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Causality of blood metabolites and metabolic pathways on Graves’ disease and Graves’ ophthalmopathy: a two-sample Mendelian randomization study

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Abstract

Objectives

There is ample that metabolic dysregulation is involved in Graves’ disease (GD) and Graves’ ophthalmopathy (GO). Recent studies have identified numerous metabolites associated with GD and GO. However, the causal impact of metabolites on GD and GO remains to be investigated.

Methods

This two-sample Mendelian randomization (MR) analysis investigated the causal relationships between 486 blood metabolites and GD and GO. Sensitivity analysis was also performed to examine heterogeneity and pleiotropy.

Results

MR analysis showed that 9 and 13 metabolites were associated with GD and GO, respectively, each meeting the nominal significance criteria (inverse variance weighted, p < 0.05). Additionally, four metabolic pathways were identified for each condition using network-based MetaboAnalyst 5.0.

Conclusions

The metabolites and pathways discovered in this study could serve as circulating metabolic biomarkers for clinical screening and prevention of GD and GO. They can be also used for further studies on the mechanisms and drug targets in GD and GO.

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References

  1. S.Y. Lee et al. Hyperthyroidism: A Review. JAMA 330(15), 1472–1483 (2023)

    Article  CAS  PubMed  Google Scholar 

  2. T.J. Smith et al. Graves’ Disease. N. Engl. J. Med. 375(16), 1552–1565 (2016)

    Article  PubMed  Google Scholar 

  3. T. Milo et al. Autoimmune thyroid diseases as a cost of physiological autoimmune surveillance. Trends Immunol. 44(5), 365–371 (2023)

    Article  CAS  PubMed  Google Scholar 

  4. J. Cao et al. The risk factors for Graves’ ophthalmopathy. Graefes Arch. Clin. Exp. Ophthalmol. 260(4), 1043–1054 (2022)

    Article  PubMed  Google Scholar 

  5. L. Bartalena et al. Epidemiology, Natural History, Risk Factors, and Prevention of Graves’ Orbitopathy. Front Endocrinol. 11, 615993 (2020)

    Article  Google Scholar 

  6. R. Ma et al. Insights Into Ferroptosis: Targeting Glycolysis to Treat Graves’ Orbitopathy. J. Clin. Endocrinol. Metab. 107(7), 1994–2003 (2022)

    Article  PubMed  Google Scholar 

  7. X. Chen et al. Influence of 4-week or 12-week glucocorticoid treatment on metabolic changes in patients with active moderate-to-severe thyroid-associated ophthalmopathy. Clin. Transl. Sci. 14(5), 1734–1746 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. H.O. Ueland et al. Systemic Activation of the Kynurenine Pathway in Graves Disease With and Without Ophthalmopathy. J. Clin. Endocrinol. Metab. 108(6), 1290–1297 (2023)

    Article  PubMed  PubMed Central  Google Scholar 

  9. S.K. Byeon et al. Lipidomic differentiation of Graves’ ophthalmopathy in plasma and urine from Graves’ disease patients. Anal. Bioanal. Chem. 410(27), 7121–7133 (2018)

    Article  CAS  PubMed  Google Scholar 

  10. D.Y. Ji et al. Comparative assessment of Graves’ disease and main extrathyroidal manifestation, Graves’ ophthalmopathy, by non-targeted metabolite profiling of blood and orbital tissue. Sci. Rep. 8(1), 9262 (2018)

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  11. X. Zhang et al. Exploring blood metabolites and thyroid disorders: a bidirectional mendelian randomization study. Front Endocrinol. 14, 1270336 (2023)

    Article  Google Scholar 

  12. B.L. Pierce et al. Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am. J. Epidemiol. 178(7), 1177–1184 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  13. J. Bowden et al. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 40(4), 304–314 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  14. S. Burgess et al. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur. J. Epidemiol. 32(5), 377–389 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  15. A.F. Schmidt et al. Mendelian randomization with Egger pleiotropy correction and weakly informative Bayesian priors. Int J. Epidemiol. 47(4), 1217–1228 (2018)

