Summary
Inherited susceptibility to Type 1 (insulin-dependent) diabetes mellitus is partly determined by HLA genes. It has been suggested that protection from disease may be conferred by HLA-DQB1 genes which encode molecules with aspartate at position 57. We investigated the contributions of HLA-DRB1, DQA1 and DQB1 genes to protection from disease. Restriction fragment length polymorphism and sequence specific oligonucleotide analysis in 156 British Caucasian Type 1 diabetic and 116 control subjects showed protection from disease was associated with DR2, DRw6 and DR7 haplotypes. The most protective DQA1 allele was DQA1*0102 which occurred on both DR2 and DRw6 haplotypes. The DQB1 alleles DQB1*0303, DQB1*0602 and DQB1*0603 were associated with protection, as was DQB1*0604, which encodes an Asp-57 negative DQβmolecule. Heterozygosity for both protective and predisposing HLA markers was reduced in diabetic compared with control subjects. We conclude that both DQA1 and DQB1 genes are implicated in HLA-associated protection from Type 1 diabetes in this British Caucasian population. The overall structure of the DQ heterodimer is critical and DQβ-Asp 57 is of secondary importance in determining protection from disease. The effect of protective HLA types may predominate over that of predisposing markers.
Article PDF
Similar content being viewed by others
References
Rotter JI, Landaw EM (1984) Measuring the genetic contribution of a single locus to a multilocus disease. Clin Genet 26: 529–542
Risch N (1987) Assessing the role of HLA-linked and unlinked determinants of disease. Am J Hum Genet 40: 1–14
Wolf E, Spencer KM, Cudworth AG (1983) The genetic susceptibility to type 1 (insulin-dependent) diabetes: analysis of the HLA-DR association. Diabetologia 24: 224–230
Nepom BS, Palmer J, Kim SJ, Jansen JA, Holbeck SL, Nepom GT (1986) Specific genomic markers for the HLA-DQ subregion discriminate between DR4+ insulin-dependent diabetes mellitus and DR4 + seropositive juvenile rheumatoid arthritis. J Exp Med 164: 345–450
Nepom GT (1990) A unified hypothesis for the complex genetics of HLA associations with IDDM. Diabetes 39: 1153–1157
Todd JA, Bell JI, McDevitt HO (1987) HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329: 599–604
Awata T, Kuzuya T, Matsuda A et al. (1990) High frequency of aspartic acid at position 57 of HLA-DQ β-chain in Japanese IDDM patients and nondiabetic subjects. Diabetes 39: 266–269
Khalil I, d'Auriol L, Gobet M et al. (1990) A combination of HLA-DQβ Asp 57-negative and HLA DQα Arg 52 confers susceptibility to insulin-dependent diabetes mellitus. J Clin Invest 85: 1315–1319
Bill J, Kanagawa O, Woodland DL, Palmer E (1989) The MHC molecule I-E is necessary but not sufficient for the clonal deletion of VβII-bearing T cells. J Exp Med 169: 1405–1419
Nepom BS, Schwarz D, Palmer JP, Nepom GT (1987) Transcomplementation of HLA genes in IDDM. Diabetes 36: 114–117
Jenkins D, Fletcher J, Penny MA et al. (1991) DRB genotyping supports recessive inheritance of DR3-associated susceptibility to insulin-dependent diabetes mellitus. Am J Hum Genet 49: 49–53
Fletcher J, Odugbesan O, Mijovic C, Mackay E, Bradwell AR, Barnett AH (1988) Class II HLA DNA polymorphisms in type 1 (insulin-dependent) diabetic patients of North Indian origin. Diabetologia 31: 343–350
Jacobs KH, Jenkins D, Mijovic CH et al. (1992) An investigation of Japanese subjects maps susceptibility to type 1 (insulin-dependent) diabetes mellitus close to the DQA1 gene. Hum Immunol 33: 24–28
Jenkins D, Mijovic C, Jacobs KH, Penny MA, Fletcher J, Barnett AH (1991) Allele-specific gene probing supports the DQ molecule as a determinant of inherited susceptibility to type 1 (insulin-dependent) diabetes mellitus. Diabetologia 34: 109–113
Mathews JD (1984) Statistical aspects of immunogenetic association with disease. In: Simons MJ, Tait BD (eds) Detection of immune-associated genetic markers of human disease. Churchill Livingstone, London pp 106–136
Thomson G (1984) HLA DR antigens and susceptibility to insulin-dependent diabetes mellitus. Am J Hum Genet 36: 1309–1317
Thomson G, Robinson WP, Kuhner MK et al. (1988) Genetic heterogeneity, modes of inheritance and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus. Am J Hum Genet 43: 799–816
Kohonen-Corish MRJ, Serjeantson SW, Lee HK, Zimmet P (1987) Insulin-dependent diabetes mellitus: HLA-DR and -DQ genotyping in three ethnic groups. Disease Markers 5: 153–164
Ronningen KS, Spurkland A, Iwe T, Vartdal F, Thorsby E (1991) Distribution of HLA-DRB1, -DQA1 and -DQB1 alleles and DQA1-DQB1 genotypes among Norwegian patients with insulin-dependent diabetes mellitus. Tissue Antigens 37: 105–111
Cohen N, Brautbar C, Font M-P et al. (1986) HLA-DR2-associated Dw subtypes correlate with RFLP clusters: most DR2 IDDM patients belong to one of these clusters. Immunogenetics 23: 84–89
Reijonen H, Ilonen J, Knip M, Åkerblom HK (1991) HLA-DQ and absence of Asp 57 as susceptibility factors of IDDM in Finland. Diabetes 40: 1640–1644
Todd JA, Mijovic C, Fletcher J, Jenkins D, Bradwell AR, Barnett AH (1989) Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping. Nature 338: 587–589
Todd JA, Fukui Y, Kitagawa T, Sasazuki T (1990) The A3 allele of the HLA-DQA1 locus is associated with susceptibility to type I diabetes in the Japanese. Proc Natl Acad Sci USA 87: 1094–1098
Erlich HA, Griffith RL, Bugawan TL, Aiegler R, Alper C, Eisenbarth G (1990) Implication of specific DQB1 alleles in genetic susceptibility and resistance by investigation of IDDM siblings with novel HLA-DQB1 allele and unusual DR2 and DR1 haplotypes. Diabetes 40: 478–481
Zeliszewski D, Tiercy JM, Boitard C et al. (1991) Extensive study of DRB, DQA and DQB gene polymorphism in 23 DR2-positive, insulin-dependent diabetes mellitus patients. Hum Immunol 33: 140–147
Mijovic CH, Jenkins D, Jacobs KH, Penny MA, Fletcher J, Barnett AH (1991) HLA-DQA1 and -DQB1 alleles associated with genetic susceptibility to IDDM in a black population. Diabetes 40: 748–753
Penny MA, Jenkins D, Mijovic CH et al. (1992) Susceptibility to insulin-dependent diabetes mellitus in a Chinese population: role of HLA class II alleles. Diabetes 41: 914–919
Awata T, Kuzuya T, Matsuda A, Iwamoto Y, Kanazawa Y (1992) Genetic analysis of HLA class II alleles and susceptibility to type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. Diabetologia 35: 419–424
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Cavan, D.A., Jacobs, K.H., Penny, M.A. et al. Both DQA1 and DQB1 genes are implicated in HLA-associated protection from type 1 (insulin-dependent) diabetes mellitus in a British Caucasian population. Diabetologia 36, 252–257 (1993). https://doi.org/10.1007/BF00399959
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00399959