging evidence highlights the role of thyroid hormones in cancer, although findings are controversial. Research on thyroid-related traits in lung carcinogenesis is limited. Using UK Biobank data, we performed bidirectional Mendelian randomization (MR) to assess causal associations between lung cancer risk and thyroid dysfunction (hypothyroidism and hyperthyroidism) or functional traits (free thyroxine [FT4] and normal-range thyroid-stimulating hormone [TSH]). Furthermore, in the smoking-behavior-stratified MR analysis, we evaluated the mediating effect of thyroid-related phenotypes on the association between smoking behaviors and lung cancer. We demonstrated significant associations between lung cancer risk and hypothyroidism (hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 1.03-1.26, P = 0.009) and hyperthyroidism (HR = 1.55, 95% CI = 1.29-1.87, P = 1.90 × 10⁻⁶) in the UKB. Moreover, the MR analysis indicated a causal effect of thyroid dysfunction on lung cancer risk (OR_{inverse variance weighted [IVW]} = 1.09, 95% CI = 1.05-1.13, P = 3.12 × 10⁻⁶ for hypothyroidism; OR_IVW = 1.08, 95% CI = 1.04-1.12, P = 8.14 × 10⁻⁵ for hyperthyroidism). We found that FT4 levels were protective against lung cancer risk (OR_IVW = 0.93, 95% CI = 0.87-0.99, P = 0.030). Additionally, the stratified MR analysis demonstrated distinct causal effects of thyroid dysfunction on lung cancer risk among smokers. Hyperthyroidism mediated the effect of smoking behaviors, especially the age of smoking initiation (17.66% mediated), on lung cancer risk. Thus, thyroid dysfunction phenotypes play causal roles in lung cancer development exclusively among smokers and act as mediators in the causal pathway from smoking to lung cancer.

Keywords

hypothyroidism / hyperthyroidism / lung neoplasms / smoking / causality / Mendelian randomization analysis

Fundings

The study was funded by the National Natural Science Foundation of China (Grant Nos. 82220108002 to F.C., 82273737 to R.Z., and 82473728 to Y.W.), the US National Institutes of Health (Grant Nos. CA209414, HL060710, and ES000002 to D.C.C.; CA209414 and CA249096 to Y.L.), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). R.Z. was partially supported by the Qing Lan Project of the Higher Education Institutions of Jiangsu Province and the Outstanding Young-Level Academic Leadership Training Program of Nanjing Medical University.

Acknowledgments

We thank all the GWAS consortia involved in this work for making the summary statistics publicly available. We are grateful to all the investigators and participants who contributed to these studies.

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