HLA-DQA1 and -DQB1 Alleles Associated With Genetic Susceptibility to IDDM in a Black Population

Mijovic, C.; Jenkins, David; Jacobs, K. H.; Penny, M. A.; Fletcher, J.; Barnett, Anthony

doi:10.2337/diab.40.6.748

Cited by 47 publications

(27 citation statements)

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“…The results were similar to those of our previous study of a UK-based Jamaican population, demonstrating that differences in environment do not alter the genetic requirements for disease development. Subtyping at the DRB1 locus has revealed heterogeneity between associations with type 1 Significant in UK-based study of 37 D and 82 C only (Mijovic et al , 1991); NS in the present study.…”

Section: Discussioncontrasting

confidence: 47%

“…In our previous UK-based study (Mijovic et al , 1991), DRB1*07 and DRB1*11 haplotypes carrying DQA1*0301/DQB1*02 were positively associated with diabetes. In contrast, in the present study neither haplotype showed any significant association with disease ( Table 3).…”

Section: Discussionmentioning

confidence: 71%

“…This is the first study of HLA class II alleles in the indigenous Jamaican population. We have previously reported on DRB1 and DQ associations with type 1 diabetes in a UK-based Jamaican population but the HLA typing was of low resolution (Mijovic et al , 1991). The aim of the current study was to further define the role of DRB1 and DQ alleles in determining susceptibility to type 1 diabetes by comparing disease associations in African and white Caucasian populations.…”

Section: Introductionmentioning

confidence: 98%

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HLA‐DQ and DRB1 polymorphism and susceptibility to type 1 diabetes in Jamaica

Heward

Mijovic²,

Kelly³

et al. 2002

European Journal of Immunogenetics

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Genetic susceptibility to type 1 diabetes is determined by a combination of HLA-DQ and DRB1 alleles. In the present study, HLA associations with type 1 diabetes were investigated in the Jamaican population. DRB1 and DQ genotyping was performed on 45 type 1 diabetic patients and 132 control subjects born and resident in Jamaica. The small number of patients available for study reflected the low prevalence of type 1 diabetes in Jamaica. The results were compared with those from other African heritage populations and white Caucasians. The highest relative risk was associated with the DRB1*03-DQ2/DRB1*04-DQ8 genotype. Both DRB1*0401-DQ8 and DRB1*0408-DQ8 were positively associated with disease. DRB1*0408-DQ8 is uncommon amongst white Caucasians, where DRB1*0401-DQ8 is the major predisposing haplotype. The DRB1*1503-DQ6 haplotype was associated with protection from diabetes in the Jamaican population. This haplotype is rare amongst white Caucasians, where DRB1*1501-DQ6 is the protective haplotype. Data from African heritage populations suggest that DRB1*1503-DQ6 might be less protective than DRB1*1501-DQ6. DRB1*03-DQA1*0401-DQB1*0402 was associated with protection from diabetes in the Jamaican population, whereas in white Caucasians DRB1*08-DQA1*0401-DQB1*0402 is predisposing. These data demonstrate that comparison of genetic associations with type 1 diabetes in races with population-specific DRB1-DQ haplotypes provides new information as to the exact determinants of disease susceptibility. Further support is provided for roles of the DQ genes and the DRB1 gene (or a gene in linkage disequilibrium with it) in determining susceptibility to type 1 diabetes.

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Section: Discussioncontrasting

confidence: 47%

Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 98%

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HLA‐DQ and DRB1 polymorphism and susceptibility to type 1 diabetes in Jamaica

Heward

Mijovic²,

Kelly³

et al. 2002

European Journal of Immunogenetics

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“…In disease association studies, an allele is considered negatively associated, or protective, when there is a significantly lower frequency of the allele in the patient population compared with the controls. This has been observed for the DQB1*0602 allele and IDDM in numerous studies and in most races [10,11,[19][20][21][22][23][24][25][26]. In many of these studies some patients have been identified as having the protective allele, as occurred when we originally studied 266 IDDM patients [10].…”

Section: Discussionmentioning

confidence: 59%

Molecular Modelling of HLA‐DQ Suggests a Mechanism of Resistance in Type 1 Diabetes

