Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1981 Nov;33(6):865–882.

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.

P Rubinstein, F Ginsberg-Fellner, C Falk
PMCID: PMC1685153  PMID: 7034534

Abstract

Three different published sets of HLA-typed families of juvenile diabetes mellitus (JDM) patients have been analyzed. There was no significant genetic heterogeneity between them according to the criterion of Morton, and the total material was analyzed on the assumption of a single recessive (JDM-P) gene with incomplete penetrance. The analysis, carried out with the NYLIP program modified to account for penetrance less than 1 and for selection bias, yields highly significant lod scores for linkage between HLA and JDM-P, with a maximum value of 7.40 at theta = .05 +/- .03. The segregation of HLA and GLO in five affected sib pairs, in which one of the sibs carries an HLA/GLO recombinant, places JDM-P closer to HLA than the GLO locus: four of these five pairs are HLA-identical and GLO-different, in agreement with the conclusions of the formal linkage analysis. The data from these three independent sets of families are therefore consistent with our earlier claim that JDM is inherited as a recessive trait closely linked to HLA with reduced penetrance, and its analysis does not require more complicated genetic models.

Full text

PDF
865

Selected References

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

  1. Arnaiz-Villena A., Rodríguez de Córdoba S., Dujovne I. L., Regueiro J. R., Bootello A., Serrano-Rios M. HLA factors in non-insulin-dependent diabetes mellitus. N Engl J Med. 1980 Oct 30;303(18):1065–1065. [PubMed] [Google Scholar]
  2. Barbosa J., Chern M. M., Anderson V. E., Noreen H., Johnson S., Reinsmoen N., McCarty R., King R., Greenberg L. Linkage analysis between the major histocompatibility system and insulin-dependent diabetes in families with patients in two consecutive generations. J Clin Invest. 1980 Mar;65(3):592–601. doi: 10.1172/JCI109704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barbosa J., Chern M. M., Noreen H., Anderson V. E. Analysis of linkage between the major histocompatibility system and juvenile, insulin-dependent diabetes in multiplex families. Reanalysis of data. J Clin Invest. 1978 Aug;62(2):492–495. doi: 10.1172/JCI109151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barbosa J., King R., Noreen H., Yunis E. J. The histocompatibility system in juvenile, insulin-dependent diabetic multiplex kindreds. J Clin Invest. 1977 Nov;60(5):989–998. doi: 10.1172/JCI108879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bertrams J., Jansen F. K., Grüneklee D., Reis H. E., Drost H., Beyer J., Gries F. A., Kuwert E. HLA antigens and immunoresponsiveness to insulin in insulin-dependent diabetes mellitus. Tissue Antigens. 1976 Jul;8(1):13–19. doi: 10.1111/j.1399-0039.1976.tb00546.x. [DOI] [PubMed] [Google Scholar]
  6. Cahill G. F., Jr Current concepts of diabetic complications with emphasis on hereditary factors: a brief review. Prog Clin Biol Res. 1979;32:113–125. [PubMed] [Google Scholar]
  7. 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]
  8. Christy M., Nerup J., Bottazzo G. F., Doniach D., Platz P., Svejgaard A., Ryder L. P., Thomsen M. Letter: Association between HLA-B8 and autoimmunity in juvenile diabetes mellitus. Lancet. 1976 Jul 17;2(7977):142–143. doi: 10.1016/s0140-6736(76)92864-6. [DOI] [PubMed] [Google Scholar]
  9. Cudworth A. G. Type I diabetes mellitus. Diabetologia. 1978 May;14(5):281–291. doi: 10.1007/BF01223018. [DOI] [PubMed] [Google Scholar]
  10. Cudworth A. G., White G. B., Woodrow J. C., Gamble D. R., Lendrum R., Bloom A. Aetiology of juvenile-onset diabetes. A prospective study. Lancet. 1977 Feb 19;1(8008):385–388. doi: 10.1016/s0140-6736(77)92602-2. [DOI] [PubMed] [Google Scholar]
