Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1992 Dec;90(6):2242–2250. doi: 10.1172/JCI116110

Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus.

S Caillat-Zucman 1, H J Garchon 1, J Timsit 1, R Assan 1, C Boitard 1, I Djilali-Saiah 1, P Bougnères 1, J F Bach 1
PMCID: PMC443375  PMID: 1469084

Abstract

The association of insulin-dependent diabetes mellitus (IDDM) with certain HLA alleles is well documented in pediatric patients. Whether a similar association is found in adult-on-set IDDM is not clear, although the disease occurs after the age of 20 in 50% of cases. HLA class II DRB1, DQA1, and DQB1 alleles were studied in 402 type I diabetics and 405 healthy controls (all Caucasian) using oligonucleotide typing after gene amplification. Alleles DRB1*03, DRB1*04, DQB1*0201, DQB1*0302, DQA1*0301, and DQA1*0501 were indeed enriched in diabetics and the highest relative risk was observed in patients carrying both the DRB1*03-DQB1*0201 and the DRB1*0402 or DRB1*0405-DQB1*0302 haplotypes. However none of these alleles, or specific residues, could alone account for the susceptibility to IDDM. Furthermore, there were major differences in HLA class II gene profiles according to the age of onset. Patients with onset after 15 yr (n = 290) showed a significantly higher percentage of non-DR3/non-DR4 genotypes than those with childhood onset (n = 112) and a lower percentage of DR3/4 genotypes. These non-DR3/non-DR4 patients, although presenting clinically as IDDM type 1 patients, showed a lower frequency of islet cell antibodies at diagnosis and a significantly milder initial insulin deficiency. These subjects probably represent a particular subset of IDDM patients in whom frequency increases with age. The data confirm the genetic heterogeneity of IDDM and call for caution in extrapolating to adult patients the genetic concepts derived from childhood IDDM.

