Genetic Basis of Type I (Insulin-Dependent) Diabetes

HLA-DR4 is associated with insulin-dependent diabetes mellitus (IDDM) in many populations. Many recent studies suggest that the DR4 effect is really due to DQ3.2, an allele of the nearby DQB1 locus. We used T cell clones, MAb, and allelespecific oligonucleotides to test IDDM and control subjects for DR4 subtypes (Dw4, DwlO, Dwl3, and Dw14) and for DR4-associated DQB1 alleles (DQ3.1 and DQ3.2). We find that (a) IDDM is approximately equally associated with alleles of the DRB1 locus (Dw4 and DwlO, combined relative risk, RR = 6.4) and the DQB1 locus (DQ3.2, RR = 5.9); and (b) there is significant interaction, in a statistical sense, between these DR and DQ alleles in IDDM. The only IDDM-associated DR4 haplotypes were those carrying the IDDM-associated alleles at both loci (RR = 12.1); haplotypes with Dw4 or 10 but not DQ3.2, or vice versa, had a RR < 1. Alternative explanations include: (a) that susceptibility requires specific allelic products of both DR and DQ loci; (b) that the combination ofcertain DR and DQ alleles marks haplotypes with the true susceptibility allele at a third locus; or (c) that Dw4 and 10 mark haplotypes with an allele at another locus that interacts with DQ3.2. As discussed, this third locus is unlikely to be DQA1 (DQa). The data thus are not easily reconciled with an exclusive effect of HLA-DQ. This information increases our ability to predict IDDM by genetic typing: in the population studied, heterozygotes DR3/IDQ3.2, Dw41 or DR3/[DQ3.2, DwlOj had a relative risk of 38.0 and an absolute risk of I in 15.

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“…Recent papers from our laboratories (3)(4)(5) and others (6)(7)(8)(9)(10)(11)(12)(13)(14)(15) show that some DR4 haplotypes are IDDM associated,…”

Section: Introductionmentioning

confidence: 99%

A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles.

Sheehy

Scharf²,

Rowe³

et al. 1989

J. Clin. Invest.

246

137

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“…As mentioned earlier, testing for islet cell antibodies is useful for identifying high-risk individuals who are genetically susceptible in families with type I diabetes (3,5,44). How helpful it is to screen for islet cell antibodies on a population level remains to be seen.…”

Section: Prevention Of Type I Diabetes In the General Populationmentioning

confidence: 95%

“…In type I diabetes, subclass a, which has early onset, a slight male predominance, and may be initiated by an immune-mediated destructive process of the pancreatic (3-cells, can be differentiated from the rarer subclass b diabetes. This type has a later and more insidious age of onset, a female preponderance, a strong family history of autoimmune endoc'rinopathy, and may be a primary autoimmune form of the disease characterized by persistence of islet cell antibodies (5).…”

mentioning

confidence: 99%

Primary Prevention of Diabetes Mellitus

Tuomilehto

Wolf

1987

Diabetes Care

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Diabetes mellitus is one of the chronic noncommunicable diseases that have increased markedly in this century. The discovery of insulin and other drugs for lowering hyperglycemia have certainly reduced mortality from acute complications of diabetes and improved the quality of life of many diabetic patients. Recent advances in research into the etiology and natural history of diabetes have increased our knowledge about different types of diabetes to such an extent that primary prevention of diabetes mellitus is becoming a reality. Until now, few studies have attempted to test measures for primary prevention of diabetes. Therefore, the data supporting the possibility for primary prevention are largely indirect and need to be tested in preventive trials or in community-based prevention programs. We believe, however, that the time is right to start action in populations in which the prevalence of diabetes is known to have clearly increased recently. We summarize the evidence that can be used as the scientific basis of primary prevention of diabetes mellitus.

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Variation in HLA‐associated risks of childhood insulin‐dependent diabetes in the finnish population: II. Haplotype effects

Thomas¹,

Pitkäniemi²,

Langholz³

et al. 1995

Genetic Epidemiology

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We fitted models for the main effects of alleles at the HLA-A, B, and DR loci and their haplotypes on the risk of insulin-dependent diabetes mellitus (IDDM). Empirical Bayes methods were used, assuming independent exchangeable normal priors for effects at each locus separately and for haplotype effects. A pure main effects model, pure haplotype effects model, and a combined model were fitted using Gibbs sampling. The main effects model showed that the DR locus had the largest variation in risk between alleles, followed by the B locus; significance tests for each allele in this model were in general agreement with those in the companion paper [Langholz et al. (1995) Genet Epidemiol 12:441-453], although all relative risks were shrunk toward 1.0 in the empirical Bayes analysis. The variance estimate for pure haplotype effects was substantially larger than for any of the three main effects considered in this analysis, but in the combined model, the DR locus showed larger variability than the haplotype deviations. We confirmed that haplotype A2/B56/DR4 previously reported to be common in Finnish diabetics does indeed confer unusually high risk (relative risk = 7.6, P < 0.001), but found this to be only 1.9 times higher than predicted by its component main effects (P = 0.046). All of the other haplotypes could be adequately explained by their main effects. Empirical Bayes methods provide a natural means of dealing with the problems of multiple comparisons, multicolinearity, and sparse data that complicate the analysis of HLA data.

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Genetic Basis of Type I (Insulin-Dependent) Diabetes

Cited by 5 publications

References 71 publications

A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles.

A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles.

Primary Prevention of Diabetes Mellitus

Variation in HLA‐associated risks of childhood insulin‐dependent diabetes in the finnish population: II. Haplotype effects

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