3.8
CiteScore
2.4
Impact Factor
- ISSN 1674-8301
- CN 32-1810/R
3.8
2.4
| Citation: |
Xiang Wang, Xuan Wang, Mengsheng Zhao, Lijuan Lin, Yi Li, Ning Xie, Yanru Wang, Aoxuan Wang, Xiaowen Xu, Can Ju, Qiuyuan Chen, Jiajin Chen, Ruili Hou, Zhongwen Zhang, David C. Christiani, Feng Chen, Yongyue Wei, Ruyang Zhang. Bidirectional Mendelian randomization and mediation analysis of million-scale data reveal causal relationships between thyroid-related phenotypes, smoking, and lung cancer[J]. The Journal of Biomedical Research. DOI: 10.7555/JBR.38.20240421
|
Online publication: The manuscript has been published online and can be indexed in databases like PubMed and WoS. It will be available in the next/future issue of the journal, depending on the journal's publication schedule.
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 (ORinverse variance weighted [IVW] = 1.09, 95% CI = 1.05–1.13, P = 3.12 × 10−6 for hypothyroidism; ORIVW = 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 (ORIVW = 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.
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.
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.
CLC number: R734.2, Document code: A
The authors reported no conflict of interests.
| [1] |
Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023[J]. CA Cancer J Clin, 2023, 73(1): 17–48. doi: 10.3322/caac.21763
|
| [2] |
Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2017, 28(S4): iv1–iv21. https://pubmed.ncbi.nlm.nih.gov/28881918/
|
| [3] |
Hirsch FR, Scagliotti GV, Mulshine JL, et al. Lung cancer: Current therapies and new targeted treatments[J]. Lancet, 2017, 389(10066): 299–311. doi: 10.1016/S0140-6736(16)30958-8
|
| [4] |
Garon EB, Hellmann MD, Rizvi NA, et al. Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: Results from the phase Ⅰ KEYNOTE-001 study[J]. J Clin Oncol, 2019, 37(28): 2518–2527. doi: 10.1200/JCO.19.00934
|
| [5] |
Krashin E, Piekiełko-Witkowska A, Ellis M, et al. Thyroid hormones and cancer: A comprehensive review of preclinical and clinical studies[J]. Front Endocrinol (Lausanne), 2019, 10: 59. doi: 10.3389/fendo.2019.00059
|
| [6] |
Chi HC, Chen C, Tsai MM, et al. Molecular functions of thyroid hormones and their clinical significance in liver-related diseases[J]. Biomed Res Int, 2013, 2013: 601361. https://pubmed.ncbi.nlm.nih.gov/23878812/
|
| [7] |
Liu YC, Yeh CT, Lin KH. Molecular functions of thyroid hormone signaling in regulation of cancer progression and anti-apoptosis[J]. Int J Mol Sci, 2019, 20(20): 4986. doi: 10.3390/ijms20204986
|
| [8] |
Journy NMY, Bernier MO, Doody MM, et al. Hyperthyroidism, hypothyroidism, and cause-specific mortality in a large cohort of women[J]. Thyroid, 2017, 27(8): 1001–1010. doi: 10.1089/thy.2017.0063
|
| [9] |
Rinaldi S, Plummer M, Biessy C, et al. Thyroid-stimulating hormone, thyroglobulin, and thyroid hormones and risk of differentiated thyroid carcinoma: The EPIC study[J]. J Natl Cancer Inst, 2014, 106(6): dju097. doi: 10.1093/jnci/dju097
|
| [10] |
Khan SR, Chaker L, Ruiter R, et al. Thyroid function and cancer risk: The rotterdam study[J]. J Clin Endocrinol Metab, 2016, 101(12): 5030–5036. doi: 10.1210/jc.2016-2104
|
| [11] |