Full text

PDF
2242

Selected References

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

  1. Andersen L. C., Beaty J. S., Nettles J. W., Seyfried C. E., Nepom G. T., Nepoom B. S. Allelic polymorphism in transcriptional regulatory regions of HLA-DQB genes. J Exp Med. 1991 Jan 1;173(1):181–192. doi: 10.1084/jem.173.1.181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Angelini G., de Preval C., Gorski J., Mach B. High-resolution analysis of the human HLA-DR polymorphism by hybridization with sequence-specific oligonucleotide probes. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4489–4493. doi: 10.1073/pnas.83.12.4489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Aparicio J. M., Wakisaka A., Takada A., Matsuura N., Aizawa M. HLA-DQ system and insulin-dependent diabetes mellitus in Japanese: does it contribute to the development of IDDM as it does in Caucasians? Immunogenetics. 1988;28(4):240–246. doi: 10.1007/BF00345500. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Assan R., Feutren G., Debray-Sachs M., Quiniou-Debrie M. C., Laborie C., Thomas G., Chatenoud L., Bach J. F. Metabolic and immunological effects of cyclosporin in recently diagnosed type 1 diabetes mellitus. Lancet. 1985 Jan 12;1(8420):67–71. doi: 10.1016/s0140-6736(85)91964-6. [DOI] [PubMed] [Google Scholar]
  6. Assan R., Feutren G., Sirmai J., Laborie C., Boitard C., Vexiau P., Du Rostu H., Rodier M., Figoni M., Vague P. Plasma C-peptide levels and clinical remissions in recent-onset type I diabetic patients treated with cyclosporin A and insulin. Diabetes. 1990 Jul;39(7):768–774. doi: 10.2337/diab.39.7.768. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Baisch J. M., Weeks T., Giles R., Hoover M., Stastny P., Capra J. D. Analysis of HLA-DQ genotypes and susceptibility in insulin-dependent diabetes mellitus. N Engl J Med. 1990 Jun 28;322(26):1836–1841. doi: 10.1056/NEJM199006283222602. [DOI] [PubMed] [Google Scholar]
  9. Bottazzo G. F., Florin-Christensen A., Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet. 1974 Nov 30;2(7892):1279–1283. doi: 10.1016/s0140-6736(74)90140-8. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Charron D. Molecular basis of human leukocyte antigen class II disease associations. Adv Immunol. 1990;48:107–159. doi: 10.1016/S0065-2776(08)60753-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. Cohen D., Cohen O., Marcadet A., Massart C., Lathrop M., Deschamps I., Hors J., Schuller E., Dausset J. Class II HLA-DC beta-chain DNA restriction fragments differentiate among HLA-DR2 individuals in insulin-dependent diabetes and multiple sclerosis. Proc Natl Acad Sci U S A. 1984 Mar;81(6):1774–1778. doi: 10.1073/pnas.81.6.1774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Cornall R. J., Prins J. B., Todd J. A., Pressey A., DeLarato N. H., Wicker L. S., Peterson L. B. Type 1 diabetes in mice is linked to the interleukin-1 receptor and Lsh/Ity/Bcg genes on chromosome 1. Nature. 1991 Sep 19;353(6341):262–265. doi: 10.1038/353262a0. [DOI] [PubMed] [Google Scholar]
  15. Dawkins R. L., Martin E., Saueracker G., Kay P. H., Leaver A., Christiansen F. T. Supratypes and ancestral haplotypes in IDDM: potential importance of central non-HLA MHC genes. J Autoimmun. 1990 Apr;3 (Suppl 1):63–68. doi: 10.1016/s0896-8411(09)90011-7. [DOI] [PubMed] [Google Scholar]
  16. Eisenbarth G. S. Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med. 1986 May 22;314(21):1360–1368. doi: 10.1056/NEJM198605223142106. [DOI] [PubMed] [Google Scholar]
  17. Erlich H. A., Griffith R. L., Bugawan T. L., Ziegler R., Alper C., Eisenbarth G. Implication of specific DQB1 alleles in genetic susceptibility and resistance by identification of IDDM siblings with novel HLA-DQB1 allele and unusual DR2 and DR1 haplotypes. Diabetes. 1991 Apr;40(4):478–481. doi: 10.2337/diab.40.4.478. [DOI] [PubMed] [Google Scholar]
  18. Foulis A. K., Francis N. D., Farquharson M. A., Boylston A. Massive synchronous B-cell necrosis causing type 1 (insulin-dependent) diabetes--a unique histopathological case report. Diabetologia. 1988 Jan;31(1):46–50. doi: 10.1007/BF00279132. [DOI] [PubMed] [Google Scholar]
  19. Garchon H. J., Bedossa P., Eloy L., Bach J. F. Identification and mapping to chromosome 1 of a susceptibility locus for periinsulitis in non-obese diabetic mice. Nature. 1991 Sep 19;353(6341):260–262. doi: 10.1038/353260a0. [DOI] [PubMed] [Google Scholar]
  20. Grimberg J., Nawoschik S., Belluscio L., McKee R., Turck A., Eisenberg A. A simple and efficient non-organic procedure for the isolation of genomic DNA from blood. Nucleic Acids Res. 1989 Oct 25;17(20):8390–8390. doi: 10.1093/nar/17.20.8390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Groop L. C., Bottazzo G. F., Doniach D. Islet cell antibodies identify latent type I diabetes in patients aged 35-75 years at diagnosis. Diabetes. 1986 Feb;35(2):237–241. doi: 10.2337/diab.35.2.237. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Karjalainen J., Salmela P., Ilonen J., Surcel H. M., Knip M. A comparison of childhood and adult type I diabetes mellitus. N Engl J Med. 1989 Apr 6;320(14):881–886. doi: 10.1056/NEJM198904063201401. [DOI] [PubMed] [Google Scholar]