Hoover

Marta

1997

Scand J Immunol

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Genetic resistance and susceptibility to insulin-dependent diabetes mellitus (IDDM) have been associated with the HLA class II region on chromosome 6. In many races, the DQB1*0602 allele has been observed at a decreased frequency in IDDM, suggesting a protective role. A DNA sequence analysis of five patients, previously typed as having allele DQB1*0602, revealed sequence variation: one is DQB1*0603 and four possess unique sequences related to DQB1*0602 (one patient) or DQB1*0603 (three patients). Samples from four unaffected controls possessed normal DQB1*0602 sequences, and all patients and controls have normal DQA1 sequences. Each of the four unique patient sequences yields predicted amino acid sequences differing from the more common DQB1 alleles by variation at codons 9, 38 (silent), 59, and/or 62. Molecular modelling of the predicted protein sequence of these permissive variants reveals an HLA-DQ structure from diabetic patients that differs in the surface contour of the peptide-binding groove from normal DQB1*0602 sequence. In all the models of permissive molecules, the surface area corresponding to the HLA-DR pockets 6, 7 and 9 are modified. These pockets accommodate side chains of the bound peptide; thus modification of this region could alter peptide specificity. This 'pocket change' suggests that the normal allele could confer dominant protection against the development of IDDM by affecting peptide and/or T cell receptor (TCR) binding. This could regulate the deletion or suppression of T cell clones inappropriately recognizing the beta cells of the pancreas.

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“…The latter shows significant abnormalities, including basement membrane thickening, which is the histological hallmark of diabetes microangiopathy. demonstrating the primacy of the HLA D region in susceptibility to Type 1 diabetes [26][27][28][29][30][31][32] and later suggesting that specifically the HLA DQA1 and HLA DQB1 alleles were the primary susceptibility determinants [33][34][35][36][37][38][39][40][41][42][43][44]. A successful collaboration with John Todd (now Professor of Human Genetics in Cambridge) led to an important paper in Nature in 1989 [39].…”

Section: And So To Geneticsmentioning

confidence: 99%

Diabetes—science, serendipity and common sense

Barnett

2011

Diabetic Medicine

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This paper is dedicated to young researchers in diabetes. One such person was Frederick Banting who, with his colleagues, isolated insulin in 1921, saving the lives of literally millions of people. What factors allowed Banting and other scientists to produce work that has immensely benefited the human race? I propose that it is the combination of good scientific background (the 'prepared mind'), commonly some serendipity taken with a good dose of common sense and supplemented by enthusiasm, tenacity and good mentoring, which drives the 'power of observation' and the ability to take forward the good idea. I give examples from history to support this and then discuss some of the 'truths, perspectives and controversies' within the diabetes arena when I first started in diabetes research in the late 1970s. I describe how my appetite was initially 'whetted' for research by moving to an excellent clinical research environment with encouragement to test ideas and controversies initially in a clinical research programme, followed by more scientific ⁄ basic research. The work that I performed as a young doctor and research fellow led to a lifelong professional interest in three major areas-causes and interventions for diabetes vascular disease, studies of the molecular genetics of Type 1 and Type 2 diabetes and work on diabetes in different ethnic groups. I provide a summation of my own and other people's work to demonstrate how research can be progressed and lead to patient benefit as well as providing an incredibly rewarding career. I believe that we need to encourage and put more resources into development of young doctors and scientists wishing to undertake research in our discipline. Areas ripe for much-needed clinical research programmes, for example, include work on best practice ⁄ provision of health care, application of the evidence base from clinical trials to achieve public health gains, attention to adherence issues and better-tolerated therapies. Most importantly, a greater emphasis on prevention through public health measures and 'buy in' from the whole population is urgently required.

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HLA-DQA1 and -DQB1 Alleles Associated With Genetic Susceptibility to IDDM in a Black Population

Cited by 47 publications

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HLA‐DQ and DRB1 polymorphism and susceptibility to type 1 diabetes in Jamaica

HLA‐DQ and DRB1 polymorphism and susceptibility to type 1 diabetes in Jamaica

Molecular Modelling of HLA‐DQ Suggests a Mechanism of Resistance in Type 1 Diabetes

Diabetes—science, serendipity and common sense

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