Tran TVT, Kitahara CM, de Vathaire F, et al. Thyroid dysfunction and cancer incidence: A systematic review and meta-analysis[J]. Endocr Relat Cancer, 2020, 27(4): 245–259. doi: 10.1530/ERC-19-0417
|
| [12] |
Chan YX, Knuiman MW, Divitini ML, et al. Lower TSH and higher free thyroxine predict incidence of prostate but not breast, colorectal or lung cancer[J]. Eur J Endocrinol, 2017, 177(4): 297–308. doi: 10.1530/EJE-17-0197
|
| [13] |
Jorde R, Sundsfjord J. Serum TSH levels in smokers and non-smokers. The 5th Tromsø study[J]. Exp Clin Endocrinol Diabetes, 2006, 114(7): 343–347. doi: 10.1055/s-2006-924264
|
| [14] |
Fisher CL, Mannino DM, Herman WH, et al. Cigarette smoking and thyroid hormone levels in males[J]. Int J Epidemiol, 1997, 26(5): 972–977. doi: 10.1093/ije/26.5.972
|
| [15] |
Prummel MF, Wiersinga WM. Smoking and risk of Graves' disease[J]. JAMA, 1993, 269(4): 479–482. doi: 10.1001/jama.1993.03500040045034
|
| [16] |
Gruppen EG, Kootstra-Ros J, Kobold AM, et al. Cigarette smoking is associated with higher thyroid hormone and lower TSH levels: The PREVEND study[J]. Endocrine, 2020, 67(3): 613–622. doi: 10.1007/s12020-019-02125-2
|
| [17] |
Sekula P, Del Greco MF, Pattaro C, et al. Mendelian randomization as an approach to assess causality using observational data[J]. J Am Soc Nephrol, 2016, 27(11): 3253–3265. doi: 10.1681/ASN.2016010098
|
| [18] |
Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians[J]. BMJ, 2018, 362: k601. https://pubmed.ncbi.nlm.nih.gov/30002074/
|
| [19] |
Swanson SA, Tiemeier H, Ikram MA, et al. Nature as a trialist?: Deconstructing the analogy between Mendelian randomization and randomized trials[J]. Epidemiology, 2017, 28(5): 653–659. doi: 10.1097/EDE.0000000000000699
|
| [20] |
Sudlow C, Gallacher J, Allen N, et al. UK Biobank: An open access resource for identifying the causes of a wide range of complex diseases of middle and old age[J]. PLoS Med, 2015, 12(3): e1001779. doi: 10.1371/journal.pmed.1001779
|
| [21] |
Psaty BM, O'Donnell CJ, Gudnason V, et al. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts[J]. Circ: Cardiovasc Genet, 2009, 2(1): 73–80. doi: 10.1161/CIRCGENETICS.108.829747
|
| [22] |
Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population[J]. Nature, 2023, 613(7944): 508–518. doi: 10.1038/s41586-022-05473-8
|
| [23] |
Teumer A, Chaker L, Groeneweg S, et al. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation[J]. Nat Commun, 2018, 9(1): 4455. doi: 10.1038/s41467-018-06356-1
|
| [24] |
Zhou W, Brumpton B, Kabil O, et al. GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer[J]. Nat Commun, 2020, 11(1): 3981. doi: 10.1038/s41467-020-17718-z
|
| [25] |
Saunders GRB, Wang X, Chen F, et al. Genetic diversity fuels gene discovery for tobacco and alcohol use[J]. Nature, 2022, 612(7941): 720–724. doi: 10.1038/s41586-022-05477-4
|
| [26] |
Wootton RE, Richmond RC, Stuijfzand BG, et al. Evidence for causal effects of lifetime smoking on risk for depression and schizophrenia: A Mendelian randomisation study[J]. Psychol Med, 2020, 50(14): 2435–2443. doi: 10.1017/S0033291719002678
|
| [27] |
McKay JD, Hung RJ, Han Y, et al. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes[J]. Nat Genet, 2017, 49(7): 1126–1132. doi: 10.1038/ng.3892
|
| [28] |