  24. Khalil I., d'Auriol L., Gobet M., Morin L., Lepage V., Deschamps I., Park M. S., Degos L., Galibert F., Hors J. A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus. J Clin Invest. 1990 Apr;85(4):1315–1319. doi: 10.1172/JCI114569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Knip M., Ilonen J., Mustonen A., Akerblom H. K. Evidence of an accelerated B-cell destruction in HLA-Dw3/Dw4 heterozygous children with type 1 (insulin-dependent) diabetes. Diabetologia. 1986 Jun;29(6):347–351. doi: 10.1007/BF00903342. [DOI] [PubMed] [Google Scholar]
  26. Kwok W. W., Mickelson E., Masewicz S., Milner E. C., Hansen J., Nepom G. T. Polymorphic DQ alpha and DQ beta interactions dictate HLA class II determinants of allo-recognition. J Exp Med. 1990 Jan 1;171(1):85–95. doi: 10.1084/jem.171.1.85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kwok W. W., Schwarz D., Nepom B. S., Hock R. A., Thurtle P. S., Nepom G. T. HLA-DQ molecules form alpha-beta heterodimers of mixed allotype. J Immunol. 1988 Nov 1;141(9):3123–3127. [PubMed] [Google Scholar]
  28. Melton L. J., 3rd, Palumbo P. J., Chu C. P. Incidence of diabetes mellitus by clinical type. Diabetes Care. 1983 Jan-Feb;6(1):75–86. doi: 10.2337/diacare.6.1.75. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Morel P. A., Dorman J. S., Todd J. A., McDevitt H. O., Trucco M. Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8111–8115. doi: 10.1073/pnas.85.21.8111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. 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]
  32. Nepom G. T., Erlich H. MHC class-II molecules and autoimmunity. Annu Rev Immunol. 1991;9:493–525. doi: 10.1146/annurev.iy.09.040191.002425. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Papoz L., Vauzelle F., Vexiau P., Cathelineau G. Pattern of treatment among diabetic patients in France. Diabetes Care. 1988 Jul-Aug;11(7):586–591. doi: 10.2337/diacare.11.7.586. [DOI] [PubMed] [Google Scholar]
  35. Pilcher C., Elliott R. B. Improved sensitivity of islet cell cytoplasmic antibody assay in diabetics. Lancet. 1984 Jun 16;1(8390):1352–1352. doi: 10.1016/s0140-6736(84)91842-7. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. Rønningen K. S., Iwe T., Halstensen T. S., Spurkland A., Thorsby E. The amino acid at position 57 of the HLA-DQ beta chain and susceptibility to develop insulin-dependent diabetes mellitus. Hum Immunol. 1989 Nov;26(3):215–225. doi: 10.1016/0198-8859(89)90040-2. [DOI] [PubMed] [Google Scholar]
  38. Saiki R. K., Scharf S., Faloona F., Mullis K. B., Horn G. T., Erlich H. A., Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. doi: 10.1126/science.2999980. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. Segall M., Noreen H., Schluender L., Swenson M., Barbosa J., Bach F. H. DR2+ haplotypes in insulin-dependent diabetes: analysis of DNA restriction fragment length polymorphisms. Hum Immunol. 1986 Sep;17(1):61–68. doi: 10.1016/0198-8859(86)90075-3. [DOI] [PubMed] [Google Scholar]
  41. Sterkers G., Zeliszewski D., Chaussée A. M., Deschamps I., Font M. P., Freidel C., Hors J., Betuel H., Dausset J., Levy J. P. HLA-DQ rather than HLA-DR region might be involved in dominant nonsusceptibility to diabetes. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6473–6477. doi: 10.1073/pnas.85.17.6473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tait B. D., Mraz G., Harrison L. C. Association of HLA-DQw3 (TA10-) with type I diabetes occurs with DR3/4 but not DR1/4 patients. Diabetes. 1988 Jul;37(7):926–929. doi: 10.2337/diab.37.7.926. [DOI] [PubMed] [Google Scholar]
  43. Thomson G., Robinson W. P., Kuhner M. K., Joe S., MacDonald M. J., Gottschall J. L., Barbosa J., Rich S. S., Bertrams J., Baur M. P. Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus. Am J Hum Genet. 1988 Dec;43(6):799–816. [PMC free article] [PubMed] [Google Scholar]
  44. Tiercy J. M., Morel C., Freidel A. C., Zwahlen F., Gebuhrer L., Bétuel H., Jeannet M., Mach B. Selection of unrelated donors for bone marrow transplantation is improved by HLA class II genotyping with oligonucleotide hybridization. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7121–7125. doi: 10.1073/pnas.88.16.7121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. 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]
  46. Todd J. A., Mijovic C., Fletcher J., Jenkins D., Bradwell A. R., Barnett A. H. Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping. Nature. 1989 Apr 13;338(6216):587–589. doi: 10.1038/338587a0. [DOI] [PubMed] [Google Scholar]
  47. Winter W. E., Maclaren N. K., Riley W. J., Clarke D. W., Kappy M. S., Spillar R. P. Maturity-onset diabetes of youth in black Americans. N Engl J Med. 1987 Feb 5;316(6):285–291. doi: 10.1056/NEJM198702053160601. [DOI] [PubMed] [Google Scholar]
  48. Wolf E., Spencer K. M., Cudworth A. G. The genetic susceptibility to type 1 (insulin-dependent) diabetes: analysis of the HLA-DR association. Diabetologia. 1983 Apr;24(4):224–230. doi: 10.1007/BF00282704. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES