Transcomplementation of HLA DQA1-DQB1 in DR3/DR4 and DR3/DR9 Heterozygotes and IDDM in Taiwanese Families

Chuang, Lee‐Ming; Wu, Huey Peir; Tsai, Wen–Yu; Lin, Boniface J.; Tai, Tong Yuan

doi:10.2337/diacare.18.11.1483

Cited by 25 publications

(42 citation statements)

References 17 publications

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“…The DRB1*01-DQB1*0501 haplotype-encoded DQ b1 and a1 chains cannot form trans dimers with the DQ b1 and a1 chains from the DRB1*0401-DQB1*0302 or DRB1*03-DQB1*02 haplotypes 22 and, therefore, the difference in risk of the DRB1*0401-DQB1*0302/DRB1*01-DQB1*0501 genotype (RTP ¼ 8.8) compared to the DRB1*03-DQB1*02/ DRB1*01-DQB1*0501 genotype (RTP ¼ 2.5) can be taken as the 'neutral' reference for the difference in risk between DRB1*0401-DQB1*0302 and DRB1*03-DQB1*02 DRB1, DQA1, and DQB1 haplotypes are given. For some haplotypes (partial), subtyping of the alleles is present, otherwise serological typing is given.…”

Section: Genotype Risksmentioning

confidence: 98%

“…Apart from their incomplete disease penetrance, the risk of the DRB1*03-DQB1*02/DRB1* 0401-DQB1*0302 heterozygote genotype was found to be increased compared to that of the individual DRB1*03-DQB1*02 and DRB1*0401-DQB1*0302 homozygous genotypes, indicating an epistatic or synergistic effect. 4,21 Other genotype effects have been found for DRB1*08-DQB1*0402 (increased risk when together with DRB1*0401-DQB1*0302) and DRB1*09-DQB1*0303 (increased risk mainly with DRB1*03-DQB1*02), 6,22,23 occurring fairly consistently across several ethnic groups. 4 It has been postulated that the unexpected increase in risk of these genotypes is caused by highly susceptible transencoded DQ(a1, b1) heterodimers as formed in the DRB1*03-DQB1*02/DRB1*0401-DQB1*0302 genotype.…”

Section: Introductionmentioning

confidence: 94%

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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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Section: Genotype Risksmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 94%

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

et al. 2004

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“…in 22,26,27). In studies of Asian populations, in which the DRB1*0901-DQA1*0301g-DQB1*0303 haplotype is much more frequent, this haplotype is associated with type 1 diabetes in many studies (Table 3) (28,5,29) but not all (30). The three most protective haplotypes are DRB1*1501-DQA1*0102-DQB1*0602 (OR 0.03; P ϭ 2 ϫ 10 Ϫ29 ), DRB1*1401-DQA1*0101-DQB*0503 (0.02; P ϭ 1 ϫ 10 Ϫ6 ), and DRB1*0701-DQA1*0201-DQB1*0303 (0.02; P ϭ 4 ϫ 10 Ϫ12 ).…”

Section: ϫ05mentioning

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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“…DR4 is one of the most common DR antigens in Han Chinese. However, its phenotype frequency can be as low as 11.0% [37] or as high as 41.7% [36] in different regions. Most reported frequencies have been between 23.9 and 41.0% [36,[38][39][40][41][42][43][44].…”

Section: Dr4 In Chinesementioning

confidence: 99%

DQA1Arg52, DQB1nonAsp57, and DRB1*04 Genotypes in Chinese Children with Insulin-Dependent Diabetes mellitus

Huang

Lee

et al. 1998

Exp Clin Immunogenet

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Ethnic comparisons are extremely important and useful for studying the HLA component involved in insulin-dependent diabetes mellitus (IDDM) predisposition. To date there have been only a few reports on the association of HLA loci and IDDM in Chinese. We report here a study on DQA1*Arg52, DQB1*nonAsp57, and DRB1*04 in IDDM children and control adults among Han Chinese living in Taiwan. One hundred and fourteen unrelated children (62 boys) with IDDM were studied. Their ages at diagnosis were between 0.3 and 15.0 years (6.8 ± 3.6 years). The control population consisted of 120 randomly selected normal adults. DQA1*Arg52(+/+), DQB1*nonAsp57(+/+), and DRB1*04(+/–) were associated with IDDM (RR = 11.50, 2.21, and 2.82; p = 1.11 × 10^–15, 2.84 × 10^–3, and 1.98 × 10^–4, respectively). DQA1*Arg52, DQB1*nonAsp57, and DRB1*04 conferred risks for IDDM (RR = 12.79, 7.11, and 2.83; pc = 8.22 × 10^–4, 5.35 × 10^–3, and 5.68 × 10^–4, respectively). Combinations of DQA1*Arg52 and DRB1*04 conferred the highest risk for IDDM (RR = 19.64, pc = 5.4 × 10^–5). DQA1*Arg52 was associated with IDDM in subjects with DQB1*nonAsp57+ (RR = 14.87, pc = 2.41 × 10^–4) and DQB1*nonAsp57 was also associated with IDDM in subjects with DQA1*Arg52+ (RR = 8.41, pc = 1.54 × 10^–3), suggesting that DQA1*Arg52 and DQB1*nonAsp57 are interacting. This study demonstrates that DQA1*Arg52, DQB1*nonAsp57, and DRB1*04 confer susceptibility for IDDM to Chinese children. A combination of DQA1*Arg52 and DRB1*04 confers the highest risk and it is suggested that a susceptibility gene might be situated between DQA1*Arg52 and DRB1*04 or both are synergistic. There is an interaction between DQA1*Arg52 and DQB1*nonAsp57 and homozygosity for DQA1*Arg52/DQB1*nonAsp57, which encodes four susceptibility DQ heterodimers, confers a high risk.

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Transcomplementation of HLA DQA1-DQB1 in DR3/DR4 and DR3/DR9 Heterozygotes and IDDM in Taiwanese Families

Abstract: These data strongly suggest that the HLA-DR-associated IDDM susceptibility is most likely explained by the formation of the susceptible DQ heterodimers encoded by the DQA1/DQB1 either in cis or in trans.

Cited by 25 publications

References 17 publications

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

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

DQA1Arg52, DQB1nonAsp57, and DRB1*04 Genotypes in Chinese Children with Insulin-Dependent Diabetes mellitus

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Transcomplementation of HLA DQA1-DQB1 in DR3/DR4 and DR3/DR9 Heterozygotes and IDDM in Taiwanese Families

Abstract: These data strongly suggest that the HLA-DR-associated IDDM susceptibility is most likely explained by the formation of the susceptible DQ heterodimers encoded by the DQA1/DQB1 either in cis or in trans.

Cited by 25 publications

References 17 publications

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

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

DQA1*Arg52, DQB1*nonAsp57, and DRB1*04 Genotypes in Chinese Children with Insulin-Dependent Diabetes mellitus

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Product

Resources

About

DQA1Arg52, DQB1nonAsp57, and DRB1*04 Genotypes in Chinese Children with Insulin-Dependent Diabetes mellitus