Chang CC, Chow CC, Tellier LC, et al. Second-generation PLINK: Rising to the challenge of larger and richer datasets[J]. GigaScience, 2015, 4: 7. doi: 10.1186/s13742-015-0047-8
|
| [29] |
Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data[J]. Genet Epidemiol, 2013, 37(7): 658–665. doi: 10.1002/gepi.21758
|
| [30] |
Waterworth DM, Ricketts SL, Song K, et al. Genetic variants influencing circulating lipid levels and risk of coronary artery disease[J]. Arterioscler Thromb Vasc Biol, 2010, 30(11): 2264–2276. doi: 10.1161/ATVBAHA.109.201020
|
| [31] |
Bowden J, Spiller W, Del Greco MF, et al. Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and Radial regression[J]. Int J Epidemiol, 2018, 47(6): 2100. doi: 10.1093/ije/dyy265
|
| [32] |
Zhu Z, Zheng Z, Zhang F, et al. Causal associations between risk factors and common diseases inferred from GWAS summary data[J]. Nat Commun, 2018, 9(1): 224. doi: 10.1038/s41467-017-02317-2
|
| [33] |
Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases[J]. Nat Genet, 2018, 50(5): 693–698. doi: 10.1038/s41588-018-0099-7
|
| [34] |
Mounier N, Kutalik Z. Bias correction for inverse variance weighting Mendelian randomization[J]. Genet Epidemiol, 2023, 47(4): 314–331. doi: 10.1002/gepi.22522
|
| [35] |
Carter AR, Sanderson E, Hammerton G, et al. Mendelian randomisation for mediation analysis: Current methods and challenges for implementation[J]. Eur J Epidemiol, 2021, 36(5): 465–478. doi: 10.1007/s10654-021-00757-1
|
| [36] |
Xin J, Jiang X, Ben S, et al. Association between circulating vitamin E and ten common cancers: Evidence from large-scale Mendelian randomization analysis and a longitudinal cohort study[J]. BMC Med, 2022, 20(1): 168. doi: 10.1186/s12916-022-02366-5
|
| [37] |
Benjamini, Y, Hochberg Y. Controlling the false discovery rate: A practical and powerful approach to multiple testing[J]. J R Stat Soc Series B (Methodological), 1995, 57(1): 289–300. https://sites.duke.edu/workblog/files/2014/09/benjamini_hochberg1995.pdf
|
| [38] |
Gómez-Izquierdo J, Filion KB, Boivin JF, et al. Subclinical hypothyroidism and the risk of cancer incidence and cancer mortality: A systematic review[J]. BMC Endocr Disord, 2020, 20(1): 83. doi: 10.1186/s12902-020-00566-9
|
| [39] |
Hellevik AI, Asvold BO, Bjøro T, et al. Thyroid function and cancer risk: A prospective population study[J]. Cancer Epidemiol Biomarkers Prev, 2009, 18(2): 570–574. doi: 10.1158/1055-9965.EPI-08-0911
|
| [40] |
Angelousi AG, Anagnostou VK, Stamatakos MK, et al. Mechanisms in endocrinology: Primary HT and risk for breast cancer: a systematic review and meta-analysis[J]. Eur J Endocrinol, 2012, 166(3): 373–381. doi: 10.1530/EJE-11-0838
|
| [41] |
L'Heureux A, Wieland DR, Weng CH, et al. Association between thyroid disorders and colorectal cancer risk in adult patients in Taiwan[J]. JAMA Netw Open, 2019, 2(5): e193755. doi: 10.1001/jamanetworkopen.2019.3755
|
| [42] |
Wiersinga WM. Smoking and thyroid[J]. Clin Endocrinol (Oxf), 2013, 79(2): 145–151. doi: 10.1111/cen.12222
|
| [43] |
Knight BA, Shields BM, He X, et al. Effect of perchlorate and thiocyanate exposure on thyroid function of pregnant women from South-West England: A cohort study[J]. Thyroid Res, 2018, 11: 9. doi: 10.1186/s13044-018-0053-x
