Thyroiditis and human blood metabolites: a Mendelian randomization study

Thyroiditis and Blood Metabolites: A Mendelian Study

  • Lijie Shao College of Integrated Traditional Chinese and Western Medicine, Changchun University of Chinese Medicine
  • Siqi Liu Precision Medicine Center, Jilin Province People's Hospital
  • Yongfu Song College of Integrated Traditional Chinese and Western Medicine, Changchun University of Chinese Medicine
  • Shaoyu Han Shanghai Lixin University of Accounting and Finance
  • Yue Ma College of Integrated Traditional Chinese and Western Medicine, Changchun University of Chinese Medicine
  • Kunpeng Yang College of Integrated Traditional Chinese and Western Medicine, Changchun University of Chinese Medicine
  • Jingbin Zhang Precision Medicine Center, Jilin Province People's Hospital
  • Bingxue Qi Precision Medicine Center, Jilin Province People's Hospital
  • Yan Guo College of Integrated Traditional Chinese and Western Medicine, Changchun University of Chinese Medicine
  • Xiaodan Lu College of Integrated Traditional Chinese and Western Medicine, Changchun University of Chinese Medicine
DOI: https://doi.org/10.5937/jomb0-56217
Keywords: autoimmune thyroiditis, subacute thyroiditis, mendelian randomization analysis, metabolites

Abstract


Background: The risk factors for thyroiditis, an inflammatory disease with a complex etiology, remain poorly understood. Blood metabolites are known to change during thyroiditis development, suggesting a close relationship between blood metabolites and thyroiditis progression. However, evidence for a causal link is lacking. We employed Mendelian randomization (MR) methodology to systematically investigate the putative causal relationships between blood metabolite profiles and two clinically distinct thyroiditis phenotypes—subacute and autoimmune thyroiditis—providing insights into their metabolic underpinnings.

Methods: We analyzed genomic and health data from 88 million Finnish Biobank participants in the Genome-Wide Association Study (GWAS). The primary analytical method was random-effects inverse variance weighting (IVW), supplemented by the weighted median method (WME) and MR-Egger. We implemented comprehensive sensitivity analyses encompassing Cochran's Q test, MR-Egger intercept, leave-one-out analysis (LOO), and MR-PRESSO to assess heterogeneity, pleiotropy, and outliers. Extended genetic investigations incorporated the linkage disequilibrium score regression (LDSC) method, multivariable MR (MVMR), and metabolic pathway analyses to provide deeper mechanistic insights.

Results: Ten metabolites were significantly associated with autoimmune thyroiditis, and fifteen with subacute thyroiditis. Nonadecanoate (19:0) and 1-palmitoylglycerophosphoinositol* were found to directly affect subacute thyroiditis. MVMR analyses identified pelargonate (9:0), carnitine, and ADpSGEGDFXAEGGGVR* as having an independent and direct effect on autoimmune thyroiditis. Additionally, metabolic pathways such as neomycin, kanamycin, and gentamicin biosynthesis, histidine metabolism, and starch and sucrose metabolism were linked to autoimmune thyroiditis, while phenylalanine, tyrosine, tryptophan biosynthesis, phenylalanine metabolism, and arginine biosynthesis were associated with subacute thyroiditis.

Conclusion: Our findings establish causal relationships between circulating metabolites and thyroiditis, revealing novel mechanistic insights through integrated genomic and metabolomic analyses. These results not only advance our understanding of thyroiditis pathogenesis but also suggest potential biomarkers for disease screening and therapeutic targets for intervention.