  11. Cudworth A. G., Woodrow J. C. Evidence for HL-A-linked genes in "juvenile" diabetes mellitus. Br Med J. 1975 Jul 19;3(5976):133–135. doi: 10.1136/bmj.3.5976.133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cudworth A. G., Woodrow J. C. Genetic susceptibility in diabetes mellitus: analysis of the HLA association. Br Med J. 1976 Oct 9;2(6040):846–848. doi: 10.1136/bmj.2.6040.846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Degnbol B., Green A. Diabetes mellitus among first- and second-degree relatives of early onset diabetics. Ann Hum Genet. 1978 Jul;42(1):25–47. doi: 10.1111/j.1469-1809.1978.tb00929.x. [DOI] [PubMed] [Google Scholar]
  14. Eff C., Faber O., Deckert T. Persistent insulin secretion, assessed by plasma C-peptide estimation in long-term juvenile diabetics with a low insulin requirement. Diabetologia. 1978 Sep;15(3):169–172. doi: 10.1007/BF00421234. [DOI] [PubMed] [Google Scholar]
  15. Falk C. T., Rubinstein P. The effect of association of genetic factors on relative risk. Ann Hum Genet. 1980 Jan;43(3):295–301. doi: 10.1111/j.1469-1809.1980.tb01562.x. [DOI] [PubMed] [Google Scholar]
  16. Falk C. T., Suciu-Foca N., Rubinstein P. Possible localization of the gene(s) for juvenile diabetes mellitus (JDM) to the HLA region of chromosome 6. Cytogenet Cell Genet. 1978;22(1-6):298–300. doi: 10.1159/000130958. [DOI] [PubMed] [Google Scholar]
  17. Falk C. T., Walker M. E., Martin M. D., Allen F. H., Jr Autosomal linkage in humans (methodology and results of computer analysis). Ser Haematol. 1975;8(2):153–237. [PubMed] [Google Scholar]
  18. Gorwitz K., Howen G. G., Thompson T. Prevalence of diabetes in Michigan school-age children. Diabetes. 1976 Feb;25(2):122–127. doi: 10.2337/diab.25.2.122. [DOI] [PubMed] [Google Scholar]
  19. Kyllo C. J., Nuttall F. Q. Prevalence of diabetes mellitus in school-age children in Minnesota. Diabetes. 1978 Jan;27(1):57–60. doi: 10.2337/diab.27.1.57. [DOI] [PubMed] [Google Scholar]
  20. Kömpf J., Bissbort S., Gussmann S., Ritter H. Polymorphism of red cell glyoxalase I (EI: 4.4.1.5); a new genetic marker in man. Investigation of 169 mother-child combinations. Humangenetik. 1975;27(2):141–143. doi: 10.1007/BF00273329. [DOI] [PubMed] [Google Scholar]
  21. Lamm L. U., Weitkamp L. R., Jensson O., Pedersen G. B., Kissmeyer-Nielsen F. On the mapping of PGM3, GLO and HLA. Tissue Antigens. 1978 Feb;11(2):132–138. doi: 10.1111/j.1399-0039.1978.tb01237.x. [DOI] [PubMed] [Google Scholar]
  22. Lendrum R., Walker G., Cudworth A. G., Woodrow J. C., Gamble D. R. HLA-linked genes and islet-cell antibodies in diabetes mellitus. Br Med J. 1976 Jun 26;1(6025):1565–1567. doi: 10.1136/bmj.1.6025.1565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ludwig H., Schernthaner G., Mayr W. R. The importance of HLA genes to susceptibility in the development of juvenile diabetes mellitus. A study of 93 patients and 68 first degree blood relations. Diabete Metab. 1977 Mar;3(1):43–48. [PubMed] [Google Scholar]
  24. MORTON N. E. Sequential tests for the detection of linkage. Am J Hum Genet. 1955 Sep;7(3):277–318. [PMC free article] [PubMed] [Google Scholar]
  25. MORTON N. E. The detection and estimation of linkage between the genes for elliptocytosis and the Rh blood type. Am J Hum Genet. 1956 Jun;8(2):80–96. [PMC free article] [PubMed] [Google Scholar]
  26. MacDonald M. J. The frequencies of juvenile diabetes in American Blacks and Caucasians are consistent with dominant inheritance. Diabetes. 1980 Feb;29(2):110–114. doi: 10.2337/diab.29.2.110. [DOI] [PubMed] [Google Scholar]
  27. Madsbad S., Bottazzo G. F., Cudworth A. G., Dean B., Faber O. K., Binder C. Islet-cell antibodies and beta-cell function in insulin-dependent diabetics. Diabetologia. 1980 Jan;18(1):45–47. doi: 10.1007/BF01228301. [DOI] [PubMed] [Google Scholar]
  28. Martel J. L., Jaramillo S., Allen F. H., Jr, Rubinstein P. Serology for automated cytotoxicity assays. Contrast fluorescence test. Vox Sang. 1974;27(1):13–20. doi: 10.1111/j.1423-0410.1974.tb02384.x. [DOI] [PubMed] [Google Scholar]
  29. Morris P. J., Irvine W. J., Gray R. S., Duncan L. J., Vaughan H., McCallum F. J., Campbell C. J., Farquhar J. W. HLA and pancreatic islet cell antibodies in diabetes. Lancet. 1976 Sep 25;2(7987):652–653. doi: 10.1016/s0140-6736(76)92464-8. [DOI] [PubMed] [Google Scholar]
  30. Nelson P. G., Pyke D. A., Cudworth A. G., Woodrow J. C., Batchelor J. R. Histocompatibility antigens in diabetic identical twins. Lancet. 1975 Aug 2;2(7927):193–194. doi: 10.1016/s0140-6736(75)90668-6. [DOI] [PubMed] [Google Scholar]
  31. Nerup J., Platz P., Andersen O. O., Christy M., Lyngsoe J., Poulsen J. E., Ryder L. P., Nielsen L. S., Thomsen M., Svejgaard A. HL-A antigens and diabetes mellitus. Lancet. 1974 Oct 12;2(7885):864–866. doi: 10.1016/s0140-6736(74)91201-x. [DOI] [PubMed] [Google Scholar]
  32. Ott J. Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am J Hum Genet. 1974 Sep;26(5):588–597. [PMC free article] [PubMed] [Google Scholar]
  33. Reitnauer P. J., Roseman J. M., Barger B. O., Murphy C. C., Acton R. T. HLA in juvenile diabetes. N Engl J Med. 1980 Feb 14;302(7):406–406. [PubMed] [Google Scholar]
  34. Richens E. R., Quilley J., Hartog M. Immunological features of juvenile onset diabetic patients correlated to HLA type. Clin Exp Immunol. 1979 May;36(2):198–204. [PMC free article] [PubMed] [Google Scholar]
  35. Rotter J. I., Hodge S. E. Racial differences in juvenile-type diabetes are consistent with more than one mode of inheritance. Diabetes. 1980 Feb;29(2):115–118. doi: 10.2337/diab.29.2.115. [DOI] [PubMed] [Google Scholar]
  36. Rotter J. I., Rimoin D. L. Heterogeneity in diabetes mellitus--update, 1978. Evidence for further genetic heterogeneity within juvenile-onset insulin-dependent diabetes mellitus. Diabetes. 1978 May;27(5):599–605. doi: 10.2337/diab.27.5.599. [DOI] [PubMed] [Google Scholar]
  37. Rubinstein P., Suciu-Foca N., Nicholson J. F., Fotino M., Molinaro A., Harisiadis L., Hardy M. A., Reemtsma K., Allen F. H., Jr The HLA system in the families of patients with juvenile diabetes mellitus. J Exp Med. 1976 May 1;143(5):1277–1282. doi: 10.1084/jem.143.5.1277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Rubinstein P., Suciu-Foca N., Nicholson J. F. Genetics of juvenile diabetes mellitus. A recessive gene closely linked to HLA D and with 50 per cent penetrance. N Engl J Med. 1977 Nov 10;297(19):1036–1040. doi: 10.1056/NEJM197711102971905. [DOI] [PubMed] [Google Scholar]
  39. Schernthaner G., Ludwig H., Mayr W. R. Immunoglobulin G-insulin antibodies and immune region-associated alloantigens in insulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1979 Mar;48(3):403–407. doi: 10.1210/jcem-48-3-403. [DOI] [PubMed] [Google Scholar]
  40. Schernthaner G., Ludwig H., Mayr W. R., Willvonseder R. Letter: Genetic factors on insulin antibodies in juvenile-onset diabetes. N Engl J Med. 1976 Sep 9;295(11):622–622. doi: 10.1056/NEJM197609092951115. [DOI] [PubMed] [Google Scholar]
  41. Singal D. P., Blajchman M. A. Histocompatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes. 1973 Jun;22(6):429–432. doi: 10.2337/diab.22.6.429. [DOI] [PubMed] [Google Scholar]
  42. Spielman R. S., Baker L., Zmijewski C. M. Gene dosage and suceptibility to insulin-dependent diabetes. Ann Hum Genet. 1980 Oct;44(Pt 2):135–150. doi: 10.1111/j.1469-1809.1980.tb00954.x. [DOI] [PubMed] [Google Scholar]
  43. 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]
  44. Zeidler A., Loon J., Frasier S. D., Kumar D., Penny R., Terasaki P. HLA-DRw antigens in Mexican-American and Black-American diabetic patients. Diabetes. 1980 Apr;29(4):247–250. doi: 10.2337/diab.29.4.247. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES