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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1985 Dec;82(23):8100–8104. doi: 10.1073/pnas.82.23.8100

Polymorphic restriction endonuclease sites linked to the HLA-DR alpha gene: localization and use as genetic markers of insulin-dependent diabetes.

D Stetler, F C Grumet, H A Erlich
PMCID: PMC391450  PMID: 2999792

Abstract

Polymorphic restriction endonuclease sites within the HLA-DR alpha gene have been defined, localized, and used as genetic markers in the analysis of susceptibility to insulin-dependent diabetes mellitus (IDDM). Hybridization of Bgl II-digested human genomic DNA with a cDNA clone for the HLA-DR alpha chain (pDR alpha-1) has revealed three allelic restriction fragment lengths: 3.8 kilobase pairs (kb), 4.2 kb, and 4.5 kb. Hybridization of EcoRV-digested human genomic DNA with the same probe has revealed two allelic polymorphic restriction fragment lengths: 9.2 kb and 13.0 kb. By analysis of double digests of genomic DNA from individuals homozygous for each of the allelic variants, the polymorphic restriction sites were found to be clustered near the 3' end of the HLA-DR alpha gene. The observed correlations of DR alpha Bgl II restriction site variants with serologically determined DR specificities suggest linkage disequilibrium between the DR alpha and DR beta loci. The 3.8-kb fragment is correlated with the DR1 type (Pc = 4.4 X 10(-4)); and the 4.2-kb fragment, with a subset (B8,DR3) of the DR3 type (Pc = 5.1 X 10(-4)) and with the DR6 type. The segregation pattern of HLA-DR alpha polymorphic Bgl II restriction fragments was analyzed in six IDDM families. The observed association of IDDM with the Bgl II 4.2-kb DR alpha restriction variant is higher than with existing serological markers and supports the utility of this approach in elucidating IDDM inheritance.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Buck D., Greene A. E., Coriell L. L., Mulivor R. A. Juvenile onset diabetes. Cytogenet Cell Genet. 1980;28(3):213–216. doi: 10.1159/000131533. [DOI] [PubMed] [Google Scholar]
  2. Charron D. J., Aellen-Schulz M. F., St Geme J., 3rd, Erlich H. A., McDevitt H. O. Biochemical characterization of an invariant polypeptide associated with Ia antigens in human and mouse. Mol Immunol. 1983 Jan;20(1):21–32. doi: 10.1016/0161-5890(83)90101-3. [DOI] [PubMed] [Google Scholar]
  3. Charron D. J., McDevitt H. O. Analysis of HLA-D region-associated molecules with monoclonal antibody. Proc Natl Acad Sci U S A. 1979 Dec;76(12):6567–6571. doi: 10.1073/pnas.76.12.6567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Conner B. J., Reyes A. A., Morin C., Itakura K., Teplitz R. L., Wallace R. B. Detection of sickle cell beta S-globin allele by hybridization with synthetic oligonucleotides. Proc Natl Acad Sci U S A. 1983 Jan;80(1):278–282. doi: 10.1073/pnas.80.1.278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Das H. K., Lawrance S. K., Weissman S. M. Structure and nucleotide sequence of the heavy chain gene of HLA-DR. Proc Natl Acad Sci U S A. 1983 Jun;80(12):3543–3547. doi: 10.1073/pnas.80.12.3543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dawkins R. L., Christiansen F. T., Kay P. H., Garlepp M., McCluskey J., Hollingsworth P. N., Zilko P. J. Disease associations with complotypes, supratypes and haplotypes. Immunol Rev. 1983;70:5–22. doi: 10.1111/j.1600-065x.1983.tb00707.x. [DOI] [PubMed] [Google Scholar]
  7. De Kretser T. A., Crumpton M. J., Bodmer J. G., Bodmer W. F. Two-dimensional gel analysis of the polypeptides precipitated by a polymorphic HLA-DR1,2,w6 monoclonal antibody: evidence for a third locus. Eur J Immunol. 1982 Jul;12(7):600–606. doi: 10.1002/eji.1830120713. [DOI] [PubMed] [Google Scholar]
  8. Doniach D., Bottazzo G. F., Cudworth A. G. Etiology of Type I diabetes mellitus: heterogeneity and immunological events leading to clinical onset. Annu Rev Med. 1983;34:13–20. doi: 10.1146/annurev.me.34.020183.000305. [DOI] [PubMed] [Google Scholar]
  9. Erlich H. A., Stetler D., Saiki R., Gladstone P., Pious D. Mapping of the genes encoding the HLA-DR alpha chain and the HLA-related antigens to a chromosome 6 deletion by using genomic blotting. Proc Natl Acad Sci U S A. 1983 Apr;80(8):2300–2304. doi: 10.1073/pnas.80.8.2300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Groner J. P., Watson A. J., Bach F. H. Dw/LD-related molecular polymorphism of DR4 beta-chains. J Exp Med. 1983 May 1;157(5):1687–1691. doi: 10.1084/jem.157.5.1687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Korman A. J., Auffray C., Schamboeck A., Strominger J. L. The amino acid sequence and gene organization of the heavy chain of the HLA-DR antigen: homology to immunoglobulins. Proc Natl Acad Sci U S A. 1982 Oct;79(19):6013–6017. doi: 10.1073/pnas.79.19.6013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Korman A. J., Knudsen P. J., Kaufman J. F., Strominger J. L. cDNA clones for the heavy chain of HLA-DR antigens obtained after immunopurification of polysomes by monoclonal antibody. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1844–1848. doi: 10.1073/pnas.79.6.1844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Larhammar D., Gustafsson K., Claesson L., Bill P., Wiman K., Schenning L., Sundelin J., Widmark E., Peterson P. A., Rask L. Alpha chain of HLA-DR transplantation antigens is a member of the same protein superfamily as the immunoglobulins. Cell. 1982 Aug;30(1):153–161. doi: 10.1016/0092-8674(82)90021-6. [DOI] [PubMed] [Google Scholar]
  14. Lee J. S., Trowsdale J., Bodmer W. F. cDNA clones coding for the heavy chain of human HLA-DR antigen. Proc Natl Acad Sci U S A. 1982 Jan;79(2):545–549. doi: 10.1073/pnas.79.2.545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Nepom B. S., Nepom G. T., Mickelson E., Antonelli P., Hansen J. A. Electrophoretic analysis of human HLA-DR antigens from HLA-DR4 homozygous cell lines: correlation between beta-chain diversity and HLA-D. Proc Natl Acad Sci U S A. 1983 Nov;80(22):6962–6966. doi: 10.1073/pnas.80.22.6962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Platz P., Jakobsen B. K., Morling N., Ryder L. P., Svejgaard A., Thomsen M., Christy M., Kromann H., Benn J., Nerup J. HLA-D and -DR antigens in genetic analysis of insulin dependent diabetes mellitus. Diabetologia. 1981 Aug;21(2):108–115. doi: 10.1007/BF00251276. [DOI] [PubMed] [Google Scholar]
  17. Ryder L. P., Svejgaard A., Dausset J. Genetics of HLA disease association. Annu Rev Genet. 1981;15:169–187. doi: 10.1146/annurev.ge.15.120181.001125. [DOI] [PubMed] [Google Scholar]
  18. Shackelford D. A., Kaufman J. F., Korman A. J., Strominger J. L. HLA-DR antigens: structure, separation of subpopulations, gene cloning and function. Immunol Rev. 1982;66:133–187. doi: 10.1111/j.1600-065x.1982.tb00437.x. [DOI] [PubMed] [Google Scholar]
  19. Stetler D., Das H., Nunberg J. H., Saiki R., Sheng-Dong R., Mullis K. B., Weissman S. M., Erlich H. A. Isolation of a cDNA clone for the human HLA-DR antigen alpha chain by using a synthetic oligonucleotide as a hybridization probe. Proc Natl Acad Sci U S A. 1982 Oct;79(19):5966–5970. doi: 10.1073/pnas.79.19.5966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Thomson G. A review of theoretical aspects of HLA and disease associations. Theor Popul Biol. 1981 Oct;20(2):168–208. doi: 10.1016/0040-5809(81)90009-5. [DOI] [PubMed] [Google Scholar]
  21. Thomson G. Investigation of the mode of inheritance of the HLA associated diseases by the method of antigen genotype frequencies among diseased individuals. Tissue Antigens. 1983 Feb;21(2):81–104. doi: 10.1111/j.1399-0039.1983.tb00377.x. [DOI] [PubMed] [Google Scholar]
  22. Wake C. T., Long E. O., Strubin M., Gross N., Accolla R., Carrel S., Mach B. Isolation of cDNA clones encoding HLA-DR alpha chains. Proc Natl Acad Sci U S A. 1982 Nov;79(22):6979–6983. doi: 10.1073/pnas.79.22.6979. [DOI] [PMC free article] [PubMed] [Google Scholar]

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