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Evidence of at least two type 1 diabetes susceptibility genes in the HLA complex distinct from HLA-DQB1, -DQA1 and –DRB1

Genes & Immunity volume 4, pages 46–53 (2003)Cite this article

Abstract

Susceptibility to, and protection against development of type 1 diabetes (T1D) are primarily associated with the highly polymorphic exon 2 sequences of the HLA class II genes: DQB1, DQA1 and DRB1. However, several studies have also suggested that additional genes in the HLA complex influence T1D risk, albeit to a lesser degree than the class II genes. We have previously shown that allele 3 of microsatellite marker D6S2223, 4.9 Mb telomeric of DQ in the extended class I region, is associated with a reduction in risk conferred by the DQ2-DR3 haplotype. Here we replicate this finding in two populations from Sweden and France. We also show that markers in the HLA class II, III and centromeric class I regions contribute to the DQ2-DR3 associated risk of T1D, independently of linkage disequilibrium (LD) with both the DQ/DR genes and the D6S2223 associated gene. The associated marker alleles are carried on the DQ2-DR3-B18 haplotype in a region of strong LD. By haplotype mapping, we have located the most likely location for this second DQ2-DR3 haplotype-modifying locus to the 2.35 Mb region between HLA-DOB and marker D6S2702, located 970 kb telomeric of HLA-B.

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References

  1. Concannon P, Gogolin-Ewens KJ, Hinds DA et al. A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus. Nat Genet 1998; 19: 292–296.

    Article  CAS  PubMed  Google Scholar 

  2. Mein CA, Esposito L, Dunn MG et al. A search for type 1 diabetes susceptibility genes in families from the United Kingdom. Nat Genet 1998; 19: 297–300.

    Article  CAS  PubMed  Google Scholar 

  3. She JX . Susceptibility to type 1 diabetes: HLA-DQ and DR revisited. Immunol Today 1996; 17: 323–329.

    Article  CAS  PubMed  Google Scholar 

  4. Thorsby E . HLA associated diseases. Anniversary review article Hum Immunol 1997; 53: 1–11.

    CAS  PubMed  Google Scholar 

  5. Robinson WP, Barbosa J, Rich SS, Thomson G . Homozygous parent affected sib pair method for detecting disease predisposing variants: application to insulin dependent diabetes mellitus. Genet Epidemiol 1993; 10: 273–288.

    Article  CAS  PubMed  Google Scholar 

  6. Degli-Esposti MA, Abraham LJ, McCann V, Spies T, Christiansen FT, Dawkins RL . Ancestral haplotypes reveal the role of the central MHC in the immunogenetics of IDDM. Immunogenetics 1992; 36: 345–356.

    Article  CAS  PubMed  Google Scholar 

  7. Reijonen H, Nejentsev S, Tuokko J et al. HLA-DR4 subtype and -B alleles in DQB1*0302-positive haplotypes associated with IDDM. The Childhood Diabetes in Finland Study Group. Eur J Immunogenet 1997; 24: 357–363.

    Article  CAS  PubMed  Google Scholar 

  8. Lie BA, Todd JA, Pociot F et al. The predisposition to type 1 diabetes linked to the human leukocyte antigen complex includes at least one non-class II gene. Am J Hum Genet 1999; 64: 793–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nejentsev S, Gombos Z, Laine AP et al. Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B. Diabetes 2000; 49: 2217–2221.

    Article  CAS  PubMed  Google Scholar 

  10. Zavattari P, Lampis R, Motzo C et al. Conditional linkage disequilibrium analysis of a complex disease superlocus, IDDM1, in the HLA region reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1, -DRB1 disease loci. Hum Mol Genet 2001; 10: 881–889.

    Article  CAS  PubMed  Google Scholar 

  11. Undlien DE, Lie BA, Thorsby E . HLA complex genes in type 1 diabetes and other autoimmune diseases. Which genes are involved? Trends Genet 2001; 17: 93–100.

