Type 1 Diabetes and Autoimmune Thyroid Disease-The Genetic Link

Abstract

Type 1 diabetes (T1D) and autoimmune thyroid disease (AITD) are the most frequent chronic autoimmune diseases worldwide. Several autoimmune endocrine and non-endocrine disorders tend to occur together. T1D and AITD often cluster in individuals and families, seen in the formation of autoimmune polyendocrinopathy (AP). The close relationship between these two diseases is largely explained by sharing a common genetic background. The HLA antigens DQ2 (DQA1*0501-DQB1*0201) and DQ8 (DQA1*0301-DQB1*0302), tightly linked with DR3 and DR4, are the major common genetic predisposition. Moreover, functional single nucleotide polymorphisms (or rare variants) of various genes, such as 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-necrosis-factor-α (TNF) that are involved in immune regulation have been identified to confer susceptibility to both T1D and AITD. Other genes including cluster of differentiation 40 (CD40), the forkhead box P3 (FOXP3), the MHC Class I Polypeptide-Related Sequence A (MICA), insulin variable number of tandem repeats (INS-VNTR), the C-Type Lectin Domain Containing 16A (CLEC16A), the Erb-B2 Receptor Tyrosine Kinase 3 (ERBB3) gene, the interferon-induced helicase C domain-containing protein 1 (IFIH1), and various cytokine genes are also under suspicion to increase susceptibility to T1D and AITD. Further, BTB domain and CNC homolog 2 (BACH2), C-C motif chemokine receptor 5 (CCR5), SH2B adaptor protein 3 (SH2B3), and Rac family small GTPase 2 (RAC2) are found to be associated with T1D and AITD by various independent genome wide association studies and overlap in our list, indicating a strong common genetic link for T1D and AITD. As several susceptibility genes and environmental factors contribute to the disease aetiology of both T1D and AITD and/or AP subtype III variant (T1D+AITD) simultaneously, all patients with T1D should be screened for AITD, and vice versa.

Keywords: HLA antigens; autoimmune polyendocrinopathy; autoimmune thyroid disease; genetic link; single nucleotide polymorphisms; susceptibility genes; type 1 diabetes.

Figure 1

T1D and AITD associated HLA alleles and haplotypes. Position of the HLA gene complex on the p arm of chromosome 6p21 (6p21.1-6p21.3) with around 3,500 kilo bases. The HLA class I region (blue) is located at the telomere side, while the HLA class II region (green) is located at the centromere side. DRB1, DQA1, and DQB1 alleles and haplotypes of the HLA class II (red) are associated with both T1D and AITD (AP III variant) in Caucasian subjects. Major susceptibility alleles in Caucasians are HLA-DRB1-03:01, HLA-DRB1-03:02, HLA-DRB1-04:01, HLA-DQA1-03:01, HLA-DQA1-05:01, HLA-DQB1-02:01, HLA-DQB1-03:01, and HLA-DQB1-03:02. The resulting haplotypes are HLA-DRB1-03:01-DQA1-05:01-DQB1-02:01, HLA-DRB1-04:01-DQA1-03:01-DQB1-03:01, and HLA-DRB1-04:01-DQA1-03:01-DQB1-03:02.

Figure 2

Binding mechanisms of islet and thyroid peptides. Two potential mechanisms for immunologically targeting several glands in patients with polyglandular autoimmunity. Panel (A) One APC expresses both pancreas as well as thyroid autoantigens (peptides) which are embedded in pockets with HLA class II molecules and presented to the T cell within the immunological synapse. Panel (B) Two APC express either a pancreas or thyroid antigen, however both APC share a common amino acid, which facilitates the anchoring of T cells.