Genetic Link Connects Type 1 Diabetes, Autoimmune Thyroid Disease; Testing Urged

A recent review article finds genetic connections between type 1 diabetes (T1D) and autoimmune thyroid disease and (AITD) calls for children of these patients to be screened for autoimmune endocrine diseases regularly.

The review, appearing March 10, 2021, in Frontiers in Endocrinology, notes that T1D and AITD are the most common, chronic autoimmune diseases worldwide, but they are hardly the only endocrine and nonendocrine disorders that cluster together. T1D and AITD in particular, the authors wrote, tend to appear in families, as seen in autoimmune polyendocrinopathy (AP).

“The close relationship between these 2 diseases is largely explained by sharing a common genetic background,” they wrote.

The authors explored in detail the role of HLA antigens in those with a genetic disposition to develop autoimmune disease. “There is a correlation between carriage of certain HLA class II alleles and an increased probability of developing the most common autoimmune diseases, including T1D and AITD,” the authors wrote.

They explained that the HLA genes are important messengers generally, and the proteins that receive messages from HLA class II in particular are important in signaling T-cells, which play a major role in the adaptive immune system. The authors discussed processes in which an immune response causes recognition by the T-cell receptor on the CD4+ T-cell surface, which in turn activates B cells to produce autoantibodies, triggering an additional immune response.

“In patients with autoimmune diseases, such as T1D and AITD, autoantibodies are synthesized and lymphocytes often infiltrate into the target organ, leading to inflammation and even partial destruction,” the authors explained. “Because antigen presentation and further T cell activation are considered key components of the immune response, studying the peculiarities of antigen presentation as well as the structure and features of HLA proteins in particular is of utmost importance.”

The review discusses other rare variants long known to be involved in immune regulation that can make one susceptible to both T1D and AITD, some of which have already been targets in highly successful therapies: they include the cytotoxic T-lymphocyte- associated antigen (CTLA4), the protein tyrosine phosphatase non-receptor type 22 (PTPN22), the interleukin-2 Receptor (IL2Ra), the vitamin D receptor (VDR), and the tumor-necrosisfactor-a (TNF).

Genes and environmental factors both have a role in T1D and AITD, which the authors say are “multifactorial autoimmune endocrine diseases,” in which a few genes can increase the risk for both conditions. HLA, the authors wrote, “remains the most important contributor to overall risk, while additional gene interactions are likely to confer either protection or susceptibility.”

Different genes are associated with disease risk in persons of different racial or ethnic backgrounds, strengthening the case for the combined role of genetics, epigenetics, and environmental factors in the development of autoimmune disorders. This, the authors say, strengthens the case for genetic screening for patients with monoglandular autoimmunity, such as T1D and Addison's disease, along with their first-degree relatives.

“In view of the possible long interval between the first manifestation of AP and the subsequent development of further autoimmune endocrinopathies, regular and long-term observation of patients is warranted,” they wrote. “Furthermore, screening for autoimmune endocrine diseases is recommended regularly, especially for the offspring of patients with T1D and AITD, and AP III variant.”

Reference

Frommer L, Kahaly GJ. Type 1 diabetes and autoimmune thyroid disease: the genetic link. Front Endocrinol. 2021;10(12):618213. doi:10.3389/fendo.2021.618213.