Mendelian randomization to investigate the link between TSH and thyroid cancer

in Endocrine-Related Cancer
View More View Less
  • 1 Head and Neck Surgery, Royal Devon and Exeter Hospital, Exeter, Devon, UK
  • | 2 Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, Devon, UK
  • | 3 Endocrinology, Royal Devon and Exeter Hospital, Exeter, Devon, UK

Correspondence should be addressed to J M Fussey: jfussey@doctors.org.uk
Restricted access

Evidence from observational studies suggests a positive association between serum thyroid-stimulating hormone (TSH) levels and differentiated thyroid carcinoma. However, the cause-effect relationship is poorly understood, and these studies are susceptible to bias and confounding. Using Mendelian randomization (MR) methodology, this study aimed to investigate the causal role of TSH in both benign thyroid nodules and thyroid cancer in up to 451,025 participants in the UK Biobank. Hospital Episode Statistics and Cancer Registry databases were used to identify 462 patients with differentiated thyroid carcinoma and 2031 patients with benign nodular thyroid disease. MR methods using genetic variants associated with serum TSH were used to test causal relationships between TSH and the two disease outcomes. We observed evidence of an inverse association between TSH levels and both thyroid cancer and benign nodular thyroid disease. Two-sample MR suggested that one standard deviation higher genetically instrumented TSH (approximately 0.8 mlU/L) resulted in an 80% reduction of risk of benign nodular disease (OR 0.20; 95% CI 0.10–0.41) and a 50% reduction of risk of thyroid cancer (OR 0.50; 95% CI 0.27–0.92). In keeping with other recently published studies, our results refute a causal role for TSH in both benign nodular thyroid disease and thyroid cancer, with increasing genetically instrumented TSH resulting in a lower risk of both diseases.

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 561 561 149
Full Text Views 32 32 1
PDF Downloads 58 58 2
  • Bowden J, Del Greco F, Minelli C, Davey Smith G, Sheehan NA & Thompson JR 2016 Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic. International Journal of Epidemiology 45 19611974. (https://doi.org/10.1093/ije/dyw220)

    • Search Google Scholar
    • Export Citation
  • Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, Motyer A, Vukcevic D, Delaneau O, O’Connell J, et al. 2018 The UK Biobank resource with deep phenotyping and genomic data. Nature 562 203209. (https://doi.org/10.1038/s41586-018-0579-z)

    • Search Google Scholar
    • Export Citation
  • Collins R 2012 What makes UK Biobank special? Lancet 379 11731174. (https://doi.org/10.1016/s0140-6736(12)60404-8)

  • Davey Smith GD & Ebrahim S 2003 ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? International Journal of Epidemiology 32 122. (https://doi.org/10.1093/ije/dyg070)

    • Search Google Scholar
    • Export Citation
  • Fussey JM, Beaumont RN, Wood AR, Vaidya B, Smith J & Tyrrell J 2020 Mendelian randomization supports a causative effect of TSH on thyroid carcinoma. Endocrine-Related Cancer 27 55155 9. (https://doi.org/10.1530/ERC-20-0067)

    • Search Google Scholar
    • Export Citation
  • Loh PR, Tucker G, Bulik-Sullivan BK, Vilhjálmsson BJ, Finucane HK, Salem RM, Chasman DI, Ridker PM, Neale BM, Berger B, et al. 2015 Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nature Genetics 47 284290. (https://doi.org/10.1038/ng.3190)

    • Search Google Scholar
    • Export Citation
  • McLeod DS, Watters KF, Carpenter AD, Ladenson PW, Cooper DS & Ding EL 2012 Thyrotropin and thyroid cancer diagnosis: a systematic review and dose-response meta-analysis. Journal of Clinical Endocrinology and Metabolism 97 268226 92. (https://doi.org/10.1210/jc.2012-1083)

    • Search Google Scholar
    • Export Citation
  • Porcu E, Medici M, Pistis G, Volpato CB, Wilson SG, Cappola AR, Bos SD, Deelen J, den Heijer M, Freathy RM, et al.2013 A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLoS Genetics 9 e1003266. (https://doi.org/10.1371/journal.pgen.1003266)

    • Search Google Scholar
    • Export Citation
  • Rinaldi S, Plummer M, Biessy C, Tsilidis KK, Østergaard JN, Overvad K, Tjønneland A, Halkjær J, Boutron-Ruault MC, Clavel-Chapelon F, et al.2014 Thyroid-stimulating hormone, thyroglobulin, and thyroid hormones and risk of differentiated thyroid carcinoma: the EPIC study. Journal of the National Cancer Institute 106 dju097. (https://doi.org/10.1093/jnci/dju097)

    • Search Google Scholar
    • Export Citation
  • Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, Downey P, Elliott P, Green J, Landray M & Liu B 2015 UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Medicine 12 e1001779. (https://doi.org/10.1371/journal.pmed.1001779)

    • Search Google Scholar
    • Export Citation
  • Yuan S, Kar S, Vithayathil M, Carter P, Mason AM, Burgess S & Larsson SC 2020 Causal associations of thyroid function and dysfunction with overall, breast and thyroid cancer: a two-sample Mendelian randomization study. International Journal of Cancer 147 1 8951903.(https://doi.org/10.1002/ijc.32988)

    • Search Google Scholar
    • Export Citation
  • Zhou W, Brumpton B, Kabil O, Gudmundsson J, Thorleifsson G, Weinstock J, Zawistowski M, Nielsen JB, Chaker L, Medici M, et al.2020 GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer. Nature Communications 7 13.(https://doi.org/10.1038/s41467-020-17718-z)

    • Search Google Scholar
    • Export Citation