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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #167: Molecular Genetics of Type 1 Diabetes Part 4

Mar 5, 2019
 

The CTLA4 gene

The CTLA4 gene on chromosome 2q33.2 encodes a transmembrane co-receptor expressed on the surface of T cells.This functions as a negative regulator of T-cell activation via interaction with the B7 molecule on antigen-presenting cells (Figure 30.3). The G allele of the +49A/G SNP in exon 1 of CTLA4 has been implicated as a susceptibility marker for T1DM, but was rejected as a causal SNP by a fine-mapping study, which showed that its effect could be explained by more strongly associated variants in a 6.1 kb noncoding region, 3′ of the gene [41]. These polymorphisms were also associated with susceptibility to Graves’ disease and autoimmune hypothyroidism, suggesting that CTLA4 is a general autoimmunity risk locus. The associated variants were suggested to reduce the production of a secreted, soluble form of CTLA4, which is able to inhibit T-cell proliferation by binding to B7 [41]. This was not replicated in a subsequent study, however, and there is doubt as to whether the 3′ SNPs are directly causal for T1DM [42,43].

The CTLA4 gene

The CTLA4 gene on chromosome 2q33.2 encodes a transmembrane co-receptor expressed on the surface of T cells.This functions as a negative regulator of T-cell activation via interaction with the B7 molecule on antigen-presenting cells (Figure 30.3). The G allele of the +49A/G SNP in exon 1 of CTLA4 has been implicated as a susceptibility marker for T1DM, but was rejected as a causal SNP by a fine-mapping study, which showed that its effect could be explained by more strongly associated variants in a 6.1 kb noncoding region, 3′ of the gene [41]. These polymorphisms were also associated with susceptibility to Graves’ disease and autoimmune hypothyroidism, suggesting that CTLA4 is a general autoimmunity risk locus. The associated variants were suggested to reduce the production of a secreted, soluble form of CTLA4, which is able to inhibit T-cell proliferation by binding to B7 [41]. This was not replicated in a subsequent study, however, and there is doubt as to whether the 3′ SNPs are directly causal for T1DM [42,43].

The PTPN22 gene

The PTPN22 gene, located on chromosome 1p13, encodes the lymphoid-specific tyrosine phosphatase, LYP. This enzyme dephosphorylates key molecules in the T-cell receptor signaling pathway and hence functions as a negative regulator of T-cell activation (Figure 30.3). Susceptibility to T1DM (and a range of other autoimmune diseases) is associated with the T allele at the nonsynonymous C1858T SNP of PTPN22 (OR=1.96) [44]. This polymorphism results in an arginine-tryptophan substitution at position 620, an amino acid residue that plays a critical role in the interaction of LYP with its inhibitor, SRC kinase. The gain-of-function polymorphism results in a phosphatase with increased catalytic activity, which is a more potent negative regulator of T-cell activation [45]. This is thought to interfere with the induction of immune tolerance in the thymus or periphery, hence predisposing to autoimmunity.

The IL2RA gene

The interleukin-2 (IL-2) receptor α chain (CD25), encoded by the IL2RA gene on chromosome 10p15, is upregulated in activated effector T cells but constitutively expressed by FOXP3-positive regulatory T cells, which are known to play an important role in self-tolerance. The α subunit greatly enhances the affinity of the IL-2 receptor for its ligand and signaling through IL-2R is crucial for the function of both effector and regulatory T cells (Figure 30.3). Risk of T1DM is associated with three independent haplotypes, spanning a region from 18 kb immediately 5′ of IL2RA to 25 kb into intron 1 of the gene [46–48]. Disease-associated alleles/haplotypes have been shown to influence levels of soluble IL2Rα in peripheral blood [47], while a protective haplotype, defined by the rs12722495G allele, correlated with higher expression of CD25 on CD4-positive memory T cells and increased IL-2 responsiveness by these cells [48]. The susceptible haplotype, defined by the A allele of this SNP, was associated with reduced IL-2 responsiveness, decreased expression of FOXP3 by regulatory T cells and a reduction in the ability of Tregs to suppress the proliferation of autologous effector cells [49]. Like CTLA4 and PTPN22, the IL2RA gene appears to be a general autoimmunity locus, with reports of associations in rheumatoid arthritis, multiple sclerosis, and Crohn’s disease.

Genome-wide analyses

Over the last 20 years, advances in high-throughput genotyping techniques and improved understanding of genetic variation in human DNA have enabled researchers to screen the entire genome to identify disease susceptibility loci. Two main approaches have been used: linkage studies and genome-wide association studies.

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