Combinations of specific DRB1, DQA1, DQB1 haplotypes are associated with insulin-dependent diabetes mellitus in sardinia

Cucca, Francesco; Muntoni, F.; Lampis, Rosanna; Frau, Franco; Argiolas, Luisa; Silvetti, M; Angius, Efisio; Cao, Antonio; Virgiliis, Stefano De; Congia, Mauro

doi:10.1016/0198-8859(93)90146-r

Cited by 119 publications

(106 citation statements)

References 38 publications

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“…While other studies have shown that DRB1*16-DQ5 and DRB1*15-DQ5 are permissive for childhood diabetes among Sardinians 28 and Filipinos, 29 respectively, it is not known if this is an isolated effect of DQ5 or a genotypic effect that depends on the haplotype paired with DQ5, and in particular, on the presence of DR3-DQ2.…”

Section: Resultsmentioning

confidence: 91%

Differential effects of DRB10301 and DQA10501-DQB1*0201 on the activation and progression of islet cell autoimmunity

et al. 2007

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Autoimmune diabetes shows extreme variation in age of onset and clinical presentation, although most studies have been done in children with the most severe subtype. Disease risk is strongly associated with HLA-DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2), but it has not been possible to separate the effects of the DR and DQ alleles. We have identified a large Bedouin kindred in which a high prevalence of islet autoimmunity is associated with two different DR3 haplotypes, one carrying the usual DQ2 and the other carrying DQA1*0102-DQB1*0502 (DQ5). Results of prospective follow-up studies indicate that DR3 is associated with the initial activation of islet autoimmunity whereas DQ2 is associated with early-onset and severe clinical disease. The association signals map to a 350-kb interval, thus implicating primary effects for DR3 and DQ2. Overall, our results emphasize the importance of prospective genetic studies that examine the full range of variation in the initiation, progression and expression of autoimmune disease.

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Section: Resultsmentioning

confidence: 91%

Differential effects of DRB10301 and DQA10501-DQB1*0201 on the activation and progression of islet cell autoimmunity

et al. 2007

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“…Most clear is the lower risk of DRB1*0403 and DRB1*0406 as previously described. [35][36][37] DRB1*0403 and DRB1*0406 share the E at position -74, which differentiates the two from the high-risk DRB1*0401 allele. Position -74 is part of the P4 pocket of the DRB1 molecule, which has been consistently implicated in several models for disease prediction in rheumatoid arthritis.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4] A large number of publications have established that particular combinations of alleles at HLA-DQB1, -DQA1, and -DRB1 show strong association with T1D. [5][6][7][8][9][10][11][12] The complex nature of this association is partly caused by the presence of multiple susceptible and protective HLA class II haplotypes, and may be modified by the presence of multiple other loci in the MHC region. 13,14 The haplotypes DRB1*0401-DQA1*0301-DQB1*0302 and DRB1*0301-DQA1*0501-DQB1*0201 have been found to be the major susceptible haplotypes in most populations, whereas DRB1*1501-DQA1*0102-DQB1* 0602 has been described to be protective in a dominant manner.…”

Section: Introductionmentioning

confidence: 99%

Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease

et al. 2004

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Alleles of HLA class II genes DQB1, DQA1, and DRB1 in the MHC region are major determinants of genetic predisposition to type 1 diabetes (T1D). Several alleles of each of these three loci are associated with susceptibility or protection from disease. In addition, relative risks for some DR-DQ genotypes are not simply the sum or product of the single haplotype relative risks. For example, the risk of the DRB1*03-DQB1*02/DRB1*0401-DQB1*0302 genotype is often found to be higher than for the individual DRB1*03-DQB1*02 and DRB1*0401-DQB1*0302 homozygous genotypes. It has been hypothesized that this synergy or epistasis occurs through formation of highly susceptible trans-encoded HLA-DQ(a1, b1) heterodimers. Here, we evaluated this hypothesis by estimating the disease associations of the range of DR-DQ genotypes and their inferred dimers in a large collection of nuclear families. We determined whether the risk of haplotypes in DRB1*0401-DQB1*0302-positive genotypes relative to the DRB1*03-DQB1*02-positive genotypes is different from that of DRB1*01-DQB1*0501, which we used as a baseline reference. Several haplotypes showed a different risk compared to DRB1*01-DQB1*0501, which correlated with their ability to form certain trans-encoded DQ dimers. This result provides new evidence for the potential importance of transencoded HLA DQ molecules in the determination of HLA-associated risk in T1D.

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“…We have analyzed the disease associations at the level of these three-locus haplotypes rather than that of individual loci because it has been well established that the extent of type 1 diabetes risk is determined by specific combinations of DRB1, DQA1, and DQB1 alleles (3,6,7). For example, the DRB1*0401-DQA1*0301g-DQB1*0302 haplotype has an odds ratio (OR) of 8.39 while the DRB1*0401-DQA1*0301g-DQB1*0301 has an OR of 0.35 (Table 2), implicating the DQB1*0302 allele as a critical susceptibility allele.…”

Section: Association Of Dr-dq Haplotypesmentioning

confidence: 99%

HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk

Erlich

Valdes²,

Noble³

et al. 2008

Diabetes

686

571

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OBJECTIVE-The Type 1 Diabetes Genetics Consortium has collected type 1 diabetic families worldwide for genetic analysis. The major genetic determinants of type 1 diabetes are alleles at the HLA-DRB1 and DQB1 loci, with both susceptible and protective DR-DQ haplotypes present in all human populations. The aim of this study is to estimate the risk conferred by specific DR-DQ haplotypes and genotypes.RESEARCH DESIGN AND METHODS:-Six hundred and seven Caucasian families and 38 Asian families were typed at high resolution for the DRB1, DQA1, and DQB1 loci. The association analysis was performed by comparing the frequency of DR-DQ haplotypes among the chromosomes transmitted to an affected child with the frequency of chromosomes not transmitted to any affected child.RESULTS-A number of susceptible, neutral, and protective DR-DQ haplotypes have been identified, and a statistically significant hierarchy of type 1 diabetes risk has been established. The most susceptible haplotypes are the DRB1*0301-DQA1*0501-DQB1*0201 (odds ratio [OR] 3.64) and the

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Combinations of specific DRB1, DQA1, DQB1 haplotypes are associated with insulin-dependent diabetes mellitus in sardinia

Cited by 119 publications

References 38 publications

Differential effects of DRB10301 and DQA10501-DQB1*0201 on the activation and progression of islet cell autoimmunity

Differential effects of DRB10301 and DQA10501-DQB1*0201 on the activation and progression of islet cell autoimmunity

Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease

HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk

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Combinations of specific DRB1, DQA1, DQB1 haplotypes are associated with insulin-dependent diabetes mellitus in sardinia

Cited by 119 publications

References 38 publications

Differential effects of DRB1*0301 and DQA1*0501-DQB1*0201 on the activation and progression of islet cell autoimmunity

Differential effects of DRB1*0301 and DQA1*0501-DQB1*0201 on the activation and progression of islet cell autoimmunity

Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease

HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk

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Product

Resources

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Differential effects of DRB10301 and DQA10501-DQB1*0201 on the activation and progression of islet cell autoimmunity

Differential effects of DRB10301 and DQA10501-DQB1*0201 on the activation and progression of islet cell autoimmunity