    Article  CAS  PubMed  Google Scholar 

  16. C. Xue et al. Tryptophan metabolism in health and disease. Cell Metab. 35(8), 1304–1326 (2023)

    Article  CAS  PubMed  Google Scholar 

  17. Y. Chang et al. Tryptophan 2,3-dioxygenase 2 plays a key role in regulating the activation of fibroblast-like synoviocytes in autoimmune arthritis. Br. J. Pharm. 179(12), 3024–3042 (2022)

    Article  CAS  Google Scholar 

  18. K. Åkesson et al. Kynurenine pathway is altered in patients with SLE and associated with severe fatigue. Lupus Sci. Med. 5(1), e000254 (2018)

    Article  MathSciNet  PubMed  PubMed Central  Google Scholar 

  19. Y. Park et al. Kynurenine pathway can be a potential biomarker of fatigue in primary Sjögren’s syndrome. Clin. Exp. Rheumatol. 41(12), 2363–2370 (2023)

    PubMed  Google Scholar 

  20. T. Bögl et al. Plasma Metabolomic Profiling Reveals Four Possibly Disrupted Mechanisms in Systemic Sclerosis. Biomedicines 10(3), 607 (2022)

    Article  PubMed  PubMed Central  Google Scholar 

  21. S.M.T. Isık et al. Relationship of tryptophan metabolites with the type and severity of multiple sclerosis. Mult. Scler. Relat. Disord. 77, 104898 (2023)

    Article  PubMed  Google Scholar 

  22. A. Krupa et al. The Kynurenine Pathway-New Linkage between Innate and Adaptive Immunity in Autoimmune Endocrinopathies. Int J. Mol. Sci. 22(18), 9879 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. S.H. Chu et al. Circulating plasma metabolites and risk of rheumatoid arthritis in the Nurses’ Health Study. Rheumatology 59(11), 3369–3379 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. C. Chen et al. Metabolomic profiling reveals amino acid and carnitine alterations as metabolic signatures in psoriasis. Theranostics 11(2), 754–767 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. X. Cheng et al. Long-Chain Acylcarnitines Induce Senescence of Invariant Natural Killer T Cells in Hepatocellular Carcinoma. Cancer Res. 83(4), 582–594 (2023)

    Article  CAS  PubMed  Google Scholar 

  26. U. Wenzel et al. Increased mitochondrial palmitoylcarnitine/carnitine countertransport by flavone causes oxidative stress and apoptosis in colon cancer cells. Cell Mol. Life Sci. 62(24), 3100–3105 (2005)

    Article  CAS  PubMed  Google Scholar 

  27. M.C. Mutomba et al. Regulation of the activity of caspases by L-carnitine and palmitoylcarnitine. FEBS Lett. 478(1-2), 19–25 (2000)

    Article  CAS  PubMed  Google Scholar 

  28. B. Kisiel et al. Polymorphism of the oestrogen receptor beta gene (ESR2) is associated with susceptibility to Graves’ disease. Clin. Endocrinol. 68(3), 429–434 (2008)

    Article  CAS  Google Scholar 

  29. C.W. Cheng et al. Possible interplay between estrogen and the BAFF may modify thyroid activity in Graves’ disease. Sci. Rep. 11(1), 21350 (2021)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  30. A.M. FitzPatrick, Is Estrogen a Missing Culprit in Thyroid Eye Disease? Sex Steroid Hormone Homeostasis Is Key to Other Fibrogenic Autoimmune Diseases - Why Not This One? Front Immunol. 13, 898138 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. H.B. Burch et al. Superoxide radical production stimulates retroocular fibroblast proliferation in Graves’ ophthalmopathy. Exp. Eye Res 65(2), 311–316 (1997)

    Article  CAS  PubMed  Google Scholar 

  32. T. Mano et al. Changes in free radical scavengers and lipid peroxide in thyroid glands of various thyroid disorders. Horm. Metab. Res 29(7), 351–354 (1997)

    Article  CAS  PubMed  Google Scholar 

  33. R. Du et al. Metabolic features of orbital adipose tissue in patients with thyroid eye disease. Front. Endocrinol. 14, 1151757 (2023)

