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Gene polymorphisms of pro-inflammatory cytokines may affect the risk of Graves' disease: a meta-analysis

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Abstract

Purpose

Gene polymorphisms of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6) may influence the risk of Graves' disease, but the results of so far published studies remain inconclusive. Therefore, the authors conducted this meta-analysis to assess relationships between TNF-α/IL-1/IL-6 polymorphisms and the risk of Graves' disease by pooling the findings of all relevant studies.

Methods

A comprehensive literature searching of Pubmed, Embase, Web of Science and CNKI was conducted by the authors, and twenty-eight studies were found to be eligible for pooled analyses.

Results

The pooled meta-analyses results showed that genotypic frequencies of TNF-α rs1800629, IL-1A rs1800587, IL-6 rs1800795 and IL-6 rs1800796 polymorphisms among patients with Graves' disease and control subjects differed significantly. Moreover, we found that genotypic frequencies of TNF-α rs1800629 and IL-6 rs1800795 polymorphisms among patients with Graves' disease and control subjects in Caucasians differed significantly, and genotypic frequencies of IL-1A rs1800587, IL-1B rs16944, IL-6 rs1800795 and IL-6 rs1800796 polymorphisms among patients with Graves' disease and control subjects in Asians also differed significantly. Nevertheless, we did not detect such genotypic frequencies differences for TNF-α rs361525 and IL-1B rs1143627 polymorphisms.

Conclusions

This meta-analysis suggests that TNF-α rs1800629, IL-1A rs1800587, IL-6 rs1800795 and IL-6 rs1800796 polymorphisms may influence the risk of Graves' disease in overall population. Moreover, TNF-α rs1800629 and IL-6 rs1800795 polymorphisms may influence the risk of Graves' disease in Caucasians, while IL-1A rs1800587, IL-1B rs16944, IL-6 rs1800795 and IL-6 rs1800796 polymorphisms may influence the risk of Graves' disease in Asians.

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References

  1. De Leo S, Lee SY, Braverman LE (2016) Hyperthyroidism. Lancet 388:906–918

    Article  Google Scholar 

  2. Taylor PN, Albrecht D, Scholz A et al (2018) Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol 14:301–316

    Article  Google Scholar 

  3. Ramos-Leví AM, Marazuela M (2016) Pathogenesis of thyroid autoimmune disease: the role of cellular mechanisms. Endocrinol Nutr 63:421–429

    Article  Google Scholar 

  4. Huang Y, Fang S, Li D, Zhou H, Li B, Fan X (2019) The involvement of T cell pathogenesis in thyroid-associated ophthalmopathy. Eye (Lond) 33:176–182

    Article  CAS  Google Scholar 

  5. Vitales-Noyola M, Ramos-Levi AM, Martínez-Hernández R et al (2017) Pathogenic Th17 and Th22 cells are increased in patients with autoimmune thyroid disorders. Endocrine 57:409–417

    Article  CAS  Google Scholar 

  6. Lv LF, Jia HY, Zhang HF, Hu YX (2017) Expression level and clinical significance of IL-2, IL-6 and TGF-β in elderly patients with goiter and hyperthyroidism. Eur Rev Med Pharmacol Sci 21:4680–4686

    PubMed  Google Scholar 

  7. Akahane M, Watanabe M, Inoue N et al (2016) Association of the polymorphisms of chemokine genes (IL8, RANTES, MIG, IP10, MCP1 and IL16) with the pathogenesis of autoimmune thyroid diseases. Autoimmunity 49:312–319

    Article  CAS  Google Scholar 

  8. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264–269

    Article  Google Scholar 

  9. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25:603–605

    Article  Google Scholar 

  10. Anvari M, Khalilzadeh O, Esteghamati A et al (2010) Graves' disease and gene polymorphism of TNF-α, IL-2, IL-6, IL-12, and IFN-γ. Endocrine 37:344–348

    Article  CAS  Google Scholar 

  11. Bednarczuk T, Hiromatsu Y, Seki N et al (2014) Association of tumor necrosis factor and human leukocyte antigen DRB1 alleles with Graves' ophthalmopathy. Hum Immunol 65:632–639

    Article  Google Scholar 

  12. Gu LQ, Zhu W, Pan CM et al (2010) Tumor necrosis factor alpha (TNF-alpha) polymorphisms in Chinese patients with Graves' disease. Clin Biochem 43:223–227

