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. 1989 Mar;83(3):830–835. doi: 10.1172/JCI113965

A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles.

M J Sheehy 1, S J Scharf 1, J R Rowe 1, M H Neme de Gimenez 1, L M Meske 1, H A Erlich 1, B S Nepom 1
PMCID: PMC303755  PMID: 2784133

Abstract

HLA-DR4 is associated with insulin-dependent diabetes mellitus (IDDM) in many populations. Many recent studies suggest that the DR4 effect is really due to DQ3.2, an allele of the nearby DQB1 locus. We used T cell clones, MAb, and allele-specific oligonucleotides to test IDDM and control subjects for DR4 subtypes (Dw4, Dw10, Dw13, and Dw14) and for DR4-associated DQB1 alleles (DQ3.1 and DQ3.2). We find that (a) IDDM is approximately equally associated with alleles of the DRB1 locus (Dw4 and Dw10, combined relative risk, RR = 6.4) and the DQB1 locus (DQ3.2, RR = 5.9); and (b) there is significant interaction, in a statistical sense, between these DR and DQ alleles in IDDM. The only IDDM-associated DR4 haplotypes were those carrying the IDDM-associated alleles at both loci (RR = 12.1); haplotypes with Dw4 or 10 but not DQ3.2, or vice versa, had a RR less than 1. Alternative explanations include: (a) that susceptibility requires specific allelic products of both DR and DQ loci; (b) that the combination of certain DR and DQ alleles marks haplotypes with the true susceptibility allele at a third locus; or (c) that Dw4 and 10 mark haplotypes with an allele at another locus that interacts with DQ3.2. As discussed, this third locus is unlikely to be DQA1 (DQ alpha). The data thus are not easily reconciled with an exclusive effect of HLA-DQ. This information increases our ability to predict IDDM by genetic typing: in the population studied, heterozygotes DR3/[DQ3.2, Dw4] or DR3/[DQ3.2, Dw10] had a relative risk of 38.0 and an absolute risk of 1 in 15.