    Article  CAS  PubMed  Google Scholar 

  12. Carrington M . Recombination within the human MHC. Immunol Rev 1999; 167: 245–256.

    Article  CAS  PubMed  Google Scholar 

  13. Clerget-Darpoux F . The HLA component of type I diabetes. Am J Hum Genet 2000; 66: 1468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Degli-Esposti MA, Andreas A, Christiansen FT, Schalke B, Albert E, Dawkins RL . An approach to the localization of the susceptibility genes for generalized myasthenia gravis by mapping recombinant ancestral haplotypes. Immunogenetics 1992; 35: 355–364.

    Article  CAS  PubMed  Google Scholar 

  15. 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; 338: 587–589.

    Article  CAS  PubMed  Google Scholar 

  16. Goldstein DB . Islands of linkage disequilibrium. Nat Genet 2001; 29: 109–111.

    Article  CAS  PubMed  Google Scholar 

  17. Bennett ST, Wilson AJ, Esposito L et al. Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. The IMDIAB Group. Nat Genet 1997; 17: 350–352.

    Article  CAS  PubMed  Google Scholar 

  18. Jongeneel CV, Briant L, Udalova IA, Sevin A, Nedospasov SA, Cambon-Thomsen A . Extensive genetic polymorphism in the human tumor necrosis factor region and relation to extended HLA haplotypes. Proc Natl Acad Sci USA 1991; 88: 9717–9721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lie BA, Sollid LM, Ascher H et al. A gene telomeric of the HLA class I region is involved in predisposition to both type 1 diabetes and coeliac disease. Tissue Antigens 1999; 54: 162–168.

    Article  CAS  PubMed  Google Scholar 

  20. Undlien DE, Akselsen HE, Joner G et al. No independent association of LMP2 and LMP7 polymorphisms with susceptibility to IDDM. Diabetes 1997; 46: 307–312.

    Article  CAS  PubMed  Google Scholar 

  21. Kockum I, Sanjeevi CB, Eastman S, Landin-Olsson M, Dahlquist G, Lernmark A . Complex interaction between HLA DR and DQ in conferring risk for childhood type 1 diabetes. Eur J Immunogenet 1999; 26: 361–372.

    Article  CAS  PubMed  Google Scholar 

  22. Kimura A, Sasasuki T . Eleventh International Histocompatibility Workshop reference protocol for the HLA DNA-typing technique. In: Tsuji K, Sasazuki MAT (eds). HLA 1991, Vol. I. Oxford University Press: Oxford, 1992, pp 397–419.

    Google Scholar 

  23. Siegmund T, Donner H, Braun J, Usadel KH, Badenhoop K . HLA-DMA and HLA-DMB alleles in German patients with type 1 diabetes mellitus. Tissue Antigens 1999; 54: 291–294.

    Article  CAS  PubMed  Google Scholar 

  24. Zavattari P, Lampis R, Mulargia A et al. Confirmation of the DRB1-DQB1 loci as the major component of IDDM1 in the isolated founder population of Sardinia. Hum Mol Genet 2000; 9: 2967–2972.

    Article  CAS  PubMed  Google Scholar 

  25. Lie BA, Akselsen HE, Joner G et al. HLA associations in insulin-dependent diabetes mellitus: No independent association to DP genes. Hum Immunol 1997; 55: 170–175.

  26. Spielman RS, McGinnis RE, Ewens WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993; 52: 506–516.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Klitz W, Stephens JC, Grote M, Carrington M . Discordant patterns of linkage disequilibrium of the peptide-transporter loci within the HLA class II region. Am J Hum Genet 1995; 57: 1436–1444.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Schneider S, Kueffer J, Roessli D, Excoffier L . Arlequin ver 1.1: a Software for Population Genetic Data Analysis. Genetics and Biometry Laboratory, University of Geneva: Geneva, Switzerland, 1997.

    Google Scholar 

  29. Tiwari JL, Terasaki P . The data and statistical analysis. In: Tiwari JL, Terasaki P (eds). HLA and Disease Associations. Springer-Verlag: New York Heidelberg Berlin Tokyo, 1985, 18–27.

    Chapter  Google Scholar 

  30. Crouau-Roy B, Bouzekri N, Carcassi C, Clayton J, Contu L, Cambon-Thomsen A . Strong association between microsatellites and an HLA-B, DR haplotype (B18-DR3): implication for microsatellite evolution. Immunogenetics 1996; 43: 255–260.

