7 Trans-racial gene mapping studies

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Summary

A major component of inherited susceptibility to IDDM is associated with one or more loci in the MHC. Identification of the primary susceptibility genes has been complicated by the low frequency of recombination, i.e. linkage disequilibrium, within the MHC. It is difficult to distinguish whether a detected genetic association with the disease is primary, or secondary due to linkage disequilibrium with an allele at another locus which is directly predisposing. During the evolution of different races, however, recombination within the MHC has occurred and population-specific MHC haplotypes exist. Primary susceptibility alleles should be associated with disease in all racial groups, regardless of genetic background. It is unlikely that disease associations secondary to linkage disequilibrium will be consistent in these groups. This chapter reviews the known associations of candidate class II susceptibility alleles with IDDM in the five largest racial groups; white Caucasians, Asian Indians, Negroids, Japanese and Chinese.

These trans-racial studies suggest that the DQ molecule has a primary role in predisposition to IDDM. There are consistent findings of a positive association with the DQA1*0301 allele and negative associations with the DQB1*0602 and DQB1*0603 alleles. These two alleles differ by a single codon and so the encoded DQβ chains are likely to have similar functions.

DR4-associated susceptibility is associated with the DQA1*0301 allele in all races tested so far but this allele cannot be the only susceptibility factor on this haplotype. The identity of the DR3-associated susceptibility factor remains unclear but the DQB1*0201 allele is a candidate. If DQB1*0201 is involved, the existence of a protective factor on the neutral DR7-DQB1*0201 haplotypes is indicated. Analysis of DR9 associated susceptibility implicates a non-DR/DQ predisposing factor.

References (84)

  • BadenhoopK et al.

    TNF-α polymorphism in Type I (insulin-dependent) diabetes mellitus

    Diabetologia

    (1989)
  • BarnettAH

    Diabetes, race and genes

    Diabetic Medicine

    (1989)
  • BaurMP et al.

    Reference tables of two-locus haplotype frequencies for all MHC marker loci

  • BhatiaE et al.

    HLA-DR antigen frequencies in a North Indian type I diabetic population

    Diabetes

    (1985)
  • BillJ et al.

    The MHC molecule I-E is necessary but not sufficient for the clonal deletion of V-β II-bearing T cells

    Journal of Experimental Medicine

    (1989)
  • BodmerJG et al.

    Nomenclature for factors of the HLA system 1989

    Tissue Antigens

    (1990)
  • BrownJH et al.

    A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules

    Nature

    (1988)
  • ChanSH et al.

    HLA and insulin-dependent diabetes mellitus in Singaporean Chinese

    Annals of the Academy of Medicine, Singapore

    (1985)
  • CohenN et al.

    HLA-DR2-associated Dw subtypes correlate with RFLP clusters: most DR2 IDDM patients belong to one of these clusters

    Immunogenetics

    (1986)

  • Geographic patterns of childhood insulin-dependent diabetes mellitus

    Diabetes

    (1988)
  • DunstonGM et al.

    HLA-DR, DQ heterogeneity in American Blacks is associated with susceptibility and resistance to insulin-dependent diabetes mellitus

  • EastealS et al.

    HLA-DP, -DQ and -DR RFLP types in South Indian insulin-dependent diabetes mellitus patients

    Tissue Antigens

    (1990)
  • ErlichHA et al.

    HLA-DQ β sequence polymorphism and genetic susceptibility to IDDM

    Diabetes

    (1990)
  • FanLA et al.

    HLA and insulin-dependent diabetes mellitus

    Chinese Medical Journal

    (1984)
  • FieldLL

    Genes predisposing to IDDM in multiplex families

    Genetic Epidemiology

    (1989)
  • FletcherJ et al.

    Class II HLA DNA polymorphisms in Type I (insulin-dependent) diabetic patients of North Indian origin

    Diabetologia

    (1988)
  • FletcherJ et al.

    Trans-racial studies implicate HLA-DQ as a component of genetic susceptibility to Type I (insulin-dependent) diabetes

    Diabetologia

    (1988)
  • GyllenstenUB et al.

    Generation of single-stranded DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus

  • HawkinsBR et al.

    Strong association with HLA-DR3/DRw9 heterozygosity with early-onset insulin-dependent diabetes mellitus in Chinese

    Diabetes

    (1987)
  • HawkinsBR et al.

    Distribution of and co-occurrence of MHC class I, II and III markers in Southern Chinese: implications for autoimmune disease

    Disease Markers

    (1988)
  • HitmanGA et al.

    A DR3-related gene polymorphism strongly associates with insulin-dependent diabetes mellitus

    Immunogenetics

    (1986)
  • HornGT et al.

    Allelic sequence variation of the HLA-DQ loci: relationship to serology and to insulin-dependent diabetes susceptibility

  • ItoM et al.

    Association of HLA-DR phenotypes and T-lymphocyte-receptor-β-chain-region RFLP with IDDM in Japanese

    Diabetes

    (1988)
  • JenkinsD et al.

    Identification of susceptibility loci for Type 1 (insulin-dependent) diabetes by trans-racial gene mapping

    Diabetologia

    (1990)
  • JenkinsD et al.

    Allele-specific gene probing supports the DQ molecule as a determinant of inherited susceptibility to Type 1 (insulin-dependent) diabetes

    Diabetologia

    (1991)
  • KhalilI et al.

    A combination of HLA-DQ β Asp57-negative and HLA-DQ α Arg52 confers susceptibility to insulin-dependent diabetes mellitus

    Journal of Clinical Investigation

    (1990)
  • KidaK et al.

    Immunogenetic heterogeneity in Type I (insulin-dependent) diabetes among Japanese-HLA antigens and organ-specific antibodies

    Diabetologia

    (1989)
  • KobayashiT et al.

    The prevalence of islet cell antibodies in Japanese insulin-dependent and non-insulin-dependent diabetic patients studied by indirect immunofluorescence and by a new method

    Diabetes

    (1986)
  • Kohonen-CorishMRJ et al.

    Insulin-dependent diabetes mellitus: HLA-DR and -DQ genotyping in three ethnic groups

    Disease Markers

    (1987)
  • KwokWW et al.

    Polymorphic DQ α and DQ β interactions dictate HLA class II determinants of allorecognition

    Journal of Experimental Medicine

    (1990)
  • LouisEJ et al.

    Three allele synergistic mixed model for insulin-dependent diabetes

    Diabetes

    (1986)
  • MacDonaldMJ et al.

    HLA-DR associations in black type I diabetics in Nigeria: further support for models of inheritance

    Diabetes

    (1986)

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