The role of DQ alpha–beta heterodimers in genetic susceptibility to insulin‐dependent diabetes

Deschamps, I; Khalil, I.

doi:10.1002/dmr.5610090202

Cited by 17 publications

(4 citation statements)

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“…Thus, around 50 % of Type I diabetes presenting before the age of 16 years occurs in children heterozygous for HLA DQB alleles which are found together in around only 2 % of the population [53]. A Finnish study of elderly men with Type II diabetes found no difference in their frequency of diabetes-associated haplotypes from that associated with Type I diabetes [54].…”

Section: Susceptibility and Riskmentioning

confidence: 99%

The accelerator hypothesis: weight gain as the missing link between Type I and Type II diabetes

2001

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Diabetes is currently of two types. Type I (insulin-dependent) diabetes mellitus is an autoimmune disorder of childhood, characterised by acute onset, ketoacidosis and insulin dependency. Type II diabetes is a metabolic disorder of middle-life, slow in onset and non-insulin-dependent.The definitions need urgent revision. More than half of the patients with Type I diabetes present in adulthood, when their onset is slow and many do not develop acidosis or require insulin for many years [1]. Type II diabetes occurs in teenagers [2], sometimes with keto-acidosis [3], and insulin-dependency frequently ensues given time. Clinically, there is little other than tempo to distinguish two types of diabetes. The HypothesisThe`Accelerator Hypothesis' argues that Type I and Type II diabetes are one and the same, distinguishable only by their rate of beta cell loss and the accelerators responsible. The first accelerator, a constitutionally (intrinsically) high rate of beta-cell apoptosis, is necessary for diabetes to develop but in itself rarely Diabetologia (2001) AbstractBlood glucose concentrations are controlled by a loop incorporating two components, the beta cells which secrete insulin and the insulin-sensitive tissues (liver, muscle, adipose) which respond to it. Loss of blood glucose control might result from failure of the beta cells to secrete insulin, resistance of the tissues to its action, or a combination of both. The distinctions between Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus are becoming increasingly blurred both clinically and aetiologically, where beta-cell insufficiency is the shared characteristic. The`Accelerator Hypothesis' identifies three processes which variably accelerate the loss of beta cells through apoptosis: constitution, insulin resistance and autoimmunity.None of the accelerators leads to diabetes without excess weight gain, a trend which the`Accelerator Hypothesis' deems central to the rising incidence of both types of diabetes in the industrially developed world. Weight gain causes an increase in insulin resistance, which results in the weakening of glucose control. The rising blood glucose (glucotoxicity) accelerates beta-cell apoptosis directly in all and, by inducing beta-cell immunogens, further accelerates it in a subset genetically predisposed to autoimmunity. Rather than overlap between two types of diabetes, the`Accelerator Hypothesis' envisages overlay. Body mass is central to the development and rising incidence of all diabetes. Only tempo distinguishes the`types'. The control of weight gain, and with it insulin resistance, could be the means of minimising both.

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Section: Susceptibility and Riskmentioning

confidence: 99%

The accelerator hypothesis: weight gain as the missing link between Type I and Type II diabetes

2001

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“…In siblings, HLA-DR3/4 heterozygosity identifies higher risk of T1D than HLA identity (19). Deschamps and coworkers examined the predictive value of HLA typing in a study of 536 siblings of diabetic probands in France (20). The risk of T1D after 8 years, estimated by life-table analysis, was 10% for siblings who were HLA identical with the probands, 3%–4% for siblings with either DR3 or DR4, and 16% for those with the HLA-DR3/DR4 genotype.…”

Section: Hla Class II Allelesmentioning

confidence: 99%

Genetics of Type 1 Diabetes

2011

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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.

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“…Type 1 diabetes mellitus (T1DM) is an autoimmune disease resulting from destruction of insulin‐producing beta cells of the pancreas. Genetic studies of T1DM have uncovered a major role in disease susceptibility for genes in the class II subregion of the human leukocyte antigen (HLA) region on the short arm of chromosome 6 (1–9). Specific HLA genotype/haplotype combinations appear to determine the extent of disease risk, as the HLA‐DR4,DQB1*0302, HLA‐DR3,DQB1*0201 heterozygote has the highest risk ratio for T1DM (2).…”

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confidence: 99%

Newborn HLA-DR,DQ genotype screening: age- and ethnicity-specific type 1 diabetes risk estimates

et al. 2005

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Objective-Certain human leukocyte antigen (HLA)-DR,DQ genotypes have been associated with type 1 diabetes mellitus (T1DM) risk, although it is unknown whether the association is due to alleles, haplotypes, genotypes, the formation of heterodimers, or all of the above. To characterize the role of the HLA-DR,DQ genotype and ethnicity on the onset age of T1DM, we analyzed these factors in patients with T1DM and the general population.Methods-One thousand three hundred twenty-two well-characterized patients with T1DM were compared with 3339 children from the general population of Denver, Colorado, USA. Because of the extensive available data across age and ethnic groups, this study population is unique.Results-The HLA-DR3/4,DQB1*0302, DRX/4,DQB1*0302 (where X = 1, 4, 8, and 9), and HLA-DR3/3 genotypes were associated with T1DM, supporting previous research. Additionally, the DR3/9 genotype showed a positive association with T1DM, which has not previously been described in Caucasian populations. The HLA-DR3/4*0302 genotype was most strongly associated with T1DM in diabetic individuals with the youngest onset age. Genotype frequencies were similar between Hispanics and non-Hispanic whites, except for the DR3/3 genotype, which was more likely to be found in non-Hispanic whites.Conclusions-These results indicate that there are multiple alleles and genotypes associated with T1DM and that the risk associated with different genetic markers depends on the age of disease onset, suggesting that some markers may be involved in more rapid disease progression. Keywordsage of onset; ethnic groups; gene frequency; genetic predisposition to disease; genetic screening Type 1 diabetes mellitus (T1DM) is an autoimmune disease resulting from destruction of insulin-producing beta cells of the pancreas. Genetic studies of T1DM have uncovered a major role in disease susceptibility for genes in the class II subregion of the human leukocyte antigen (HLA) region on the short arm of chromosome 6 (1-9). Specific HLA genotype/haplotype combinations appear to determine the extent of disease risk, as the HLA-DR4,DQB1*0302, HLA-DR3,DQB1*0201 heterozygote has the highest risk ratio for T1DM (2). This synergistic effect can be explained by the formation of certain DQ trans-dimers, which may be responsible Racial and ethnic differences exist in the incidence of T1DM, even within the same geographic area (18,19), with highest incidence rates in non-Hispanic whites as compared with other races and ethnic groups (15,(18)(19)(20). Frequencies of specific alleles and haplotypes have been found to be similar between Hispanics and non-Hispanic whites (21-23), although haplotype relative risks between the two ethnic groups differed (24,25). This could indicate the presence of ethnically different HLA-linked genetic modifiers acting upon susceptibility genotypes or an effect of genetic admixture on predisposing factors to T1DM (24-26).The incidence of T1DM peaks at 8-12 yr of age; however, the disease can be diagnosed at any age. It has been hypothesi...

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The role of DQ alpha–beta heterodimers in genetic susceptibility to insulin‐dependent diabetes

Cited by 17 publications

References 156 publications

The accelerator hypothesis: weight gain as the missing link between Type I and Type II diabetes

The accelerator hypothesis: weight gain as the missing link between Type I and Type II diabetes

Genetics of Type 1 Diabetes

Newborn HLA-DR,DQ genotype screening: age- and ethnicity-specific type 1 diabetes risk estimates

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