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.

Autoimmune thyroiditis (AIT) has a complex aetiology and the susceptibility to it is determined by a combination of genetic and environmental factors, although these are not yet fully understood. The present research aimed to explore the DNA methylation patterns in whole blood of extrinsic apoptotic signalling pathway-related genes in AIT among areas with different iodine levels. We selected the iodine-fortification areas, iodine-adequate areas and water-based iodine-excess areas from Shandong Province of China as survey sites. Totally, 176 AIT cases and 176 controls were included. MethylTargetTM and QT-PCR technology were used to detect candidate genes’ DNA methylation levels and mRNA expression levels, respectively. We found that death associated protein kinase 1 (DAPK1) DNA methylation levels in AIT cases (especially in female) were significantly higher than controls (t = 2·7715, P = 0·0059; t = 2·4638, P = 0·0143 in female). There were differences in DAPK1 (t = 2·5384, P = 0·0121), TNF superfamily member 8 (t = 2·1667, P = 0·0334) and TNF-α-induced protein 8 (TNFAIP8) (t = 2·5672, P = 0·0121) genes methylation between cases and controls with different water iodine levels. The mRNA expression of DAPK1 (t = 4·329, P < 0·001) and TNFAIP8 (t = 3·775, P < 0·001) in the cases was increased. We identified the differences in the DNA methylation status of the extrinsic apoptotic signalling pathway-related genes between AIT and controls and in different iodine levels areas. The results were verified at the mRNA level. The environmental iodine may affect DNA methylation to some extent.

Hashimoto's thyroiditis (HT) and Graves’ disease (GD) are examples of autoimmune thyroid disease (AITD), the commonest autoimmune condition. Antibodies to thyroid peroxidase (TPO), the enzyme that catalyses thyroid-hormone production and antibodies to the receptor for the thyroid-stimulating hormone, are characteristic of HT and GD, respectively. It is presently accepted that genetic susceptibility, environmental factors, including nutritional factors and immune disorders contribute to the development of AITD. Aiming to investigate the effect of iodine, iron and selenium in the risk, pathogenesis and treatment of thyroid disease, PubMed and the Cochrane Library were searched for relevant publications to provide a narrative review. Iodine: chronic exposure to excess iodine intake induces autoimmune thyroiditis, partly because highly-iodinated thyroglobulin (Tg) is more immunogenic. The recent introduction of universal salt iodisation can have a similar, although transient, effect. Iron: iron deficiency impairs thyroid metabolism. TPO is a haem enzyme that becomes active only after binding haem. AITD patients are frequently iron-deficient since autoimmune gastritis, which reduces iron absorption and coeliac disease which causes iron loss, are frequent co-morbidities. In two-thirds of women with persistent symptoms of hypothyroidism despite appropriate levothyroxine therapy, restoration of serum ferritin above 100 µg/l ameliorated symptoms. Selenium: selenoproteins are essential to thyroid action. In particular, the glutathione peroxidases remove excessive hydrogen peroxide produced there for the iodination of Tg to form thyroid hormones. There is evidence from observational studies and randomised controlled trials that selenium, probably as selenoproteins, can reduce TPO-antibody concentration, hypothyroidism and postpartum thyroiditis. Appropriate status of iodine, iron and selenium is crucial to thyroid health.