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Selected References

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  1. Ambinder J. N., Chiorazzi N., Gibofsky A., Fotino M., Kunkel H. G. Special characteristics of cellular immune function in normal individuals of the HLA-DR3 type. Clin Immunol Immunopathol. 1982 May;23(2):269–274. doi: 10.1016/0090-1229(82)90113-1. [DOI] [PubMed] [Google Scholar]
  2. Arnheim N., Strange C., Erlich H. Use of pooled DNA samples to detect linkage disequilibrium of polymorphic restriction fragments and human disease: studies of the HLA class II loci. Proc Natl Acad Sci U S A. 1985 Oct;82(20):6970–6974. doi: 10.1073/pnas.82.20.6970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bach F. H., Rich S. S., Barbosa J., Segall M. Insulin-dependent diabetes--associated HLA-D region encoded determinants. Hum Immunol. 1985 Feb;12(2):59–64. doi: 10.1016/0198-8859(85)90343-x. [DOI] [PubMed] [Google Scholar]
  4. Böhme J., Carlsson B., Wallin J., Möller E., Persson B., Peterson P. A., Rask L. Only one DQ-beta restriction fragment pattern of each DR specificity is associated with insulin-dependent diabetes. J Immunol. 1986 Aug 1;137(3):941–947. [PubMed] [Google Scholar]
  5. Cavender D. E., Wagener D. K., Rabin B. S., Becker D. J., Orchard T. J., Eberhardt M. S., LaPorte R. E., Drash A. L., Kuller L. H. The Pittsburgh Insulin-Dependent Diabetes Mellitus (IDDM) study. HLA antigens and haplotypes as risk factors for the development of IDDM in IDDM patients and their siblings. J Chronic Dis. 1984;37(7):555–568. doi: 10.1016/0021-9681(84)90006-7. [DOI] [PubMed] [Google Scholar]
  6. Christy M., Green A., Christau B., Kromann H., Nerup J., Platz P., Thomsen M., Ryder L. P., Svejgaard A. Studies of the HLA system and insulin-dependent diabetes mellitus. Diabetes Care. 1979 Mar-Apr;2(2):209–214. doi: 10.2337/diacare.2.2.209. [DOI] [PubMed] [Google Scholar]
  7. Cohen-Haguenauer O., Robbins E., Massart C., Busson M., Deschamps I., Hors J., Lalouel J. M., Dausset J., Cohen D. A systematic study of HLA class II-beta DNA restriction fragments in insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A. 1985 May;82(10):3335–3339. doi: 10.1073/pnas.82.10.3335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cudworth A. G., Wolf E. The genetics of Type 1 (insulin-dependent) diabetes. Curr Probl Clin Biochem. 1983;12:45–64. [PubMed] [Google Scholar]
  9. Festenstein H., Awad J., Hitman G. A., Cutbush S., Groves A. V., Cassell P., Ollier W., Sachs J. A. New HLA DNA polymorphisms associated with autoimmune diseases. Nature. 1986 Jul 3;322(6074):64–67. doi: 10.1038/322064a0. [DOI] [PubMed] [Google Scholar]
  10. Gregersen P. K., Shen M., Song Q. L., Merryman P., Degar S., Seki T., Maccari J., Goldberg D., Murphy H., Schwenzer J. Molecular diversity of HLA-DR4 haplotypes. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2642–2646. doi: 10.1073/pnas.83.8.2642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hansen J. A., Martin P. J., Kamoun M., Nisperos B., Thomas E. D. A supertypic HLA-DR specificity (DR4+5) defined by murine monoclonal antibody. Hum Immunol. 1981 Mar;2(2):103–111. doi: 10.1016/0198-8859(81)90057-4. [DOI] [PubMed] [Google Scholar]
  12. Horn G. T., Bugawan T. L., Long C. M., Erlich H. A. Allelic sequence variation of the HLA-DQ loci: relationship to serology and to insulin-dependent diabetes susceptibility. Proc Natl Acad Sci U S A. 1988 Aug;85(16):6012–6016. doi: 10.1073/pnas.85.16.6012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Klein R., Klein B. E., Moss S. E., DeMets D. L., Kaufman I., Voss P. S. Prevalence of diabetes mellitus in southern Wisconsin. Am J Epidemiol. 1984 Jan;119(1):54–61. doi: 10.1093/oxfordjournals.aje.a113725. [DOI] [PubMed] [Google Scholar]
  14. Koning F., Raghoebar J., Schreuder G. M., Schuurman R., Bruning H. A monoclonal antibody detecting an HLA-DQwl-related determinant. Tissue Antigens. 1985 Aug;26(2):100–109. doi: 10.1111/j.1399-0039.1985.tb00941.x. [DOI] [PubMed] [Google Scholar]
  15. Korman A. J., Boss J. M., Spies T., Sorrentino R., Okada K., Strominger J. L. Genetic complexity and expression of human class II histocompatibility antigens. Immunol Rev. 1985 Jul;85:45–86. doi: 10.1111/j.1600-065x.1985.tb01130.x. [DOI] [PubMed] [Google Scholar]
  16. MacDonald M. J., Gottschall J., Hunter J. B., Winter K. L. HLA-DR4 in insulin-dependent diabetic parents and their diabetic offspring: a clue to dominant inheritance. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7049–7053. doi: 10.1073/pnas.83.18.7049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Maeda H. Mouse monoclonal antibody detects a new polymorphic Ia determinant other than HLA-DR antigen: a possible allele of DC-1. Tissue Antigens. 1984 Mar;23(3):163–170. doi: 10.1111/j.1399-0039.1984.tb00027.x. [DOI] [PubMed] [Google Scholar]