    Article  CAS  Google Scholar 

  13. Kamizono S, Hiromatsu Y, Seki N et al (2000) A polymorphism of the 5' flanking region of tumour necrosis factor α gene is associated with thyroid-associated ophthalmopathy in Japanese. Clin Endocrinol (Oxf) 52:759–764

    Article  CAS  Google Scholar 

  14. Simmonds MJ, Heward JM, Howson JM et al (2004) A systematic approach to the assessment of known TNF-alpha polymorphisms in Graves' disease. Genes Immun 5:267–273

    Article  CAS  Google Scholar 

  15. Yang HW, Wang YX, Bao J et al (2017) Correlation of HLA-DQ and TNF-α gene polymorphisms with ocular myasthenia gravis combined with thyroid-associated ophthalmopathy. Biosci Rep 37:BSR20160440

    Article  CAS  Google Scholar 

  16. Chen RH, Chen WC, Wang TY, Tsai CH, Tsai FJ (2005) Lack of association between pro-inflammatory cytokine (IL-6, IL-8 and TNF-alpha) gene polymorphisms and Graves' disease. Int J Immunogenet 32:343–347

    Article  CAS  Google Scholar 

  17. Chen JD (2010) Associations between inflammatory cytokine polymorphisms and Graves' disease. Dissertation, Hebei University of Chinese Medicine.

  18. Durães C, Moreira CS, Alvelos I et al (2014) Polymorphisms in the TNFA and IL6 genes represent risk factors for autoimmune thyroid disease. PLoS ONE 9:e105492

    Article  Google Scholar 

  19. Jiang WY (2004) Associations between TNFA polymorphisms and Graves' disease. Dissertation, Shandong University.

  20. Jurecka-Lubieniecka B, Ploski R, Kula D et al (2013) Association between age at diagnosis of Graves' disease and variants in genes involved in immune response. PLoS ONE 8:e59349

    Article  CAS  Google Scholar 

  21. Kutluturk F, Yarman S, Sarvan FO, Kekik C (2013) Association of cytokine gene polymorphisms (IL6, IL10, TNF-α, TGF-β and IFN-γ) and Graves' disease in Turkish population. Endocr Metab Immune Disord Drug Targets 13:163–167

    Article  CAS  Google Scholar 

  22. Shiau MY, Huang CN, Yang TP et al (2007) Cytokine promoter polymorphisms in Taiwanese patients with Graves' disease. Clin Biochem 40:213–217

    Article  CAS  Google Scholar 

  23. Gong Y (2003) Associations between interleukin polymorphisms and Graves' disease. Dissertation, Shandong University.

  24. Kammoun-Krichen M, Bougacha-Elleuch N, Makni K et al (2007) Association analysis of interleukin gene polymorphisms in autoimmune thyroid diseases in the Tunisian population. Eur Cytokine Netw 18:196–200

    CAS  PubMed  Google Scholar 

  25. Khalilzadeh O, Anvari M, Momen-Heravi F et al (2010) Gene polymorphisms of interleukin-4, interleukin-10 and transforming growth factor-beta in Graves' disease. Clin Exp Med 10:123–128

    Article  CAS  Google Scholar 

  26. Liu N, Li X, Liu C et al (2010) The association of interleukin-1alpha and interleukin-1beta polymorphisms with the risk of Graves' disease in a case-control study and meta-analysis. Hum Immunol 71:397–401

    Article  CAS  Google Scholar 

  27. Hayashi F, Watanabe M, Nanba T et al (2009) Association of the -31C/T functional polymorphism in the interleukin-1beta gene with the intractability of Graves' disease and the proportion of T helper type 17 cells. Clin Exp Immunol 158:281–286

    Article  CAS  Google Scholar 

  28. Khalilzadeh O, Anvari M, Esteghamati A et al (2009) The interleukin-1 family gene polymorphisms and Graves' disease. Ann Endocrinol (Paris) 71:281–285

    Article  Google Scholar 

  29. Lacka K, Paradowska A, Gasinska T et al (2009) Interleukin-1beta gene (IL-1beta) polymorphisms (SNP -511 and SNP +3953) in thyroid-associated ophthalmopathy (TAO) among the Polish population. Curr Eye Res 34:215–220

    Article  CAS  Google Scholar 

  30. Reichmann I, Schulte KM, Roeher HD (2004) No association of IL-1beta C + 3954 T polymorphism and thyroid disease. Exp Clin Endocrinol Diabetes 112:440–443

