Abstract
The role of TPO gene polymorphism in the susceptibility to Graves’ disease (GD) remains unclear. However, single-nucleotide polymorphisms (SNPs) near TPO have been recently associated with serum levels of thyroid peroxidase (TPO) antibody in two independent genome-wide association studies. Moreover, we have observed a strong association between the rs11675434 SNP located near TPO and the presence of clinically evident Graves’ ophthalmopathy (GO). The aim of the current study was to reevaluate and dissect this association in an extended group of 1231 well-characterized patients with GD (1043 adults and 188 children) and 1130 healthy controls from the Polish Caucasian population, considering possible gender-dependent and age-of-onset-specific effects of the studied SNP. We found that the T allele of rs11675434 was significantly more frequent in GD patients with than without GO (odds ratio (OR)=1.26, 95% confidence interval (CI)=1.05–1.51, P=0.012), which was consistent with our previous findings. Further analyses performed in subgroups of patients showed that the association with GO was significant in adult patients with age of GD onset ⩾45 years (OR=1.34, 95% CI=1.03–1.75, P=0.031), but not in children and adolescents or adult patients with earlier onset of the disease (OR=1.72, 95% CI=0.77–3.84, P=0.18 and OR=1.05, 95% CI=0.79–1.40, P=0.75, respectively). Moreover, a strong association with GO was present in males (OR=2.06, 95% CI=1.40–3.02, P=0.0002), whereas it was absent in females (OR=1.10, 95% CI=0.90–1.35, P=0.35). The results of our study further suggest that rs11675434 SNP located near TPO is associated with the development of GO, especially in males and patients with later age of GD onset.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Ris-Stalpers, C. & Bikker, H. Genetics and phenomics of hypothyroidism and goiter due to TPO mutations. Mol. Cell. Endocrinol. 322, 38–43 (2010).
Belforte, F. S., Miras, M. B., Olcese, M. C., Sobrero, G., Testa, G., Munoz, L. et al. Congenital goitrous hypothyroidism: mutation analysis in the thyroid peroxidase gene. Clin. Endocrinol. 76, 568–576 (2012).
Medici, M., Porcu, E., Pistis, G., Teumer, A., Brown, S. J., Jensen, R. A. et al. Identification of novel genetic loci associated with thyroid peroxidase antibodies and clinical thyroid disease. PLoS Genet. 10, e1004123 (2014).
Kwak, S. H., Park, Y. J., Go, M. J., Lee, K. E., Kim, S. J., Choi, H. S. et al. A genome-wide association study on thyroid function and anti-thyroid peroxidase antibodies in Koreans. Hum. Mol. Genet. 23, 4433–4442 (2014).
Kus, A., Szymanski, K., Peeters, R. P., Miskiewicz, P., Porcu, E., Pistis, G. et al. The association of thyroid peroxidase antibody risk loci with susceptibility to and phenotype of Graves' disease. Clin. Endocrinol. 83, 556–562 (2015).
Porcu, E., Medici, M., Pistis, G., Volpato, C. B., Wilson, S. G., Cappola, A. R. et al. A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLoS Genet. 9, e1003266 (2013).
Tomer, Y., Menconi, F., Davies, T. F., Barbesino, G., Rocchi, R., Pinchera, A. et al. Dissecting genetic heterogeneity in autoimmune thyroid diseases by subset analysis. J. Autoimmun. 29, 69–77 (2007).
Jurecka-Lubieniecka, B., Ploski, R., Kula, D., Krol, A., Bednarczuk, T., Kolosza, Z. et al. Association between age at diagnosis of Graves' disease and variants in genes involved in immune response. PLoS ONE 8, e59349 (2013).
Skorka, A., Bednarczuk, T., Bar-Andziak, E., Nauman, J. & Ploski, R. Lymphoid tyrosine phosphatase (PTPN22/LYP) variant and Graves' disease in a Polish population: association and gene dose-dependent correlation with age of onset. Clin. Endocrinol. 62, 679–682 (2005).
Bossowski, A., Borysewicz-Sanczyk, H., Wawrusiewicz-Kurylonek, N., Zasim, A., Szalecki, M., Wikiera, B. et al. Analysis of chosen polymorphisms in FoxP3 gene in children and adolescents with autoimmune thyroid diseases. Autoimmunity 47, 395–400 (2014).
Pawlak-Adamska, E., Daroszewski, J., Bolanowski, M., Oficjalska, J., Janusz, P., Szalinski, M. et al. PPARg2 Ala(1)(2) variant protects against Graves' orbitopathy and modulates the course of the disease. Immunogenetics 65, 493–500 (2013).
Werner, S. C. Modification of the classification of the eye changes of Graves' disease: recommendations of the Ad Hoc Committee of the American Thyroid Association. J. Clin. Endocrinol. Metab. 44, 203–204 (1977).
Bartalena, L., Baldeschi, L., Dickinson, A. J., Eckstein, A., Kendall-Taylor, P., Marcocci, C. et al. Consensus statement of the European group on Graves' orbitopathy (EUGOGO) on management of Graves' orbitopathy. Thyroid 18, 333–346 (2008).
McLachlan, S. M. & Rapoport, B. The molecular biology of thyroid peroxidase: cloning, expression and role as autoantigen in autoimmune thyroid disease. Endocr. Rev. 13, 192–206 (1992).
Kimura, S., Hong, Y. S., Kotani, T., Ohtaki, S. & Kikkawa, F. Structure of the human thyroid peroxidase gene: comparison and relationship to the human myeloperoxidase gene. Biochemistry 28, 4481–4489 (1989).
Rodien, P., Madec, A. M., Ruf, J., Rajas, F., Bornet, H., Carayon, P. et al. Antibody-dependent cell-mediated cytotoxicity in autoimmune thyroid disease: relationship to antithyroperoxidase antibodies. J. Clin. Endocrinol. Metab. 81, 2595–2600 (1996).
Rebuffat, S. A., Nguyen, B., Robert, B., Castex, F. & Peraldi-Roux, S. Antithyroperoxidase antibody-dependent cytotoxicity in autoimmune thyroid disease. J. Clin. Endocrinol. Metab. 93, 929–934 (2008).
Lai, O. F., Zaiden, N., Goh, S. S., Mohamed, N. E., Seah, L. L., Fong, K. S. et al. Detection of thyroid peroxidase mRNA and protein in orbital tissue. Eur. J. Endocrinol. 155, 213–218 (2006).
Feliciello, A., Porcellini, A., Ciullo, I., Bonavolonta, G., Avvedimento, E. V. & Fenzi, G. Expression of thyrotropin-receptor mRNA in healthy and Graves' disease retro-orbital tissue. Lancet 342, 337–338 (1993).
Paschke, R., Vassart, G. & Ludgate, M. Current evidence for and against the TSH receptor being the common antigen in Graves' disease and thyroid associated ophthalmopathy. Clin. Endocrinol. 42, 565–569 (1995).
Eckstein, A. K., Plicht, M., Lax, H., Neuhauser, M., Mann, K., Lederbogen, S. et al. Thyrotropin receptor autoantibodies are independent risk factors for Graves' ophthalmopathy and help to predict severity and outcome of the disease. J. Clin. Endocrinol. Metab. 91, 3464–3470 (2006).
Khoo, D. H., Ho, S. C., Seah, L. L., Fong, K. S., Tai, E. S., Chee, S. P. et al. The combination of absent thyroid peroxidase antibodies and high thyroid-stimulating immunoglobulin levels in Graves' disease identifies a group at markedly increased risk of ophthalmopathy. Thyroid 9, 1175–1180 (1999).
Lee, J. H., Park, S. H., Koh, D. G. & Suh, B. K. Thyroid peroxidase antibody positivity and triiodothyronine levels are associated with pediatric Graves' ophthalmopathy. World J. Pediatr. 10, 155–159 (2014).
McLachlan, S. M., Bahn, R. & Rapoport, B. Endocrine ophthalmopathy: a re-evaluation of the association with thyroid autoantibodies. Autoimmunity 14, 143–148 (1992).
Sawicka-Gutaj, N., Bednarczuk, T., Daroszewski, J., Waligorska-Stachura, J., Miskiewicz, P., Sowinski, J. et al. GO-QOL–-disease-specific quality of life questionnaire in Graves' orbitopathy. Endokrynol. Pol. 66, 362–366 (2015).
Jurecka-Lubieniecka, B., Ploski, R., Kula, D., Szymanski, K., Bednarczuk, T., Ambroziak, U. et al. Association between polymorphisms in the TSHR gene and Graves' orbitopathy. PLoS ONE 9, e102653 (2014).
Brix, T. H., Kyvik, K. O., Christensen, K. & Hegedus, L. Evidence for a major role of heredity in Graves' disease: a population-based study of two Danish twin cohorts. J. Clin. Endocrinol. Metab. 86, 930–934 (2001).
Chu, X., Pan, C. M., Zhao, S. X., Liang, J., Gao, G. Q., Zhang, X. M. et al. A genome-wide association study identifies two new risk loci for Graves' disease. Nat. Genet. 43, 897–901 (2011).
Manolio, T. A., Collins, F. S., Cox, N. J., Goldstein, D. B., Hindorff, L. A., Hunter, D. J. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).
Acknowledgements
The study was supported by National Science Center grant 2014/15/N/NZ5/01656. The authors alone are responsible for the content and writing of the paper.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on Journal of Human Genetics website
Supplementary information
Rights and permissions
About this article
Cite this article
Kuś, A., Szymański, K., Jurecka-Lubieniecka, B. et al. Gender-dependent and age-of-onset-specific association of the rs11675434 single-nucleotide polymorphism near TPO with susceptibility to Graves’ ophthalmopathy. J Hum Genet 62, 373–377 (2017). https://doi.org/10.1038/jhg.2016.135
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2016.135
This article is cited by
-
Significance of HLA in the development of Graves’ orbitopathy
Genes & Immunity (2023)
-
The risk factors for Graves’ ophthalmopathy
Graefe's Archive for Clinical and Experimental Ophthalmology (2022)