    Article  Google Scholar 

  34. J. Zhou et al. Detection and Correlation Analysis of Serum Uric Acid in Patients with Thyroid-Associated Ophthalmopathy. Comput. Math. Methods Med. 2022, 8406834 (2022)

    Article  PubMed  PubMed Central  Google Scholar 

  35. N.F. Marques et al. Guanosine Protects Striatal Slices Against 6-OHDA-Induced Oxidative Damage, Mitochondrial Dysfunction, and ATP Depletion. Neurotox. Res. 35(2), 475–483 (2019)

    Article  CAS  PubMed  Google Scholar 

  36. B. Bellaver et al. Guanosine inhibits LPS-induced pro-inflammatory response and oxidative stress in hippocampal astrocytes through the heme oxygenase-1 pathway. Purinergic. Signal 11(4), 571–580 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. L.E. Bettio et al. Guanosine prevents behavioral alterations in the forced swimming test and hippocampal oxidative damage induced by acute restraint stress. Pharm. Biochem. Behav. 127, 7–14 (2014)

    Article  CAS  Google Scholar 

  38. T.Y. Hou et al. The Role of Oxidative Stress and Therapeutic Potential of Antioxidants in Graves’ Ophthalmopathy. Biomedicines 9(12), 1871 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. C.C. Tsai et al. Increased oxidative DNA damage, lipid peroxidation, and reactive oxygen species in cultured orbital fibroblasts from patients with Graves’ ophthalmopathy: evidence that oxidative stress has a role in this disorder. Eye 24(9), 1520–1525 (2010)

    Article  CAS  PubMed  Google Scholar 

  40. J. Liu et al. Serum Metabolomic Patterns in Patients with Autoimmune Thyroid Disease. Endocr. Pr. 26(1), 82–96 (2020)

    Article  CAS  Google Scholar 

  41. T.J. Smith, Insulin-Like Growth Factor Pathway and the Thyroid. Front Endocrinol. 12, 653627 (2021)

    Article  Google Scholar 

  42. P. Castrogiovanni et al. Effects of high-tryptophan diet on pre- and postnatal development in rats: a morphological study. Eur. J. Nutr. 53(1), 297–308 (2014)

    Article  CAS  PubMed  Google Scholar 

  43. F. Liang et al. Tobacco carcinogen induces tryptophan metabolism and immune suppression via induction of indoleamine 2,3-dioxygenase 1. Signal Transduct. Target Ther. 7(1), 311 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. L. Zhu et al. Advancing metabolic networks and mapping updated urinary metabolic fingerprints after exposure to typical carcinogenic heterocyclic aromatic amines. Environ. Pollut. 319, 120936 (2023)

    Article  CAS  PubMed  Google Scholar 

  45. R.D. Michalek et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186(6), 3299–3303 (2011)

    Article  CAS  PubMed  Google Scholar 

  46. Z. Wu et al. Purine metabolism-related genes and immunization in thyroid eye disease were validated using bioinformatics and machine learning. Sci. Rep. 13(1), 18391 (2023)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors’ gratitude is extended to the GWAS consortia for openly providing the summary statistics. The authors also wish to convey appreciation to the researchers and participants involved in these studies.

Funding

National Natural Science Foundation of China, Grant/Award Numbers: 82260159.

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Authors and Affiliations

  1. Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China

    Tingliang Wang, Yun Zhang, Chunjiao Wu, Haiyan Yang & Zuojie Luo

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  1. Tingliang Wang
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  2. Yun Zhang
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  3. Chunjiao Wu
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  4. Haiyan Yang
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  5. Zuojie Luo
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Contributions

All authors contributed to the study conception and design. Data acquisition and analysis were conducted by T.W., Y.Z., and C.W.. Manuscript revision was carried out by H.Y. and Z.L.. The final manuscript was reviewed and approved by all authors.

Corresponding author

Correspondence to Zuojie Luo.

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Wang, T., Zhang, Y., Wu, C. et al. Causality of blood metabolites and metabolic pathways on Graves’ disease and Graves’ ophthalmopathy: a two-sample Mendelian randomization study. Endocrine (2024). https://doi.org/10.1007/s12020-024-03761-z

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