  18. Michelsen B., Lernmark A. Molecular cloning of a polymorphic DNA endonuclease fragment associates insulin-dependent diabetes mellitus with HLA-DQ. J Clin Invest. 1987 Apr;79(4):1144–1152. doi: 10.1172/JCI112931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Miettinen O. Estimability and estimation in case-referent studies. Am J Epidemiol. 1976 Feb;103(2):226–235. doi: 10.1093/oxfordjournals.aje.a112220. [DOI] [PubMed] [Google Scholar]
  20. Nepom B. S., Palmer J., Kim S. J., Hansen J. A., Holbeck S. L., Nepom G. T. Specific genomic markers for the HLA-DQ subregion discriminate between DR4+ insulin-dependent diabetes mellitus and DR4+ seropositive juvenile rheumatoid arthritis. J Exp Med. 1986 Jul 1;164(1):345–350. doi: 10.1084/jem.164.1.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nishimoto H., Kikutani H., Yamamura K., Kishimoto T. Prevention of autoimmune insulitis by expression of I-E molecules in NOD mice. 1987 Jul 30-Aug 5Nature. 328(6129):432–434. doi: 10.1038/328432a0. [DOI] [PubMed] [Google Scholar]
  22. Owerbach D., Lernmark A., Platz P., Ryder L. P., Rask L., Peterson P. A., Ludvigsson J. HLA-D region beta-chain DNA endonuclease fragments differ between HLA-DR identical healthy and insulin-dependent diabetic individuals. Nature. 1983 Jun 30;303(5920):815–817. doi: 10.1038/303815a0. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Raum D., Awdeh Z., Yunis E. J., Alper C. A., Gabbay K. H. Extended major histocompatibility complex haplotypes in type I diabetes mellitus. J Clin Invest. 1984 Aug;74(2):449–454. doi: 10.1172/JCI111441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Reinsmoen N. L., Bach F. H. Five HLA-D clusters associated with HLA-DR4. Hum Immunol. 1982 Jun;4(3):249–258. doi: 10.1016/0198-8859(82)90040-4. [DOI] [PubMed] [Google Scholar]
  26. Rotter J. I., Anderson C. E., Rubin R., Congleton J. E., Terasaki P. I., Rimoin D. L. HLA genotypic study of insulin-dependent diabetes the excess of DR3/DR4 heterozygotes allows rejection of the recessive hypothesis. Diabetes. 1983 Feb;32(2):169–174. doi: 10.2337/diab.32.2.169. [DOI] [PubMed] [Google Scholar]
  27. Rowe J. R., Mickelson E. M., Hansen J. A., MacDonald M. J., Allen C. I., Gabbay K. H., Yunis E. J., Sheehy M. J. T-cell-defined DR4 subtypes as markers for type 1 diabetes. Hum Immunol. 1988 May;22(1):51–60. doi: 10.1016/0198-8859(88)90051-1. [DOI] [PubMed] [Google Scholar]
  28. Scharf S. J., Friedmann A., Brautbar C., Szafer F., Steinman L., Horn G., Gyllensten U., Erlich H. A. HLA class II allelic variation and susceptibility to pemphigus vulgaris. Proc Natl Acad Sci U S A. 1988 May;85(10):3504–3508. doi: 10.1073/pnas.85.10.3504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Scharf S. J., Long C. M., Erlich H. A. Sequence analysis of the HLA-DR beta and HLA-DQ beta loci from three Pemphigus vulgaris patients. Hum Immunol. 1988 May;22(1):61–69. doi: 10.1016/0198-8859(88)90052-3. [DOI] [PubMed] [Google Scholar]
  30. Schreuder G. M., Maeda H., Koning F., D'Amaro J. TA10 and 2B3, two new alleles in the HLA-DQ region recognized by monoclonal antibodies. Hum Immunol. 1986 Jun;16(2):127–136. doi: 10.1016/0198-8859(86)90041-8. [DOI] [PubMed] [Google Scholar]
  31. Shaw S., Duquesnoy R. J., Smith P. L. Population studies of the HLA-linked SB antigens. Immunogenetics. 1981;14(1-2):153–162. doi: 10.1007/BF00344308. [DOI] [PubMed] [Google Scholar]
  32. Sheehy M. J., Quintieri F. B., Yang S. Y., Alosco S. M., Matsui Y., Yunis E. J., Gabbay K. H. HLA antigens of insulin-dependent diabetics. I. PLT colonies detecting Dw10 and a new class II determinant distinct from HLA-D, DR, MB(DC), MT, and SB. Tissue Antigens. 1984 May;23(5):290–300. [PubMed] [Google Scholar]
  33. Sheehy M. J., Rowe J. R., MacDonald M. J. A particular subset of HLA-DR4 accounts for all or most of the DR4 association in type I diabetes. Diabetes. 1985 Sep;34(9):942–944. doi: 10.2337/diab.34.9.942. [DOI] [PubMed] [Google Scholar]
  34. Suciu-Foca N., Rubinstein P., Nicholson J., Susinno E., Weiner J., Godfrey M., Hardy M., Rayfield E., Reemtsma K. Juvenile diabetes mellitus and the HLA system. Transplant Proc. 1979 Jun;11(2):1309–1313. [PubMed] [Google Scholar]
  35. Svejgaard A., Platz P., Ryder L. P. HLA and disease 1982--a survey. Immunol Rev. 1983;70:193–218. doi: 10.1111/j.1600-065x.1983.tb00715.x. [DOI] [PubMed] [Google Scholar]
  36. Tait B. D., Boyle A., Solty S., Cunningham T., Mandel T., Martin F. I., Doran T. DR4 related antisera pattern differences in insulin dependent diabetes mellitus and rheumatoid arthritis. Tissue Antigens. 1984 Oct;24(4):228–233. doi: 10.1111/j.1399-0039.1984.tb02131.x. [DOI] [PubMed] [Google Scholar]
  37. Todd J. A., Bell J. I., McDevitt H. O. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature. 1987 Oct 15;329(6140):599–604. doi: 10.1038/329599a0. [DOI] [PubMed] [Google Scholar]
  38. WOOLF B. On estimating the relation between blood group and disease. Ann Hum Genet. 1955 Jun;19(4):251–253. doi: 10.1111/j.1469-1809.1955.tb01348.x. [DOI] [PubMed] [Google Scholar]

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