Genetics of type 1 diabetes
In western populations, each child has a 0.3–0.4% risk of developing diabetes by the age of 20 years; the risk increases 15-fold in siblings of an affected child. Lifetime risks are more difficult to estimate, but may be about twice as high as this. Some 50% of the genetic risk of type 1 diabetes is conferred by genes in the human leucocyte antigen (HLA) region on chromosome 6. The HLA Class II susceptibility haplotypes DR4-DQ8 and DR3-DQ2 are present in 90% of children with type 1 diabetes, whereas DR15-DQ6 is associated with protection. High risk HLA haplotypes in a child with no family history of disease confer a risk similar to that of having an affected sibling (5–6%), and this risk rises rapidly if one or both haplotypes are shared with the affected sibling. The promoter region of the insulin gene on chromosome 11 contributes about 10% of genetic susceptibility. Many other genes (currently more than 40) make a minor contribution to type 1 diabetes, and several are of particular interest because they influence different aspects of immune function. Their ability to predict diabetes is, however, limited.
By the age of 20 years, type 1 diabetes will have affected some 0.3–0.4% of children in the background population in western countries, and about 6% of siblings of childhood onset cases, giving a ratio (λs) of 15. Early-onset diabetes carries a higher familial risk, and affected fathers are more likely to transmit type 1 diabetes to their offspring than affected mothers, with risks being 6–9% and 1–3%, respectively. These estimates represent the risk of diabetes development by young adult life, not the lifetime risk. The latter is not well established, and may be as high as 1% in the background population and 15% in siblings. Siblings who are HLA-identical to the proband have a 12–15% risk of developing diabetes by the age of 20 years, as against an approximate 30% risk in monozygotic twins; lifetime estimates for twin risk is 30–70%.
The HLA system
The HLA complex on chromosome 6 contains more than 200 genes, and contributes about 50% of genetic susceptibility to type 1 diabetes. HLA molecules are located in the cell membrane and present processed antigens to cells of the immune system. HLA Class I molecules are present on most nucleated cells, whereas Class II molecules are found only on antigen-presenting cells such as dendritic cells or macrophages. Two HLA Class II haplotypes, DR4-DQ8 and DR3-DQ2, are present in about 90% of children with type I diabetes. The genotype containing both haplotypes (DR4-DQ8/DR3/DQ2) carries the highest risk of diabetes (about 5%), and is most commonly seen in early-onset disease. The risk is increased in a child who shares both high risk haplotypes with an affected sibling. In contrast, the DR15-DQ6 haplotype is highly protective, being found in only 1% of children with type 1 diabetes, as against 20% of the background population. HLA susceptibility haplotypes are over-represented in latent autoimmune diabetes in adults (LADA), but at lower frequency than in type 1 diabetes.
The insulin gene
The insulin gene (INS) on chromosome 11 was the second genetic susceptibility factor for type 1 diabetes to be identified. A section of DNA in the regulatory region of the INS gene contains a variable number tandem repeat (VNTR) with three size classes referred to as class I (26–63 repeats), class II and class III (>140 repeats). Two copies (homozygosity) of the class I allele is associated with a two- to fivefold increase in the risk of type 1 diabetes, whereas the class III allele appears to confer dominant protection. It has been proposed that the VNTR modulates insulin transcription in the thymus and pancreas. Increased INS expression in the thymus, associated with the class III allele, might confer greater tolerance to insulin precursor molecules.
The search for susceptibility genes
Two main approaches have been used in the search for type 1 susceptibility genes. Linkage studies seek to identify genes that are shared more frequently by affected individuals than by chance. They are most useful for relatively rare genes with large effect sizes. Association studies look for evidence of association between genes and disease in large populations, and are more appropriate for common genes with small effect size. Initial studies were targeted to candidate genes or pathways, but genome-wide association studies (GWAS) have proved the best way of finding genes with no previously recognised association to the disease. Most of these have odds ratios <1.3 and their contribution to disease susceptibility is modest.
Susceptibility genes: some examples
CTLA4: A number of loci have attracted attention because they are also associated with other autoimmune conditions, suggesting the existence of common pathways predisposing to loss of self-tolerance. This includes the CTLA4 gene on chromosome 2q33. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is expressed only on activated T lymphocytes, and downregulates T cell function, limiting both activation and expansion. Deletion of this gene results in lethal autoimmune disease in a knockout mouse model. Polymorphisms that impair this function might therefore result in unwanted persistence of lymphocyte activation and failure of immune tolerance.
PTPN22: This gene, which is located on chromosome 1, encodes the lymphoid protein tyrosine phosphatase (LYP). The role of LYP in T cells is to negatively regulate T cell receptor signalling. A single arginine-to-tryptophan substitution results in reduced LYP activity, with consequent T cell hyperactivity. Alternative interpretations have been suggested, but this might an example of a 'gain of function' mutation.
IL2RA: The alpha chain of the IL2 receptor complex (also called CD25 and located on chromosome 10) is expressed by activated T cells and by regulatory T cells. IL2RA is also found in soluble form (sIL2RA) in the circulation, and increased levels are seen in a number of autoimmune conditions. IL2RA susceptibility genotypes in type 1 diabetes are, however, associated with reduced circulating levels. The mechanism by which susceptibility is induced in type 1 diabetes remains unclear.
IFIH1: This gene, located on chromosome 2, has attracted interest because it encodes an interferon-induced helicase known as MDA-5. This is involved in innate immunity, and plays a role in recognition of the RNA genomes of picornaviruses – the family to which enteroviruses such as coxsackievirus B4 belong. It is suggested that high IFIH1 levels might provoke exaggerated anti-viral immune responses that predispose to autoimmunity.
Can genes predict type 1 diabetes?
The highest level of genetic risk for type 1 diabetes is found in unaffected siblings who share both DR3/DR4-DQ8 haplotypes with an affected proband. One analysis found that 55% in this category developed diabetes by the age of 12 years, as against 5% sharing one or neither haplotype. This degree of predictive ability is available for only a small minority of the childhood type 1 population, but might form the basis for early intervention trials in the newborn. The hope that non-HLA genes might make a useful contribution to disease prediction has yet to be fully realised.
^ Mehers KL, Gillespie KM. The genetic basis for type 1 diabetes. Brit Med Bull 2008;88:115–29
^ Concannon P et al. Genetics of type 1A diabetes. New Engl J Med 2009;360:1646–54
^ Bell GI et al. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 1984;33:176–83
^ Vafiadis P et al. Insulin expression in the human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 1997;15:289–92
^ Ueda H et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003;423:506–11
^ Van Belle T et al. Type 1 etiology, immunology, and therapeutic strategies. Physiol Rev 2011;91:79–118
^ Aly TA et al. Extreme genetic risk for type 1A diabetes. PNAS 2006;103:14074–79