|
| [44] |
Erdoǧan MF. Thiocyanate overload and thyroid disease[J]. Biofactors, 2003, 19(3-4): 107–111. doi: 10.1002/biof.5520190302
|
| [45] |
Sawicka-Gutaj N, Gutaj P, Sowinski J, et al. Influence of cigarette smoking on thyroid gland-an update[J]. Endokrynol Pol, 2014, 65(1): 54–62. https://pubmed.ncbi.nlm.nih.gov/24549603/
|
| [46] |
Wang X, Liu X, Li Y, et al. The causal relationship between thyroid function, autoimune thyroid dysfunction and lung cancer: a mendelian randomization study[J]. BMC Pulm Med, 2023, 23(1): 338. doi: 10.1186/s12890-023-02588-0
|
| [47] |
Luo J, Martucci VL, Quandt Z, et al. Immunotherapy-mediated thyroid dysfunction: Genetic risk and impact on outcomes with PD-1 blockade in non-small cell lung cancer[J]. Clin Cancer Res, 2021, 27(18): 5131–5140. doi: 10.1158/1078-0432.CCR-21-0921
|
| [48] |
Wang L, He W, Xu X, et al. Pathological changes and oxidative stress of the HPG axis in hypothyroid rat[J]. J Mol Endocrinol, 2021, 67(3): 107–119. doi: 10.1530/JME-21-0095
|
| [49] |
Nanda N, Bobby Z, Hamide A. Oxidative stress and protein glycation in primary hypothyroidism. Male/female difference[J]. Clin Exp Med, 2008, 8(2): 101–108. doi: 10.1007/s10238-008-0164-0
|
| [50] |
Peixoto MS, de Vasconcelos ESA, Andrade IS, et al. Hypothyroidism induces oxidative stress and DNA damage in breast[J]. Endocr Relat Cancer, 2021, 28(7): 505–519. doi: 10.1530/ERC-21-0010
|
| [51] |
Azad N, Rojanasakul Y, Vallyathan V. Inflammation and lung cancer: Roles of reactive oxygen/nitrogen species[J]. J Toxicol Environ Health B Crit Rev, 2008, 11(1): 1–15. doi: 10.1080/10937400701436460
|
| [52] |
Reczek CR, Chandel NS. The two faces of reactive oxygen species in cancer[J]. Annu Rev Cancer Biol, 2017, 1: 79–98. doi: 10.1146/annurev-cancerbio-041916-065808
|
| [53] |
Kometani T, Yoshino I, Miura N, et al. Benzo[a]pyrene promotes proliferation of human lung cancer cells by accelerating the epidermal growth factor receptor signaling pathway[J]. Cancer Lett, 2009, 278(1): 27–33. doi: 10.1016/j.canlet.2008.12.017
|
| [54] |
Weinberg F, Hamanaka R, Wheaton WW, et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity[J]. Proc Natl Acad Sci U S A, 2010, 107(19): 8788–8793. doi: 10.1073/pnas.1003428107
|
| [55] |
Wu SY, Green WL, Huang W, et al. Alternate pathways of thyroid hormone metabolism[J]. Thyroid, 2005, 15(8): 943–958. doi: 10.1089/thy.2005.15.943
|
| [56] |
Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions[J]. Endocr Rev, 2010, 31(2): 139–170. doi: 10.1210/er.2009-0007
|
| [57] |
Davis PJ, Leonard JL, Davis FB. Mechanisms of nongenomic actions of thyroid hormone[J]. Front Neuroendocrinol, 2008, 29(2): 211–218. doi: 10.1016/j.yfrne.2007.09.003
|
| [58] |
Schmohl KA, Müller AM, Wechselberger A, et al. Thyroid hormones and tetrac: New regulators of tumour stroma formation via integrin αvβ3[J]. Endocr Relat Cancer, 2015, 22(6): 941–952. doi: 10.1530/ERC-15-0245
|
| [59] |
Schmohl KA, Nelson PJ, Spitzweg C. Tetrac as an anti-angiogenic agent in cancer[J]. Endocr Relat Cancer, 2019, 26(6): R287–R304. doi: 10.1530/ERC-19-0058
|
| [60] |
Davis PJ, Mousa SA, Lin HY. Nongenomic actions of thyroid hormone: The integrin component[J]. Physiol Rev, 2021, 101(1): 319–352. doi: 10.1152/physrev.00038.2019
