Table 1.
Mutual non-HLA susceptibility genes in Type 1 diabetes and autoimmune thyroid disease.
| Gene | Location | Function | Mutations/Polymorphisms | Mutation/Polymorphism Phenotype |
|---|---|---|---|---|
| CONFIRMED | ||||
| CTLA4 | 2q33 | Encodes a receptor that is expressed on T cells and is a negative regulator of T-cell activation. | +6230G>A (rs3087243) 49A>G (rs231775) |
CTLA4 function or expression is affected by the threonine-to alanine substitution in the signal peptide of the CTLA4 protein, which leads to less efficient glycosylation in endoplasmic reticulum and reduced surface expression of CTLA4 protein. Increases susceptibility to T1D, AITD, and AP. |
| PTPN22 | 1p13 | Encodes lymphoid tyrosine phosphatase, a strong inhibitor of T-cell activation, expressed in B and T lymphocytes. Inhibits T lymphocyte antigen receptor signaling pathway | +1858C>T (rs2476601) | Polymorphisms lead to increased T-cell activation and enhanced susceptibility to T1D, AITD, and AP. |
| IL2Ra | 10p15 | Differentiation factor actively suppresses auto-reactive T cells via CD25 and regulates function of natural killer cells, B cells and Treg. | CD25 (rs10795791) | Polymorphisms in the CD25 gene region might affect function of Treg. Increased susceptibility to T1D and AITD, especially GD |
| VDR | 12q13.11 | Expressed on immune cells and directly inhibits activated T cells. Reduces production of pro-inflammatory cytokines (IFNγ). | Bsm I (rs1544410) Aps I (rs7975232) Taq I (rs731236) |
Polymorphisms lead to increased T-cell activation and enhanced susceptibility to T1D. |
| TNF | 6p21, within HLA class III region of MHC. | Located on chromosome 6p21, within HLA class III region of MHC. | -308 (rs1800629) | Increased transcription and production of TNF protein through polymorphisms in promoter region, higher levels of TNFα transcription facilitate inflammatory response in autoimmunity. Increases susceptibility to T1D and AITD. |
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| CD40 Gene | 20q13.12 | Influences both humoral and cell-mediated immune responses. | −1T>C (rs1883832) | Polymorphisms in the Kozak sequence are associated with autoimmunity, especially AITD. |
| FOXP3 | p arm of X chromosome (Xp11.23) |
FOXP3 transcription factor occupies the promoters for genes involved in regulatory T-cell function, controls regulatory T-cell differentiation, and is considered the master regulator of Treg development and function. | -2383C>T (rs3761549) | Polymorphisms might affect function of Treg hence increasing susceptibility to T1D and AITD. |
| MICA | p arm of chromosome 6 (6p21.33) | Encodes highly polymorphic cell surface glycoprotein. Protein expressed in two isoforms (MICA1 and MICA2), by alternative splicing. MICA protein is a ligand for receptors on natural killer cells and the stress-induced antigen is broadly recognized by intestinal epithelial T cells. |
MICA*A5 variant | Polymorphisms increase susceptibility for organ-specific autoimmune diseases. |
| INS-VNTR | 11p15 | Translation of pre-proinsulin, precursor of mature insulin. VNTR region of 14 to 15 bp consensus sequence upstream of insulin gene in insulin promoter. |
Short class I: (26–63 repeats), Intermediate class II: (64–139 repeats) Larger class III: (140–210 repeats) |
Polymorphisms might affect translation of pre-proinsulin, and production mature insulin. Increased susceptibility for T1D in AP type III. |
| CLEC16A | 16p13 | Encodes a member of the C-type lectin domain containing family. | rs12708716 | Polymorphisms increase susceptibility for organ-specific autoimmune diseases, T1D and AITD |
| ERBB3 | 12q13 | Encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. | rs2292399 | Polymorphisms increase risk for organ-specific autoimmunity, especially T1D and AITD. |
| IFIH1 | 2q24.3 | Belongs to the pattern recognition receptor (PPR) family and is a sensor of double-stranded RNA, initiating antiviral activity through IFN production. | A946T (rs1990760) | Polymorphisms are associated with both T1D and AITD. |
| IL1R1 | 2q14.2 | Encodes a competitive inhibitor of interleukin-1–induced proinflammatory activity | VNTR | Polymorphisms are associated with autoimmunity, especially AITD. |
| IL4 Genes | 5q31.1 | Is involved in the regulation of immune and inflammatory responses. | -590C>T | Polymorphisms are associated with autoimmunity, especially AITD. |
CTLA4, cytotoxic T-lymphocyte associated protein 4; PTPN22, protein tyrosine phosphatase non-receptor type 22; IL2Ra, interleukin 2 receptor subunit alpha; VDR, Vitamin D receptor; TNF, Tumor necrosis factor; CD40, cluster of differentiation 40; FOXP3, forkhead box P3; MICA, MHC Class I Polypeptide-Related Sequence A; INS-VNTR, insulin variable number of tandem repeats; CLEC16A, C-Type Lectin Domain Containing 16; ERBB3, Erb-B2 Receptor Tyrosine Kinase 3 gene; IFIH1, interferon induced with helicase C domain 1; IL1R1, interleukin-1 receptor antagonist; IL4, interleukin 4; GD, Graves’ disease.