    Article  CAS  Google Scholar 

  31. Shehjar F, Afroze D, Misgar RA, Malik SA, Laway BA (2018) Association of polymorphic variants of IL-1β and IL-1RN genes in the development of Graves' disease in Kashmiri population (North India). Hum Immunol 79:228–232

    Article  CAS  Google Scholar 

  32. Zaaber I, Mestiri S, Hammedi H et al (2016) Association of interleukin-1B and Interleukin-4 gene variants with autoimmune thyroid diseases in tunisian population. Immunol Invest 45:284–297

    Article  CAS  Google Scholar 

  33. Liu YH, Chen RH, Wu HH et al (2010) Association of interleukin-1beta (IL1B) polymorphisms with Graves' ophthalmopathy in Taiwan Chinese patients. Invest Ophthalmol Vis Sci 51:6238–6246

    Article  Google Scholar 

  34. Anvari M, Khalilzadeh O, Esteghamati A et al (2010) Genetic susceptibility to Graves' ophthalmopathy: the role of polymorphisms in proinflammatory cytokine genes. Eye (Lond) 24:1058–1063

    Article  CAS  Google Scholar 

  35. Zhu W, Liu N, Zhao Y et al (2010) Association analysis of polymorphisms in IL-3, IL-4, IL-5, IL-9, and IL-13 with Graves' disease. J Endocrinol Invest 33:751–755

    Article  CAS  Google Scholar 

  36. Inoue N, Watanabe M, Morita M et al (2011) Association of functional polymorphisms in promoter regions of IL5, IL6 and IL13 genes with development and prognosis of autoimmune thyroid diseases. Clin Exp Immunol 163:318–323

    Article  CAS  Google Scholar 

  37. Mestiri S, Zaaber I, Inoubli O et al (2020) Association of cytokine Th2 gene polymorphisms with autoimmune thyroid diseases in Tunisian population. Int J Immunogenet. https://doi.org/10.1111/iji.12472

    Article  PubMed  Google Scholar 

  38. Smith AJ, Humphries SE (2009) Cytokine and cytokine receptor gene polymorphisms and their functionality. Cytokine Growth Factor Rev 20:43–59

    Article  CAS  Google Scholar 

  39. Ferrari SM, Ruffilli I, Elia G et al (2019) Chemokines in hyperthyroidism. J Clin Transl Endocrinol 16:100196

    PubMed  PubMed Central  Google Scholar 

  40. Mandić JJ, Kozmar A, Kusačić-Kuna S et al (2018) The levels of 12 cytokines and growth factors in tears: hyperthyreosis vs euthyreosis. Graefes Arch Clin Exp Ophthalmol 256:845–852

    Article  Google Scholar 

  41. Li L, Ding X, Wang X et al (2018) Polymorphisms of IKZF3 gene and autoimmune thyroid diseases: associated with Graves' disease but not with Hashimoto's thyroiditis. Cell Physiol Biochem 45:1787–1796

    Article  CAS  Google Scholar 

  42. Yao Q, Li J, An X et al (2017) Association between C1q gene polymorphisms and autoimmune thyroid diseases. Arch Endocrinol Metab 61:337–342

    Article  Google Scholar 

  43. Cai T, Li J, An X et al (2017) Polymorphisms in MIR499A and MIR125A gene are associated with autoimmune thyroid diseases. Mol Cell Endocrinol 440:106–115

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Endocrinology, Huaian Hospital of Huaian District, Huaian, 223200, China

    P. Zhu, X. Wu & J. Zhou

  2. Department of Clinical Medicine, Yangzhou University Medical College, Yangzhou, 225009, China

    K. Wu

  3. Department of Endocrinology, Xiamen Haicang Hospital, Xiamen, 361026, China

    Y. Lu

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  1. P. Zhu
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  2. X. Wu
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  3. J. Zhou
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  4. K. Wu
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Contributions

PZ and YL designed this meta-analysis. PZ, XW and JZ searched literatures. JZ and KW analyzed data. PZ and YL wrote the manuscript. All authors approved the final manuscript as submitted.

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Correspondence to Y. Lu.

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Zhu, P., Wu, X., Zhou, J. et al. Gene polymorphisms of pro-inflammatory cytokines may affect the risk of Graves' disease: a meta-analysis. J Endocrinol Invest 44, 311–319 (2021). https://doi.org/10.1007/s40618-020-01300-x

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  • DOI: https://doi.org/10.1007/s40618-020-01300-x

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