|
| [61] |
Mousa SA, Yalcin M, Bharali DJ, et al. Tetraiodothyroacetic acid and its nanoformulation inhibit thyroid hormone stimulation of non-small cell lung cancer cells in vitro and its growth in xenografts[J]. Lung Cancer, 2012, 76(1): 39–45. doi: 10.1016/j.lungcan.2011.10.003
|
| [1] | I. M. Elzein, Ashraf. Chamseddine, Ahmad. Eltanboly, Adam Elzein. Cervical cancer perceived risk factors behavior using logistic regression technique[J]. The Journal of Biomedical Research. DOI: 10.7555/JBR.39.20250047 |
| [2] | Ting Liu, Jingjing Gu, Chuning Li, Mengfan Guo, Lin Yuan, Qiang Lv, Chao Qin, Mulong Du, Haiyan Chu, Hanting Liu, Zhengdong Zhang. Alternative polyadenylation-related genetic variants contribute to bladder cancer risk[J]. The Journal of Biomedical Research, 2023, 37(6): 405-417. DOI: 10.7555/JBR.37.20230063 |
| [3] | Jia Meiqun, Ren Lulu, Hu Lingmin, Ma Hongxia, Jin Guangfu, Li Dake, Li Ni, Hu Zhibin, Hang Dong. Association of long non-coding RNA HOTAIR and MALAT1 variants with cervical cancer risk in Han Chinese women[J]. The Journal of Biomedical Research, 2019, 33(5): 308-316. DOI: 10.7555/JBR.33.20180096 |
| [4] | Huanqiang Wang, Congying Yang, Siyuan Wang, Tian Wang, Jingling Han, Kai Wei, Fucun Liu, Jida Xu, Xianzhen Peng, Jianming Wang. Cell-free plasma hypermethylated CASZ1, CDH13 and ING2 are promising biomarkers of esophageal cancer[J]. The Journal of Biomedical Research, 2018, 32(6): 424-433. DOI: 10.7555/JBR.32.20170065 |
| [5] | Christopher J. Danford, Zemin Yao, Z. Gordon Jiang. Non-alcoholic fatty liver disease: a narrative review of genetics[J]. The Journal of Biomedical Research, 2018, 32(6): 389-400. DOI: 10.7555/JBR.32.20180045 |
| [6] | Anna Karolina Zuk, Xuesong Wen, Stephen Dilworth, Dong Li, Lucy Ghali. Modeling and validating three dimensional human normal cervix and cervical cancer tissues in vitro[J]. The Journal of Biomedical Research, 2017, 31(3): 240-247. DOI: 10.7555/JBR.31.20160150 |
| [7] | Il-Seok Lee, Sung Pil Seo, Yun Sok Ha, Pildu Jeong, Ho Won Kang, Won Tae Kim, YongJune Kim, Seok Joong Yun, Sang Cheol Lee, Wun-Jae Kim. Genetic variation of the PSCA gene (rs2294008) is not associated with the risk of prostate cancer[J]. The Journal of Biomedical Research, 2017, 31(3): 226-231. DOI: 10.7555/JBR.31.20160072 |
| [8] | Sijun Liu, Yun Qian, Feng Lu, Meihua Dong, Yudi Lin, Huizhang Li, Chong Shen, Juncheng Dai, Yue Jiang, Guangfu Jin, Zhibin Hu, Hongbing Shen. Genetic variants at 10q23.33 are associated with plasma lipid levels in a Chinese population[J]. The Journal of Biomedical Research, 2014, 28(1): 53-58. DOI: 10.7555/JBR.27.20120091 |
| [9] | Haiyan Chu, Meilin Wang, Zhengdong Zhang. Bladder cancer epidemiology and genetic susceptibility[J]. The Journal of Biomedical Research, 2013, 27(3): 170-178. DOI: 10.7555/JBR.27.20130026 |
| [10] | Guojun Li, Zhigang Huang, Xingming Chen, Qingyi Wei. Role of human papillomavirus and cell cycle-related variants in squamous cell carcinoma of the oropharynx[J]. The Journal of Biomedical Research, 2010, 24(5): 339-346. DOI: 10.1016/S1674-8301(10)60047-4 |
Figures(5) / Tables(1)
Supported by: Beijing Renhe Information Technology Co., Ltd. E-mail:
info@rhhz.net 
Authors and Reviewers
DownLoad: