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Effects of different iodine levels on the DNA methylation of intrinsic apoptosis-associated genes and analysis of gene–environment interactions in patients with autoimmune thyroiditis
Published online by Cambridge University Press: 15 May 2023
Abstract
Iodine is an essential nutrient that may change the occurrence of autoimmune thyroiditis (AIT). Apoptosis and DNA methylation participate in the pathogenesis and destructive mechanism of AIT. We detected the methylation and the expression of mRNA of intrinsic apoptosis-associated genes (YWHAG, ING4, BRSK2 and GJA1) to identify the potential interactions between the levels of methylation in these genes and different levels of iodine. 176 adult patients with AIT in Shandong Province, China, were included. The MethylTargetTM assay was used to verify the levels of methylation. We used PCR to detect the mRNA levels of the candidate genes. Interactions between methylation levels of the candidate genes and iodine levels were evaluated with multiplicative and addictive interaction models and GMDR. In the AIT group, YWHAG_1 and six CpG sites and BRSK2_1 and eight CpG sites were hypermethylated, whereas ING4_1 and one CpG site were hypomethylated. A negative correlation was found between methylation levels of YWHAG and mRNA expression. The combination of iodine fortification, YWHAG_1 hypermethylation and BRSK2_1 hypermethylation was significantly associated with elevated AIT risk. A four-locus model (YWHAG_1 × ING4_1 × BRSK2_1 × iodine level) was found to be the best model of the gene–environment interactions. We identified abnormal changes in the methylation status of YWHAG, ING4 and BRSK2 in patients with AIT in different iodine levels. Iodine fortification not only affected the methylation levels of YWHAG and BRSK2 but also interacted with the methylation levels of these genes and may ultimately increase the risk of AIT.
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- © The Author(s), 2023. Published by Cambridge University Press on behalf of The Nutrition Society
References
Dayan, CM & Daniels, GH (1996) Chronic autoimmune thyroiditis. N Engl J Med 335, 99–107.CrossRefGoogle ScholarPubMed
Luo, Y, Kawashima, A, Ishido, Y, et al. (2014) Iodine excess as an environmental risk factor for autoimmune thyroid disease. Int J Mol Sci 15, 12895–12912.CrossRefGoogle ScholarPubMed
Pedersen, IB, Knudsen, N, Carlé, A, et al. (2011) A cautious iodization programme bringing iodine intake to a low recommended level is associated with an increase in the prevalence of thyroid autoantibodies in the population. Clin Endocrinol 75, 120–126.CrossRefGoogle ScholarPubMed
Law, PP & Holland, ML (2019) DNA methylation at the crossroads of gene and environment interactions. Essays Biochem 63, 717–726.Google ScholarPubMed
Shalaby, SM, Mackawy, AMH, Atef, DM, et al. (2019) Promoter methylation and expression of intercellular adhesion molecule 1 gene in blood of autoimmune thyroiditis patients. Mol Biol Rep 46, 5345–5353.CrossRefGoogle ScholarPubMed
Kyrgios, I, Giza, S, Fragou, A, et al. (2021) DNA hypermethylation of PTPN22 gene promoter in children and adolescents with Hashimoto thyroiditis. J Endocrinol Invest 44, 2131–2138.CrossRefGoogle ScholarPubMed
Hashimoto, H, Watanabe, M, Inoue, N, et al. (2019) Association of IFNG gene methylation in peripheral blood cells with the development and prognosis of autoimmune thyroid diseases. Cytokine 123, 154770.CrossRefGoogle ScholarPubMed
Guo, Q, Wu, D, Yu, H, et al. (2018) Alterations of global DNA methylation and DNA methyltransferase expression in T and B lymphocytes from patients with newly diagnosed autoimmune thyroid diseases after treatment: a follow-up study. Thyroid 28, 377–385.CrossRefGoogle Scholar
Wyllie, AH, Morris, RG, Smith, AL, et al. (1984) Chromatin cleavage in apoptosis: association with condensed chromatin morphology and dependence on macromolecular synthesis. J Pathol 142, 67–77.CrossRefGoogle ScholarPubMed
Wang, SH & Baker, JR (2007) The role of apoptosis in thyroid autoimmunity. Thyroid 17, 975–979.CrossRefGoogle ScholarPubMed
Lin, JD (2001) The role of apoptosis in autoimmune thyroid disorders and thyroid cancer. BMJ 322, 1525–1527.CrossRefGoogle ScholarPubMed
Hammond, LJ, Lowdell, MW, Cerrano, PG, et al. (1997) Analysis of apoptosis in relation to tissue destruction associated with Hashimoto’s autoimmune thyroiditis. J Pathol 182, 138–144.3.0.CO;2-F>CrossRefGoogle ScholarPubMed
Stassi, G & De Maria, R (2002) Autoimmune thyroid disease: new models of cell death in autoimmunity. Nat Rev Immunol 2, 195–204.CrossRefGoogle ScholarPubMed
Wang, D, Wan, S, Liu, P, et al. (2021) Associations between water iodine concentration and the prevalence of dyslipidemia in Chinese adults: a cross-sectional study. Ecotoxicol Environ Saf 208, 111682.CrossRefGoogle ScholarPubMed
Weetman, AP (2004) Autoimmune thyroid disease. Autoimmunity 37, 337–340.CrossRefGoogle ScholarPubMed
Wan, S, Liu, L, Ren, B, et al. (2021) DNA methylation patterns in the HLA-DPB1 and PDCD1LG2 gene regions in patients with autoimmune thyroiditis from different water iodine areas. Thyroid 31, 1741–1748.CrossRefGoogle ScholarPubMed
Li, C, He, J, Wei, B, et al. (2020) Effect of metabolic syndrome on coronary heart disease in rural minorities of Xinjiang: a retrospective cohort study. BMC Public Health 20, 553.CrossRefGoogle ScholarPubMed
Xu, HM, Xu, LF, Hou, TT, et al. (2016) GMDR: versatile software for detecting gene-gene and gene-environ- ment interactions underlying complex traits. Curr Genom 17, 396–402.CrossRefGoogle ScholarPubMed
Zhao, L, Yu, C, Lv, J, et al. (2021) Fluoride exposure, dopamine relative gene polymorphism and intelligence: a cross-sectional study in China. Ecotoxicol Environ Saf 209, 111826.CrossRefGoogle ScholarPubMed
Aitken, A (2006) 14–3–3 proteins: a historic overview. Semin Cancer Biol 16, 162–172.CrossRefGoogle ScholarPubMed
Jin, J, Smith, FD, Stark, C, et al. (2004) Proteomic, functional, and domain-based analysis of in vivo 14–3–3 binding proteins involved in cytoskeletal regulation and cellular organization. Curr Biol 14, 1436–1450.CrossRefGoogle ScholarPubMed
Kuzelová, K, Grebenová, D, Pluskalová, M, et al. (2009) Isoform-specific cleavage of 14–3–3 proteins in apoptotic JURL-MK1 cells. J Cell Biochem 106, 673–681.CrossRefGoogle ScholarPubMed
Garkavtsev, I, Kozin, SV, Chernova, O, et al. (2004) The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis. Nature 428, 328–332.CrossRefGoogle ScholarPubMed
Wang, QS, Li, M, Zhang, LY, et al. (2010) Down-regulation of ING4 is associated with initiation and progression of lung cancer. Histopathol 57, 271–281.CrossRefGoogle ScholarPubMed
Byron, SA, Min, E, Thal, TS, et al. (2012) Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer. PLoS One 7, e46823.CrossRefGoogle ScholarPubMed
Wang, CJ, Yang, D & Luo, YW (2015) Recombinant ING4 suppresses the migration of SW579 thyroid cancer cells via epithelial to mesenchymal transition. Exp Ther Med 10, 603–607.CrossRefGoogle ScholarPubMed
Li, X, Zhang, Q, Cai, L, et al. (2009) Inhibitor of growth 4 induces apoptosis in human lung adenocarcinoma cell line A549 via Bcl-2 family proteins and mitochondria apoptosis pathway. J Cancer Res Clin Oncol 135, 829–835.CrossRefGoogle ScholarPubMed
Terai, K, Hiramoto, Y, Masaki, M, et al. (2005) AMP-activated protein kinase protects cardiomyocytes against hypoxic injury through attenuation of endoplasmic reticulum stress. Mol Cell Biol 25, 9554–9575.CrossRefGoogle ScholarPubMed
Wang, Y, Wan, B, Li, D, et al. (2012) BRSK2 is regulated by ER stress in protein level and involved in ER stress-induced apoptosis. Biochem Biophys Res Commun 423, 813–818.CrossRefGoogle ScholarPubMed
Bright, NJ, Thornton, C & Carling, D (2009) The regulation and function of mammalian AMPK-related kinases. Acta Physiol 196, 15–26.CrossRefGoogle ScholarPubMed
Bretz, JD & Baker, JR Jr (2001) Apoptosis and autoimmune thyroid disease: following a TRAIL to thyroid destruction? Clin Endocrinol 55, 1–11.CrossRefGoogle ScholarPubMed
Yan, L, Lavin, VA, Moser, LR, et al. (2008) PP2A regulates the pro-apoptotic activity of FOXO1. J Biol Chem 283, 7411–7420.CrossRefGoogle ScholarPubMed
Nomura, M, Shimizu, S, Sugiyama, T, et al. (2015) 14–3–3 interacts directly with and negatively regulates pro-apoptotic Bax. J Biol Chem 290, 6753.CrossRefGoogle ScholarPubMed
Tsuruta, F, Sunayama, J, Mori, Y, et al. (2004) JNK promotes Bax translocation to mitochondria through phosphorylation of 14–3–3 proteins. Embo J 23, 1889–1899.CrossRefGoogle ScholarPubMed
Cai, L, Li, X, Zheng, S, et al. (2009) Inhibitor of growth 4 is involved in melanomagenesis and induces growth suppression and apoptosis in melanoma cell line M14. Melanoma Res 19, 1–7.CrossRefGoogle ScholarPubMed
Pedersen, IB, Knudsen, N, Jørgensen, T, et al. (2003) Thyroid peroxidase and thyroglobulin autoantibodies in a large survey of populations with mild and moderate iodine deficiency. Clin Endocrinol 58, 36–42.CrossRefGoogle Scholar
Wang, C, Li, Y, Teng, D, et al. (2021) Hyperthyroidism prevalence in China after universal salt iodization. Front Endocrinol 12, 651534.CrossRefGoogle Scholar
McKay, JA & Mathers, JC (2011) Diet induced epigenetic changes and their implications for health. Acta Physiol (Oxf) 202, 103–118.CrossRefGoogle ScholarPubMed
Davis, CD, Uthus, EO & Finley, JW (2000) Dietary selenium and arsenic affect DNA methylation in vitro in Caco-2 cells and in vivo in rat liver and colon. J Nutr 130, 2903–2909.CrossRefGoogle ScholarPubMed
Pufulete, M, Al-Ghnaniem, R, Khushal, A, et al. (2005) Effect of folic acid supplementation on genomic DNA methylation in patients with colorectal adenoma. Gut 54, 648–653.CrossRefGoogle ScholarPubMed
Steegers-Theunissen, RP, Obermann-Borst, SA, Kremer, D, et al. (2009) Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child. PLoS One 4, e7845.CrossRefGoogle Scholar
Passador, J, Toffoli, LV, Fernandes, KB, et al. (2018) Dietary ingestion of calories and micronutrients modulates the DNA methylation profile of leukocytes from older individuals. J Nutr Health Aging 22, 1281–1285.CrossRefGoogle ScholarPubMed
Guo, Q, Wu, D, Fan, C, et al. (2018) Iodine excess did not affect the global DNA methylation status and DNA methyltransferase expression in T and B lymphocytes from NOD.H-2(h4) and Kunming mice. Int Immunopharmacol 55, 151–157.CrossRefGoogle ScholarPubMed
Qu, M, Wan, S, Wu, H, et al. (2022) The whole blood DNA methylation patterns of extrinsic apoptotic signaling pathway related genes in autoimmune thyroiditis among areas with different iodine levels. Br J Nutr 9, 1–35.Google Scholar
Ren, B, Wan, S, Wu, H, et al. (2022) Effect of different iodine levels on the DNA methylation of PRKAA2, ITGA6, THEM4 and PRL genes in PI3K-AKT signaling pathway and population-based validation from autoimmune thyroiditis patients. Eur J Nutr 61, 3571–3583.CrossRefGoogle ScholarPubMed
Zhou, Z, Liu, L, Jin, M, et al. (2022) Relationships between the serum TPOAb and TGAb antibody distributions and water iodine concentrations, thyroid hormones and thyroid diseases: a cross-sectional study of 2503 adults in China. Br J Nutr 25, 1–11.Google Scholar
Samollow, PB, Perez, G, Kammerer, CM, et al. (2004) Genetic and environmental influences on thyroid hormone variation in Mexican Americans. J Clin Endocrinol Metab 89, 3276–3284.CrossRefGoogle ScholarPubMed
Buisine, N, Grimaldi, A, Jonchere, V, et al. (2021) Transcriptome and methylome analysis reveal complex cross-talks between thyroid hormone and glucocorticoid signaling at xenopus metamorphosis. Cells 10, 2375.CrossRefGoogle Scholar
Lafontaine, N, Campbell, PJ, Castillo-Fernandez, JE, et al. (2021) Epigenome-wide association study of thyroid function traits identifies novel associations of fT3 with KLF9 and DOT1L. J Clin Endocrinol Metab 106, e2191–e202.CrossRefGoogle ScholarPubMed
Zhou et al. supplementary material
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Zhou et al. supplementary material
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Zhou et al. supplementary material
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