Genetics of type 1 diabetes

Abstract

Background: Type 1 diabetes, a multifactorial disease with a strong genetic component, is caused by the autoimmune destruction of pancreatic β cells. The major susceptibility locus maps to the HLA class II genes at 6p21, although more than 40 non-HLA susceptibility gene markers have been confirmed.

Content: Although HLA class II alleles account for up to 30%-50% of genetic type 1 diabetes risk, multiple non-MHC loci contribute to disease risk with smaller effects. These include the insulin, PTPN22, CTLA4, IL2RA, IFIH1, and other recently discovered loci. Genomewide association studies performed with high-density single-nucleotide-polymorphism genotyping platforms have provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remain to be performed. Children born with the high-risk genotype HLADR3/4-DQ8 comprise almost 50% of children who develop antiislet autoimmunity by the age of 5 years. Genetic risk for type 1 diabetes can be further stratified by selection of children with susceptible genotypes at other diabetes genes, by selection of children with a multiple family history of diabetes, and/or by selection of relatives that are HLA identical to the proband.

Summary: Children with the HLA-risk genotypes DR3/4-DQ8 or DR4/DR4 who have a family history of type 1 diabetes have more than a 1 in 5 risk for developing islet autoantibodies during childhood, and children with the same HLA-risk genotype but no family history have approximately a 1 in 20 risk. Determining extreme genetic risk is a prerequisite for the implementation of primary prevention trials, which are now underway for relatives of individuals with type 1 diabetes.

Fig. 1. ORs for confirmed “genes/genetic loci” associated with T1D

Adapted by permission from Macmillan Publishers, © 2007; Todd et al. (5) and reprinted with permission from Elsevier, © 2008; Baschal et al. (76).

Fig. 2. Development of islet autoimmunity and diabetes in monozygotic twins

Cumulative incidence of diabetes among the probands and the cumulative incidence of diabetes and autoantibody positivity according to life-table analysis in twins who were initially discordant for diabetes. Kaplan–Meier estimates of progression to diabetes and antiislet autoimmunity according to age are shown. Survival analyses of progression to diabetes in patients (probands) and in their monozygotic twins who initially did not have diabetes are indicated by open squares and full triangles, respectively (P < 0.001). Progression to antiislet autoimmunity in the monozygotic twins of patients is indicated by full circles. The numbers of individuals still followed at each time point are shown. I-bars denote 95% CIs. Reprinted with permission from the Massachusetts Medical Society, © 2008, all rights reserved; Redondo et al. (11).

Fig. 3. Protective effects of DPB1*0402 and DRB1*0403 in DR3/4-DQB1*0302 newborn/general population children (NECs) and progression to autoantibody positivity (A) and TID (B)

Cumulative incidence of diabetes and autoantibody positivity according to life-table analysis in NECs. Survival analyses of progression to diabetes and antiislet autoimmunity according to age are shown. The numbers of children still followed at each time point are shown. HR (high risk), no protective alleles; LR (low risk), DRB1*0403 and/or DPB1*0402. Reprinted with permission from the American Diabetes Association, © 2007; Baschal et al. (24).

Fig. 4. Cumulative risk for persistent islet autoimmunity by PTPN22 genotypes stratified by high-risk HLA-DR3/4,DQB1*0302

Cumulative risk of development of persistent islet autoimmunity by PTPN22 genotypes was estimated by survival analyses and stratified by high-risk HLA-DR3/4,DQB1*0302. The numbers of individuals still followed at each time point are shown. AB Positive %, autoantibody positivity (%); PTPN22 genotypes: CC, CT or TT; high risk, HLA-DR3/4,DQB1*0302; low risk, not HLA-DR3/4,DQB1*0302. Reprinted with permission from the American Diabetes Association, © 2009; Steck et al. (37).

Fig. 5. HLA DR3/DR4-DQB1*0302 siblings progression to islet autoimmunity (A) and T1D (B) grouped by the number of MHC haplotypes shared with proband siblings

Haplotype-sharing survival curves show progression to anti-islet autoimmunity (A) and type 1 diabetes (B) in DR3/4-DQ8 siblings stratified by the number of MHC haplotypes shared with their proband siblings. Share 2, siblings share both MHC haplotypes with their diabetic proband sibling; share 0 or 1, siblings share 0 or 1 MHC haplotype with their diabetic proband sibling. Reproduced with permission from the National Academy of Sciences, U.S.A., © 2006; Aly et al. (13).