Skip to main content
NCBI home page
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
. 1988 Nov;85(21):8111–8115. doi: 10.1073/pnas.85.21.8111

Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study.

P A Morel 1, J S Dorman 1, J A Todd 1, H O McDevitt 1, M Trucco 1
PMCID: PMC282365  PMID: 3186714

Abstract

One hundred seventy-two members from 27 randomly selected multiple case Caucasian families of patients with insulin-dependent diabetes mellitus (IDDM) were studied at the DNA level to ascertain the reliability of codon 57 of the HLA-DQ beta-chain gene as a disease protection/susceptibility marker. The analysis was carried out by polymerase chain reaction amplification of DNA encoding the first domain of the DQ beta chain and by dot blot analysis of the amplified material with allele-specific oligonucleotide probes. One hundred twenty-three randomly selected healthy Caucasian donors were also tested. The results demonstrated that haplotypes carrying an aspartic acid in position 57 (Asp-57) of their DQ beta chain were significantly increased in frequency among nondiabetic haplotypes (23/38), while non-Asp-57 haplotypes were significantly increased in frequency among diabetic haplotypes (65/69). Ninety-six percent of the diabetic probands in our study were homozygous non-Asp/non-Asp as compared to 19.5% of healthy unrelated controls. This conferred a relative risk of 107 (chi 2 = 54.97; P = 0.00003) for non-Asp-57 homozygous individuals. Even though the inheritance and genetic features of IDDM are complex and are not necessarily fully explained by DQ beta chain polymorphism, this approach is much more sensitive than HLA serolog in assessing risk for IDDM.

Full text

PDF
8111

Selected References

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

  1. 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]
  2. Babbitt B. P., Allen P. M., Matsueda G., Haber E., Unanue E. R. Binding of immunogenic peptides to Ia histocompatibility molecules. 1985 Sep 26-Oct 2Nature. 317(6035):359–361. doi: 10.1038/317359a0. [DOI] [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. Barnett A. H., Eff C., Leslie R. D., Pyke D. A. Diabetes in identical twins. A study of 200 pairs. Diabetologia. 1981 Feb;20(2):87–93. doi: 10.1007/BF00262007. [DOI] [PubMed] [Google Scholar]
  5. Bottazzo G. F., Pujol-Borrell R., Hanafusa T., Feldmann M. Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet. 1983 Nov 12;2(8359):1115–1119. doi: 10.1016/s0140-6736(83)90629-3. [DOI] [PubMed] [Google Scholar]
  6. Brown J. H., Jardetzky T., Saper M. A., Samraoui B., Bjorkman P. J., Wiley D. C. A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature. 1988 Apr 28;332(6167):845–850. doi: 10.1038/332845a0. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Cascino I., Rosenshine S., Turco E., Marrari M., Duquesnoy R. J., Trucco M. Relationship between DQ alpha and DQ beta RFLP and cell surface polymorphisms of class II HLA antigens. J Immunogenet. 1986 Oct-Dec;13(5-6):387–400. doi: 10.1111/j.1744-313x.1986.tb01124.x. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Craighead J. E. The role of viruses in the pathogenesis of pancreatic disease and diabetes mellitus. Prog Med Virol. 1975;19:161–214. [PubMed] [Google Scholar]
  11. 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]
  12. Fathman C. G., Frelinger J. G. T-lymphocyte clones. Annu Rev Immunol. 1983;1:633–655. doi: 10.1146/annurev.iy.01.040183.003221. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Kim S. J., Holbeck S. L., Nisperos B., Hansen J. A., Maeda H., Nepom G. T. Identification of a polymorphic variant associated with HLA-DQw3 and characterized by specific restriction sites within the DQ beta-chain gene. Proc Natl Acad Sci U S A. 1985 Dec;82(23):8139–8143. doi: 10.1073/pnas.82.23.8139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Landais D., Waltzinger C., Beck B. N., Staub A., McKean D. J., Benoist C., Mathis D. Functional sites on Ia molecules: a molecular dissection of A alpha immunogenicity. Cell. 1986 Oct 24;47(2):173–181. doi: 10.1016/0092-8674(86)90440-x. [DOI] [PubMed] [Google Scholar]
  16. Lange K. The affected sib-pair method using identity by state relations. Am J Hum Genet. 1986 Jul;39(1):148–150. [PMC free article] [PubMed] [Google Scholar]
  17. Nepom B. S., Schwarz D., Palmer J. P., Nepom G. T. Transcomplementation of HLA genes in IDDM. HLA-DQ alpha- and beta-chains produce hybrid molecules in DR3/4 heterozygotes. Diabetes. 1987 Jan;36(1):114–117. doi: 10.2337/diab.36.1.114. [DOI] [PubMed] [Google Scholar]
  18. Rossini A. A., Mordes J. P., Like A. A. Immunology of insulin-dependent diabetes mellitus. Annu Rev Immunol. 1985;3:289–320. doi: 10.1146/annurev.iy.03.040185.001445. [DOI] [PubMed] [Google Scholar]
  19. Rotter J. I., Landaw E. M. Measuring the genetic contribution of a single locus to a multilocus disease. Clin Genet. 1984 Dec;26(6):529–542. doi: 10.1111/j.1399-0004.1984.tb01100.x. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Rubinstein P., Ginsberg-Fellner F., Falk C. Genetics of Type I diabetes mellitus: a single, recessive predisposition gene mapping between HLA-B and GLO. With an appendix on the estimation of selection bias. Am J Hum Genet. 1981 Nov;33(6):865–882. [PMC free article] [PubMed] [Google Scholar]
  22. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  23. Scharf S. J., Horn G. T., Erlich H. A. Direct cloning and sequence analysis of enzymatically amplified genomic sequences. Science. 1986 Sep 5;233(4768):1076–1078. doi: 10.1126/science.3461561. [DOI] [PubMed] [Google Scholar]
  24. Schreuder G. M., Tilanus M. G., Bontrop R. E., Bruining G. J., Giphart M. J., van Rood J. J., de Vries R. R. HLA-DO polymorphism associated with resistance to type I diabetes detected with monoclonal antibodies, isoelectric point differences, and restriction fragment length polymorphism. J Exp Med. 1986 Sep 1;164(3):938–943. doi: 10.1084/jem.164.3.938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sheehy M. J., Rowe J. R., Fuller T. C., Yunis E. J., Gabbay K. H. A minor subset of HLA-DR3 haplotypes is preferentially increased in type 1 (insulin-dependent) diabetes. Diabetologia. 1985 Dec;28(12):891–894. doi: 10.1007/BF00703131. [DOI] [PubMed] [Google Scholar]
  26. Sinha A. A., Brautbar C., Szafer F., Friedmann A., Tzfoni E., Todd J. A., Steinman L., McDevitt H. O. A newly characterized HLA DQ beta allele associated with pemphigus vulgaris. Science. 1988 Feb 26;239(4843):1026–1029. doi: 10.1126/science.2894075. [DOI] [PubMed] [Google Scholar]
  27. Spielman R. S., Lee J., Bodmer W. F., Bodmer J. G., Trowsdale J. Six HLA-D region alpha-chain genes on human chromosome 6: polymorphisms and associations of DC alpha-related sequences with DR types. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3461–3465. doi: 10.1073/pnas.81.11.3461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. Thomson G. HLA DR antigens and susceptibility to insulin-dependent diabetes mellitus. Am J Hum Genet. 1984 Nov;36(6):1309–1317. [PMC free article] [PubMed] [Google Scholar]
  30. Todd J. A., Acha-Orbea H., Bell J. I., Chao N., Fronek Z., Jacob C. O., McDermott M., Sinha A. A., Timmerman L., Steinman L. A molecular basis for MHC class II--associated autoimmunity. Science. 1988 May 20;240(4855):1003–1009. doi: 10.1126/science.3368786. [DOI] [PubMed] [Google Scholar]
  31. Todd J. A., Bell J. I., McDevitt H. O. A molecular basis for genetic susceptibility to insulin-dependent diabetes mellitus. Trends Genet. 1988 May;4(5):129–134. doi: 10.1016/0168-9525(88)90135-7. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. Trucco M. M., Stocker J. W., Caeppellini R. Monoclonal antibodies against human lymphocyte antigens. Nature. 1978 Jun 22;273(5664):666–668. doi: 10.1038/273666a0. [DOI] [PubMed] [Google Scholar]
  34. Watts T. H., McConnell H. M. High-affinity fluorescent peptide binding to I-Ad in lipid membranes. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9660–9664. doi: 10.1073/pnas.83.24.9660. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wescott M. Z., Awdeh Z. L., Yunis E. J., Alper C. A. Molecular analysis distinguishes two HLA-DR3-bearing major histocompatibility complex extended haplotypes. Immunogenetics. 1987;26(6):370–374. doi: 10.1007/BF00343707. [DOI] [PubMed] [Google Scholar]
  36. Winearls B. C., Bodmer J. G., Bodmer W. F., Bottazzo G. F., McNally J., Mann J. I., Thorogood M., Smith M. A., Baum J. D. A family study of the association between insulin dependent diabetes mellitus, autoantibodies and the HLA system. Tissue Antigens. 1984 Oct;24(4):234–246. doi: 10.1111/j.1399-0039.1984.tb02132.x. [DOI] [PubMed] [Google Scholar]
  37. 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]
  38. Yoon J. W., Ray U. R. Perspectives on the role of viruses in insulin-dependent diabetes. Diabetes Care. 1985 Sep-Oct;8 (Suppl 1):39–44. doi: 10.2337/diacare.8.1.s39. [DOI] [PubMed] [Google Scholar]
  39. Zinkernagel R. M., Doherty P. C. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 1974 Apr 19;248(5450):701–702. doi: 10.1038/248701a0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES