Europe PMC

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy.

The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families.

Author information

Affiliations

  • 1. Department of Human Genetics, Roche Molecular Systems, Alameda, USA.
      Authors
    • Noble JA 1
    (1 author)

American Journal of Human Genetics, 01 Nov 1996, 59(5):1134-1148
PMID: 8900244 PMCID: PMC1914851

Free full text in Europe PMC

Abstract 

We report here our analysis of HLA class II alleles in 180 Caucasian nuclear families with at least two children with insulin-dependent diabetes mellitus (IDDM). DRB1, DQA1, DQB1, and DPB1 genotypes were determined with PCR/sequence-specific oligonucleotide probe typing methods. The data allowed unambiguous determination of four-locus haplotypes in all but three of the families. Consistent with other studies, our data indicate an increase in DR3/DR4, DR3/DR3, and DR4/DR4 genotypes in patients compared to controls. In addition, we found an increase in DR1/DR4, DR1/DR3, and DR4/DR8 genotypes. While the frequency of DQB1*0302 on DR4 haplotypes is dramatically increased in DR3/DR4 patients, DR4 haplotypes in DR1/DR4 patients exhibit frequencies of DQB1*0302 and DQB1*0301 more closely resembling those in control populations. The protective effect of DR2 is evident in this data set and is limited to the common DRB1*1501-DQB1*0602 haplotype. Most DR2+ patients carry the less common DR2 haplotype DRB1*1601-DQB1*0502, which is not decreased in patients relative to controls. DPB1 also appears to play a role in disease susceptibility. DPB1*0301 is increased in patients (P < .001) and may contribute to the disease risk of a number of different DR-DQ haplotypes. DPB1*0101, found almost exclusively on DR3 haplotypes in patients, is slightly increased, and maternal transmissions of DRB1*0301-DPB1*0101 haplotypes to affected children occur twice as frequently as do paternal transmissions. Transmissions of DR3 haplotypes carrying other DPB1 alleles occur at approximately equal maternal and paternal frequencies. The complex, multigenic nature of HLA class II-associated IDDM susceptibility is evident from these data.

Free full text 

Logo of ajhgGuide for AuthorsAbout this journalExplore this journalAmerican Journal of Human Genetics
Am J Hum Genet. 1996 Nov; 59(5): 1134–1148.
PMCID: PMC1914851
PMID: 8900244

The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families.

J. A. Noble, A. M. Valdes, M. Cook, W. Klitz, G. Thomson, and H. A. Erlich
Author information Copyright and License information Disclaimer

Abstract

We report here our analysis of HLA class II alleles in 180 Caucasian nuclear families with at least two children with insulin-dependent diabetes mellitus (IDDM). DRB1, DQA1, DQB1, and DPB1 genotypes were determined with PCR/sequence-specific oligonucleotide probe typing methods. The data allowed unambiguous determination of four-locus haplotypes in all but three of the families. Consistent with other studies, our data indicate an increase in DR3/DR4, DR3/DR3, and DR4/DR4 genotypes in patients compared to controls. In addition, we found an increase in DR1/DR4, DR1/DR3, and DR4/DR8 genotypes. While the frequency of DQB1*0302 on DR4 haplotypes is dramatically increased in DR3/DR4 patients, DR4 haplotypes in DR1/DR4 patients exhibit frequencies of DQB1*0302 and DQB1*0301 more closely resembling those in control populations. The protective effect of DR2 is evident in this data set and is limited to the common DRB1*1501-DQB1*0602 haplotype. Most DR2+ patients carry the less common DR2 haplotype DRB1*1601-DQB1*0502, which is not decreased in patients relative to controls. DPB1 also appears to play a role in disease susceptibility. DPB1*0301 is increased in patients (P < .001) and may contribute to the disease risk of a number of different DR-DQ haplotypes. DPB1*0101, found almost exclusively on DR3 haplotypes in patients, is slightly increased, and maternal transmissions of DRB1*0301-DPB1*0101 haplotypes to affected children occur twice as frequently as do paternal transmissions. Transmissions of DR3 haplotypes carrying other DPB1 alleles occur at approximately equal maternal and paternal frequencies. The complex, multigenic nature of HLA class II-associated IDDM susceptibility is evident from these data.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.7M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.
 
icon of scanned page 1134
1134
icon of scanned page 1135
1135
icon of scanned page 1136
1136
icon of scanned page 1137
1137
icon of scanned page 1138
1138
icon of scanned page 1139
1139
icon of scanned page 1140
1140
icon of scanned page 1141
1141
icon of scanned page 1142
1142
icon of scanned page 1143
1143
icon of scanned page 1144
1144
icon of scanned page 1145
1145
icon of scanned page 1146
1146
icon of scanned page 1147
1147
icon of scanned page 1148
1148
 

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Awata T, Kuzuya T, Matsuda A, Iwamoto Y, Kanazawa Y. Genetic analysis of HLA class II alleles and susceptibility to type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. Diabetologia. 1992 May;35(5):419–424. [Abstract] [Google Scholar]
  • Bain SC, Rowe BR, Barnett AH, Todd JA. Parental origin of diabetes-associated HLA types in sibling pairs with type I diabetes. Diabetes. 1994 Dec;43(12):1462–1468. [Abstract] [Google Scholar]
  • Begovich AB, McClure GR, Suraj VC, Helmuth RC, Fildes N, Bugawan TL, Erlich HA, Klitz W. Polymorphism, recombination, and linkage disequilibrium within the HLA class II region. J Immunol. 1992 Jan 1;148(1):249–258. [Abstract] [Google Scholar]
  • Bell GI, Horita S, Karam JH. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes. 1984 Feb;33(2):176–183. [Abstract] [Google Scholar]
  • Blackwelder WC, Elston RC. A comparison of sib-pair linkage tests for disease susceptibility loci. Genet Epidemiol. 1985;2(1):85–97. [Abstract] [Google Scholar]
  • Bodmer JG, Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Charron D, Dupont B, Erlich HA, Mach B, Mayr WR. Nomenclature for factors of the HLA system, 1995. Tissue Antigens. 1995 Jul;46(1):1–18. [Abstract] [Google Scholar]
  • Bugawan TL, Begovich AB, Erlich HA. Rapid HLA-DPB typing using enzymatically amplified DNA and nonradioactive sequence-specific oligonucleotide probes. Immunogenetics. 1990;32(4):231–241. [Abstract] [Google Scholar]
  • Bugawan TL, Erlich HA. Rapid typing of HLA-DQB1 DNA polymorphism using nonradioactive oligonucleotide probes and amplified DNA. Immunogenetics. 1991;33(3):163–170. [Abstract] [Google Scholar]
  • Bugawan TL, Horn GT, Long CM, Mickelson E, Hansen JA, Ferrara GB, Angelini G, Erlich HA. Analysis of HLA-DP allelic sequence polymorphism using the in vitro enzymatic DNA amplification of DP-alpha and DP-beta loci. J Immunol. 1988 Dec 1;141(11):4024–4030. [Abstract] [Google Scholar]
  • Caillat-Zucman S, Garchon HJ, Timsit J, Assan R, Boitard C, Djilali-Saiah I, Bougnères P, Bach JF. Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus. J Clin Invest. 1992 Dec;90(6):2242–2250. [Europe PMC free article] [Abstract] [Google Scholar]
  • Clerget-Darpoux F, Babron MC, Deschamps I, Hors J. Complementation and maternal effect in insulin-dependent diabetes. Am J Hum Genet. 1991 Jul;49(1):42–48. [Europe PMC free article] [Abstract] [Google Scholar]
  • Copeman JB, Cucca F, Hearne CM, Cornall RJ, Reed PW, Rønningen KS, Undlien DE, Nisticò L, Buzzetti R, Tosi R, et al. Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene (IDDM7) to chromosome 2q31-q33. Nat Genet. 1995 Jan;9(1):80–85. [Abstract] [Google Scholar]
  • Cucca F, Lampis R, Frau F, Macis D, Angius E, Masile P, Chessa M, Frongia P, Silvetti M, Cao A, et al. The distribution of DR4 haplotypes in Sardinia suggests a primary association of type I diabetes with DRB1 and DQB1 loci. Hum Immunol. 1995 Aug;43(4):301–308. [Abstract] [Google Scholar]
  • Cucca F, Muntoni F, Lampis R, Frau F, Argiolas L, Silvetti M, Angius E, Cao A, De Virgiliis S, Congia M. Combinations of specific DRB1, DQA1, DQB1 haplotypes are associated with insulin-dependent diabetes mellitus in Sardinia. Hum Immunol. 1993 Jun;37(2):85–94. [Abstract] [Google Scholar]
  • Cudworth AG, Woodrow JC. Letter: HL-A antigens and diabetes mellitus. Lancet. 1974 Nov 9;2(7889):1153–1153. [Abstract] [Google Scholar]
  • Davies JL, Kawaguchi Y, Bennett ST, Copeman JB, Cordell HJ, Pritchard LE, Reed PW, Gough SC, Jenkins SC, Palmer SM, et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature. 1994 Sep 8;371(6493):130–136. [Abstract] [Google Scholar]
  • de Koster HS, van Rood JJ, Termijtelen A. HLA-DR peptide-induced alloreactive T cell lines reveal an HLA-DR sequence that can be both "dominant" and "cryptic": evidence for allele-specific processing. Eur J Immunol. 1992 Jun;22(6):1531–1539. [Abstract] [Google Scholar]
  • Deschamps I, Hors J, Clerget-Darpoux F, Gardais E, Robert JJ, Marcelli-Berge A, Lestradet H, Dausset J. Excess of maternal HLA-DR3 antigens in HLA DR3,4 positive type 1 (insulin-dependent) diabetic patients. Diabetologia. 1990 Jul;33(7):425–430. [Abstract] [Google Scholar]
  • Easteal S, Kohonen-Corish MR, Zimmet P, Serjeantson SW. HLA-DP variation as additional risk factor in IDDM. Diabetes. 1990 Jul;39(7):855–857. [Abstract] [Google Scholar]
  • Erlich HA. HLA class II sequences and genetic susceptibility to insulin dependent diabetes mellitus. Baillieres Clin Endocrinol Metab. 1991 Sep;5(3):395–411. [Abstract] [Google Scholar]
  • Erlich H, Bugawan T, Begovich A, Scharf S. Analysis of HLA class II polymorphism using polymerase chain reaction. Arch Pathol Lab Med. 1993 May;117(5):482–485. [Abstract] [Google Scholar]
  • Erlich H, Bugawan T, Begovich AB, Scharf S, Griffith R, Saiki R, Higuchi R, Walsh PS. HLA-DR, DQ and DP typing using PCR amplification and immobilized probes. Eur J Immunogenet. 1991 Feb-Apr;18(1-2):33–55. [Abstract] [Google Scholar]
  • Erlich HA, Bugawan TL, Scharf S, Nepom GT, Tait B, Griffith RL. HLA-DQ beta sequence polymorphism and genetic susceptibility to IDDM. Diabetes. 1990 Jan;39(1):96–103. [Abstract] [Google Scholar]
  • Buehler James W, Berkelman Ruth L, Stroup Donna F, Klaucke Douglas N. Authors' response. Public Health Rep. 1990 Jan-Feb;105(1):103–103. [Europe PMC free article] [Google Scholar]
  • Erlich HA, Griffith RL, Bugawan TL, 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. [Abstract] [Google Scholar]
  • Erlich HA, Rotter JI, Chang JD, Shaw SJ, Raffel LJ, Klitz W, Bugawan TL, Zeidler A. Association of HLA-DPB1*0301 with IDDM in Mexican-Americans. Diabetes. 1996 May;45(5):610–614. [Abstract] [Google Scholar]
  • Erlich HA, Zeidler A, Chang J, Shaw S, Raffel LJ, Klitz W, Beshkov Y, Costin G, Pressman S, Bugawan T, et al. HLA class II alleles and susceptibility and resistance to insulin dependent diabetes mellitus in Mexican-American families. Nat Genet. 1993 Apr;3(4):358–364. [Abstract] [Google Scholar]
  • Field LL. Non-HLA region genes in insulin dependent diabetes mellitus. Baillieres Clin Endocrinol Metab. 1991 Sep;5(3):413–438. [Abstract] [Google Scholar]
  • Field LL, Tobias R, Magnus T. A locus on chromosome 15q26 (IDDM3) produces susceptibility to insulin-dependent diabetes mellitus. Nat Genet. 1994 Oct;8(2):189–194. [Abstract] [Google Scholar]
  • Fohlman J, Friman G. Is juvenile diabetes a viral disease? Ann Med. 1993 Dec;25(6):569–574. [Abstract] [Google Scholar]
  • Hashimoto L, Habita C, Beressi JP, Delepine M, Besse C, Cambon-Thomsen A, Deschamps I, Rotter JI, Djoulah S, James MR, et al. Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q. Nature. 1994 Sep 8;371(6493):161–164. [Abstract] [Google Scholar]
  • Horn GT, Bugawan TL, Long CM, Erlich HA. 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. [Europe PMC free article] [Abstract] [Google Scholar]
  • Horn GT, Bugawan TL, Long CM, Manos MM, Erlich HA. Sequence analysis of HLA class II genes from insulin-dependent diabetic individuals. Hum Immunol. 1988 Apr;21(4):249–263. [Abstract] [Google Scholar]
  • Hu CY, Allen M, Chuang LM, Lin BJ, Gyllensten U. Association of insulin-dependent diabetes mellitus in Taiwan with HLA class II DQB1 and DRB1 alleles. Hum Immunol. 1993 Oct;38(2):105–114. [Abstract] [Google Scholar]
  • Huang HS, Peng JT, She JY, Zhang LP, Chao CC, Liu KH, She JX. HLA-encoded susceptibility to insulin-dependent diabetes mellitus is determined by DR and DQ genes as well as their linkage disequilibria in a Chinese population. Hum Immunol. 1995 Dec;44(4):210–219. [Abstract] [Google Scholar]
  • Klitz W, Aldrich CL, Fildes N, Horning SJ, Begovich AB. Localization of predisposition to Hodgkin disease in the HLA class II region. Am J Hum Genet. 1994 Mar;54(3):497–505. [Europe PMC free article] [Abstract] [Google Scholar]
  • Louis EJ, Thomson G. Three-allele synergistic mixed model for insulin-dependent diabetes mellitus. Diabetes. 1986 Sep;35(9):958–963. [Abstract] [Google Scholar]
  • Luo DF, Bui MM, Muir A, Maclaren NK, Thomson G, She JX. Affected-sib-pair mapping of a novel susceptibility gene to insulin-dependent diabetes mellitus (IDDM8) on chromosome 6q25-q27. Am J Hum Genet. 1995 Oct;57(4):911–919. [Europe PMC free article] [Abstract] [Google Scholar]
  • Margaritte-Jeannin P, Clerget-Darpoux F, Hors J, Deschamps I. Testing parental imprinting in insulin-dependent diabetes mellitus by the marker-association-segregation-chi 2 method. Am J Hum Genet. 1995 May;56(5):1080–1087. [Europe PMC free article] [Abstract] [Google Scholar]
  • Nepom BS, Schwarz D, Palmer JP, Nepom GT. 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. [Abstract] [Google Scholar]
  • Nepom GT, Erlich H. MHC class-II molecules and autoimmunity. Annu Rev Immunol. 1991;9:493–525. [Abstract] [Google Scholar]
  • Nerup J, Platz P, Andersen OO, Christy M, Lyngsoe J, Poulsen JE, Ryder LP, Nielsen LS, Thomsen M, Svejgaard A. HL-A antigens and diabetes mellitus. Lancet. 1974 Oct 12;2(7885):864–866. [Abstract] [Google Scholar]
  • Owerbach D, Gabbay KH. The HOXD8 locus (2q31) is linked to type I diabetes. Interaction with chromosome 6 and 11 disease susceptibility genes. Diabetes. 1995 Jan;44(1):132–136. [Abstract] [Google Scholar]
  • Owerbach D, Gunn S, Gabbay KH. Primary association of HLA-DQw8 with type I diabetes in DR4 patients. Diabetes. 1989 Jul;38(7):942–945. [Abstract] [Google Scholar]
  • Payami H, Joe S, Farid NR, Stenszky V, Chan SH, Yeo PP, Cheah JS, Thomson G. Relative predispositional effects (RPEs) of marker alleles with disease: HLA-DR alleles and Graves disease. Am J Hum Genet. 1989 Oct;45(4):541–546. [Europe PMC free article] [Abstract] [Google Scholar]
  • Risch N. Assessing the role of HLA-linked and unlinked determinants of disease. Am J Hum Genet. 1987 Jan;40(1):1–14. [Europe PMC free article] [Abstract] [Google Scholar]
  • Rønningen KS, Gjertsen HA, Iwe T, Spurkland A, Hansen T, Thorsby E. Particular HLA-DQ alpha beta heterodimer associated with IDDM susceptibility in both DR4-DQw4 Japanese and DR4-DQw8/DRw8-DQw4 whites. Diabetes. 1991 Jun;40(6):759–763. [Abstract] [Google Scholar]
  • Rosenlicht JW, Hartung K, Deicher H, Frey J. A novel HLA-DRB1-DR2 allele associated with HLA mistyping. Immunogenetics. 1993;37(6):479–479. [Abstract] [Google Scholar]
  • Rotter JI, Anderson CE, Rubin R, Congleton JE, Terasaki PI, Rimoin DL. 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. [Abstract] [Google Scholar]
  • Saiki RK, Walsh PS, Levenson CH, Erlich HA. Genetic analysis of amplified DNA with immobilized sequence-specific oligonucleotide probes. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6230–6234. [Europe PMC free article] [Abstract] [Google Scholar]
  • Scharf SJ, Griffith RL, Erlich HA. Rapid typing of DNA sequence polymorphism at the HLA-DRB1 locus using the polymerase chain reaction and nonradioactive oligonucleotide probes. Hum Immunol. 1991 Mar;30(3):190–201. [Abstract] [Google Scholar]
  • Schroeijers WE, de Koster HS, Verduyn W, Schreuder GM, Termijtelen A. T-cell recognition of class II products that result from the combined presence of two different HLA haplotypes. Hum Immunol. 1992 Apr;33(4):229–234. [Abstract] [Google Scholar]
  • Sheehy MJ, Scharf SJ, Rowe JR, Neme de Gimenez MH, Meske LM, Erlich HA, Nepom BS. A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles. J Clin Invest. 1989 Mar;83(3):830–835. [Europe PMC free article] [Abstract] [Google Scholar]
  • Singal DP, Blajchman MA. Histocompatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes. 1973 Jun;22(6):429–432. [Abstract] [Google Scholar]
  • Spielman RS, Baur MP, Clerget-Darpoux F. Genetic analysis of IDDM: summary of GAW5 IDDM results. Genet Epidemiol. 1989;6(1):43–58. [Abstract] [Google Scholar]
  • Tait BD, Harrison LC. Overview: the major histocompatibility complex and insulin dependent diabetes mellitus. Baillieres Clin Endocrinol Metab. 1991 Jun;5(2):211–228. [Abstract] [Google Scholar]
  • Tait BD, Mraz G, Harrison LC. 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. [Abstract] [Google Scholar]
  • 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. [Abstract] [Google Scholar]
  • Thomson G, Robinson WP, Kuhner MK, Joe S, Klitz W. HLA and insulin gene associations with IDDM. Genet Epidemiol. 1989;6(1):155–160. [Abstract] [Google Scholar]
  • Thomson G, Robinson WP, Kuhner MK, Joe S, MacDonald MJ, Gottschall JL, Barbosa J, Rich SS, Bertrams J, Baur MP, et al. 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. [Europe PMC free article] [Abstract] [Google Scholar]
  • Todd JA, Bell JI, McDevitt HO. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature. 1987 Oct 15;329(6140):599–604. [Abstract] [Google Scholar]
  • Todd JA, Mijovic C, Fletcher J, Jenkins D, Bradwell AR, Barnett AH. Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping. Nature. 1989 Apr 13;338(6216):587–589. [Abstract] [Google Scholar]
  • Trucco M, LaPorte R. Exposure to superantigens as an immunogenetic explanation of type I diabetes mini-epidemics. J Pediatr Endocrinol Metab. 1995 Jan-Mar;8(1):3–10. [Abstract] [Google Scholar]
  • Undlien DE, Akselsen HE, Joner G, Dahl-Jorgensen K, Aagenaes O, Sovik O, Thorsby E, Rønningen KS. No difference in the parental origin of susceptibility HLA class II haplotypes among Norwegian patients with insulin-dependent diabetes mellitus. Am J Hum Genet. 1995 Dec;57(6):1511–1514. [Europe PMC free article] [Abstract] [Google Scholar]
  • Vadheim CM, Rotter JI, Maclaren NK, Riley WJ, Anderson CE. Preferential transmission of diabetic alleles within the HLA gene complex. N Engl J Med. 1986 Nov 20;315(21):1314–1318. [Abstract] [Google Scholar]
  • WOOLF B. On estimating the relation between blood group and disease. Ann Hum Genet. 1955 Jun;19(4):251–253. [Abstract] [Google Scholar]
Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

Citations & impact 

Impact metrics

275
Citations
Jump to Citations

Citations of article over time

Alternative metrics

Altmetric item for https://www.altmetric.com/details/170562926
Altmetric
Discover the attention surrounding your research
https://www.altmetric.com/details/170562926

Article citations

Go to all (275) article citations

Similar Articles 

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

Funding 

Funders who supported this work.

NIDDK NIH HHS (2)