DNA Methylation in Autoimmune Thyroid Disease

Abstract

Graves’ disease and Hashimoto’s disease form part of the spectrum of autoimmune thyroid disease (AITD), to which genetic and environmental factors are recognised contributors. Epigenetics provides a potential link between environmental influences, gene expression and thyroid autoimmunity. DNA methylation (DNAm) is the best studied epigenetic process, and global hypomethylation of leucocyte DNA is reported in several autoimmune disorders. This review summarises current understanding of DNAm in AITD. Targeted DNAm studies of blood samples from AITD patients have reported differential DNAm in the promoter regions of several genes implicated in AITD, including TNF, IFNG, IL2RA, IL6, ICAM1 and PTPN22. In many cases, however, the findings await replication and are unsupported by functional studies to support causal roles in AITD pathogenesis. Furthermore, thyroid hormones affect DNAm, and in many studies confounding by reverse causation has not been considered. Recent studies have shown that DNAm patterns in candidate genes including ITGA6, PRKAA2 and DAPK1 differ between AITD patients from regions with different iodine status, providing a potential mechanism for associations between iodine and AITD. Research focus in the field is moving from candidate gene studies to an epigenome-wide approach. Genome-wide methylation studies of AITD patients have demonstrated multiple differentially methylated positions, including some in immunoregulatory genes such as NOTCH1, HLA-DRB1, TNF and ICAM1. Large, epigenome-wide studies are required to elucidate the pathophysiological role of DNAm in AITD, with the potential to provide novel diagnostic and prognostic biomarkers as well as therapeutic targets.

Gestational thyroid hormones and autism‐related traits in the EARLI and HOME studies

“…Results from animal studies also suggested that hypothyroidism during the critical period of brain development causes permanent brain functional impairment, which could manifest as ASD‐related traits (Sadamatsu et al, 2006). Moreover, studies showed that TH can also alter DNA methylation patterns, by influencing gene expression, which could potentially contribute to ASD‐related outcomes (Khan et al, 2014; Lafontaine et al, 2023; Martinez et al, 2020).…”

Investigation of DNA methylation in autoimmune diseases with genome-wide association analysis

“…The results indicated that fT3, a significant hormone in the thyroid, has effects on regulating DNA methylation [31]. This means DNA methylation may not be the direct cause of HT but it was the consequence of abnormal thyroid hormones [32]. We can guess that this might be how HT is inherited.…”

“…DNA methylation plays the most significant role in this process [34]. Skewed X chromosome inactivation, which means the inactivation occurred in a higher proportion of cells (≥ 80%) than normal (50%) is suggested to be associated with the pathogenesis of HT, especially in females [32]. Multiple studies showed that a higher prevalence of skewed X chromosomes was found in the blood of patients with autoimmune thyroid disorder than in healthy individuals [35][36][37].…”

Association of autoimmune thyroid disease with type 1 diabetes mellitus and its ultrasonic diagnosis and management

“…In addition, for a given genetic risk factor in AITD, epigenetic modifications mediated by DNA methylation[ 51 ], histone modifications[ 52 ], and noncoding RNAs[ 53 ] may be necessary to trigger AITD. However, the promoting mechanism of such epigenetic modifications in AITD have not been fully elucidated, and therefore, more research should be done to further investigate their roles in AITD pathogenesis and to develop better diagnostic, prognostic, and therapeutic tools.…”