References

1. Li Q, Yang W, Li J, Shan Z. Emerging trends and hot spots in autoimmune thyroiditis research from 2000 to 2022: A bibliometric analysis. Front Immunol 2022; 13: 953465.
2. Sweeney LB, Stewart C, Gaitonde DY. Thyroiditis: an integrated approach. Am Fam Physician 2014; 90(6): 389-96.
3. Conrad N, Misra S, Verbakel JY, Verbeke G, Molenberghs G, Taylor PN, et al. Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK. Lancet 2023; 401(10391): 1878-90.
4. Benvenga S, Elia G, Ragusa F, Paparo SR, Sturniolo MM, Ferrari SM, et al. Endocrine disruptors and thyroid autoimmunity. Best Pract Res Cl En 2020; 34(1): 101377.
5. Hu Y, Yao Z, Wang G. The Relationship Between the Impairment of Endothelial Function and Thyroid Antibodies in Hashimoto's Thyroiditis Patients with Euthyroidism. Horm Metab Res 2020; 52(9): 642-6.
6. Birney E. Mendelian Randomization. Csh Perspect Med 2022; 12(4):
7. Wang Q, Dai H, Hou T, Hou Y, Wang T, Lin H, et al. Dissecting Causal Relationships Between Gut Microbiota, Blood Metabolites, and Stroke: A Mendelian Randomization Study. J Stroke 2023; 25(3): 350-60.
8. Zhao SS, Holmes MV, Alam U. Chronic pain is associated with higher risk of developing and being hospitalized for COVID-19: a Mendelian randomization study. Rheumatology 2022; 61(SI2): SI189-90.
9. Wan B, Lu L, Lv C. Mendelian randomization study on the causal relationship between leukocyte telomere length and prostate cancer. Plos One 2023; 18(6): e0286219.
10. Cayres L, de Salis L, Rodrigues G, Lengert A, Biondi A, Sargentini L, et al. Detection of Alterations in the Gut Microbiota and Intestinal Permeability in Patients With Hashimoto Thyroiditis. Front Immunol 2021; 12: 579140.
11. Jiang W, Lu G, Gao D, Lv Z, Li D. The relationships between the gut microbiota and its metabolites with thyroid diseases. Front Endocrinol 2022; 13: 943408.
12. Larsson SC, Butterworth AS, Burgess S. Mendelian randomization for cardiovascular diseases: principles and applications. Eur Heart J 2023; 44(47): 4913-24.
13. Cai J, Li X, Wu S, Tian Y, Zhang Y, Wei Z, et al. Assessing the causal association between human blood metabolites and the risk of epilepsy. J Transl Med 2022; 20(1): 437.
14. Shin SY, Fauman EB, Petersen AK, Krumsiek J, Santos R, Huang J, et al. An atlas of genetic influences on human blood metabolites. Nat Genet 2014; 46(6): 543-50.
15. Kanehisa M. Molecular network analysis of diseases and drugs in KEGG. Methods Mol Biol 2013; 939: 263-75.
16. Burgess S, Scott RA, Timpson NJ, Davey SG, Thompson SG. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol 2015; 30(7): 543-52.
17. Bowden J, Davey SG, Haycock PC, Burgess S. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol 2016; 40(4): 304-14.
18. Bowden J, Davey SG, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol 2015; 44(2): 512-25.
19. Cohen JF, Chalumeau M, Cohen R, Korevaar DA, Khoshnood B, Bossuyt PM. Cochran's Q test was useful to assess heterogeneity in likelihood ratios in studies of diagnostic accuracy. J Clin Epidemiol 2015; 68(3): 299-306.
20. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol 2017; 32(5): 377-89.
21. Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet 2018; 50(5): 693-8.
22. Zheng J, Erzurumluoglu AM, Elsworth BL, Kemp JP, Howe L, Haycock PC, et al. LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis. Bioinformatics 2017; 33(2): 272-9.
23. Sanderson E, Davey SG, Windmeijer F, Bowden J. An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings. Int J Epidemiol 2019; 48(3): 713-27.
24. Burgess S, Thompson SG. Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects. Am J Epidemiol 2015; 181(4): 251-60.
25. Bodor M, Mezosi E. Editorial: Thyroid function and its interaction with metabolic molecules. Front Endocrinol 2023; 14: 1249218.
26. Mondal S, Raja K, Schweizer U, Mugesh G. Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones. Angew Chem Int Edit 2016; 55(27): 7606-30.
27. Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev 2014; 94(2): 355-82.
28. Delitala AP, Fanciulli G, Maioli M, Delitala G. Subclinical hypothyroidism, lipid metabolism and cardiovascular disease. Eur J Intern Med 2017; 38: 17-24.
29. Pleic N, Gunjaca I, Babic LM, Zemunik T. Thyroid Function and Metabolic Syndrome: A Two-Sample Bidirectional Mendelian Randomization Study. J Clin Endocr Metab 2023; 108(12): 3190-200.
30. Wang JJ, Zhuang ZH, Shao CL, Yu CQ, Wang WY, Zhang K, et al. Assessment of causal association between thyroid function and lipid metabolism: a Mendelian randomization study. Chinese Med J-Peking 2021; 134(9): 1064-9.
31. Gutch M, Rungta S, Kumar S, Agarwal A, Bhattacharya A, Razi SM. Thyroid functions and serum lipid profile in metabolic syndrome. Biomed J 2017; 40(3): 147-53.
32. Li M, Yang X, Li R, Wu B, Hao J, Qi Y, et al. Visceral Fat Area and Subcutaneous Fat Area Increase in Hyperthyroidism Patients After Treatment-A Single-Group Repeated-Measures Trial. Diabet Metab Synd Ob 2024; 17: 2165-76.
33. Mendoza-Leon MJ, Mangalam AK, Regaldiz A, Gonzalez-Madrid E, Rangel-Ramirez MA, Alvarez-Mardonez O, et al. Gut microbiota short-chain fatty acids and their impact on the host thyroid function and diseases. Front Endocrinol 2023; 14: 1192216.
34. Benvenga S, Feldt-Rasmussen U, Bonofiglio D, Asamoah E. Nutraceutical Supplements in the Thyroid Setting: Health Benefits beyond Basic Nutrition. Nutrients 2019; 11(9):
35. Carillo MR, Bertapelle C, Scialo F, Siervo M, Spagnuolo G, Simeone M, et al. L-Carnitine in Drosophila: A Review. Antioxidants-Basel 2020; 9(12):
36. Louet JF, Le May C, Pegorier JP, Decaux JF, Girard J. Regulation of liver carnitine palmitoyltransferase I gene expression by hormones and fatty acids. Biochem Soc T 2001; 29(Pt 2): 310-6.
37. Galland S, Georges B, Le Borgne F, Conductier G, Dias JV, Demarquoy J. Thyroid hormone controls carnitine status through modifications of gamma-butyrobetaine hydroxylase activity and gene expression. Cell Mol Life Sci 2002; 59(3): 540-5.
38. Benvenga S, Lakshmanan M, Trimarchi F. Carnitine is a naturally occurring inhibitor of thyroid hormone nuclear uptake. Thyroid 2000; 10(12): 1043-50.
39. Sinclair C, Gilchrist JM, Hennessey JV, Kandula M. Muscle carnitine in hypo- and hyperthyroidism. Muscle Nerve 2005; 32(3): 357-9.
40. An JH, Kim YJ, Kim KJ, Kim SH, Kim NH, Kim HY, et al. L-carnitine supplementation for the management of fatigue in patients with hypothyroidism on levothyroxine treatment: a randomized, double-blind, placebo-controlled trial. Endocr J 2016; 63(10): 885-95.
41. Barington M, Brorson MM, Hofman-Bang J, Rasmussen AK, Holst B, Feldt-Rasmussen U. Ghrelin-mediated inhibition of the TSH-stimulated function of differentiated human thyrocytes ex vivo. Plos One 2017; 12(9): e0184992.
42. Michalek K, Morshed SA, Latif R, Davies TF. TSH receptor autoantibodies. Autoimmun Rev 2009; 9(2): 113-6.
43. Rastoldo G, Tighilet B. Thyroid Axis and Vestibular Physiopathology: From Animal Model to Pathology. Int J Mol Sci 2023; 24(12):
44. Shpakov AO, Shpakova EA, Tarasenko II, Derkach KV. (Peptide 612-627 of thyrotropin receptor and its modified derivatives as the regulators of adenylyl cyclase in the rat thyroid gland). Tsitologiia 2014; 56(7): 526-35.
45. Karras E, Yang H, Lymberi P, Christadoss P. Human thyroglobulin peptide p2340 induces autoimmune thyroiditis in HLA-DR3 transgenic mice. J Autoimmun 2005; 24(4): 291-6.
46. Li CW, Osman R, Menconi F, Concepcion ES, Tomer Y. Flexible peptide recognition by HLA-DR triggers specific autoimmune T-cell responses in autoimmune thyroiditis and diabetes. J Autoimmun 2017; 76: 1-9.
47. Xiao H, Liang J, Liu S, Zhang Q, Xie F, Kong X, et al. Proteomics and Organoid Culture Reveal the Underlying Pathogenesis of Hashimoto's Thyroiditis. Front Immunol 2021; 12: 784975.
48. Jacobson EM, Huber A, Tomer Y. The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology. J Autoimmun 2008; 30(1-2): 58-62.
Published
2025/03/06
Issue
Vol. 44 No. 4 (2025): Journal of Medical Biochemistry
Section
Original paper

Copyright (c) 2025 Lijie Shao, Siqi Liu, Yongfu Song, Shaoyu Han, Yue Ma, Kunpeng Yang, Jingbin Zhang, Bingxue Qi, Yan Guo, Xiaodan Lu

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

The published articles will be distributed under the Creative Commons Attribution 4.0 International License (CC BY). It is allowed to copy and redistribute the material in any medium or format, and remix, transform, and build upon it for any purpose, even commercially, as long as appropriate credit is given to the original author(s), a link to the license is provided and it is indicated if changes were made. Users are required to provide full bibliographic description of the original publication (authors, article title, journal title, volume, issue, pages), as well as its DOI code. In electronic publishing, users are also required to link the content with both the original article published in Journal of Medical Biochemistry and the licence used.

Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.