    Article  CAS  PubMed  Google Scholar 

  31. Ramsbottom D, Carcassi C, de Salages H et al. MHC haplotypes including eight microsatellites in French Basques and in Sardinians. In: Charron D (ed). Proceedings of the Twelfth International Histocompatibility Conference. Vol. II, EDK Medical and Scientific International Publisher: Paris, 1996; pp 178–180.

    Google Scholar 

  32. Cambon-de Mouzon A, Ohayon E, Hauptmann G et al. HLA-A, B, C, DR antigens Bf, C4 and glyoxalase I (GLO) polymorphisms in French Basques with insulin-dependent diabetes mellitus (IDDM). Tissue Antigens 1982; 19: 366–379.

    Article  CAS  PubMed  Google Scholar 

  33. Contu L, Deschamps I, Lestradet H et al. HLA haplotype study of 53 juvenile insulin-dependent diabetic (I.D.D.) families. Tissue Antigens 1982; 20: 123–140.

    Article  CAS  PubMed  Google Scholar 

  34. Deschamps I, Marcelli-Barge A, Poirier JC et al. Two distinct HLA-DR3 haplotypes are associated with age related heterogeneity in type 1 (insulin-dependent) diabetes. Diabetologia 1988; 31: 896–901.

    Article  CAS  PubMed  Google Scholar 

  35. Jeffreys AJ, Kauppi L, Neumann R . Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet 2001; 29: 217–222.

    Article  CAS  PubMed  Google Scholar 

  36. La Nasa G, Carcassi C, Cirillo R et al. Serological and molecular studies of HLA in insulin-dependent diabetes mellitus in Sardinia. Dis Markers 1990; 8: 333–340.

    CAS  PubMed  Google Scholar 

  37. Erlich HA, Rotter JI, Chang JD et al. Association of HLA-DPB1*0301 with IDDM in Mexican-Americans. Diabetes 1996; 45: 610–614.

    Article  CAS  PubMed  Google Scholar 

  38. Valdes AM, Thomson G, Erlich HA, Noble JA . Association between type 1 diabetes age of onset and HLA among sibling pairs. Diabetes 1999; 48: 1658–1661.

    Article  CAS  PubMed  Google Scholar 

  39. Noble JA . The HLA class II locus DPB1 can influence susceptibility to type 1 diabetes. Diabetes 2000; 49: 121–125.

    Article  CAS  PubMed  Google Scholar 

  40. Cucca F, Dudbridge F, Loddo M et al. The HLA-DPB1–associated component of the IDDM1 and its relationship to the major loci HLA-DQB1, -DQA1, and -DRB1. Diabetes 2001; 50: 1200–1205.

    Article  CAS  PubMed  Google Scholar 

  41. Cordell HJ, Clayton DG . A Unified Stepwise Regression Procedure for Evaluating the Relative Effects of Polymorphisms within a Gene Using Case/Control or Family Data: Application to HLA in Type 1 Diabetes. Am J Hum Genet 2001; 70: 1.

    Google Scholar 

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Acknowledgements

We thank Anne Brit Thoresen and Siri Flåm for excellent technical assistance. The study was financially supported by The Norwegian Research Council, Juvenile Diabetes Research Foundation International (grants 1-2000-514, 3-2000-515 and 4-2000-948), the Welcome Trust, The Novo Nordisk Foundation, The Norwegian Diabetes Association, the Swedish Diabetes Association, the Swedish Childhood Diabetes Fund and the Swedish Medical Research Council (K98-19X-12674-01A). We thank the Norwegian Bone Marrow Donor Registry, the Norwegian Study Group for Childhood Diabetes, the Danish Study Group of Diabetes in Childhood, the Danish IDDM Epidemiology and Genetics Group, Diabetes UK, Swedish Childhood Diabetes Study, the Diabetes Incidence Study in Sweden, the French Network Inserm for IDDM and MS in Atlantic Pyrenees and the Regional Observatory of Health in Aquitaine region (Dr J Doutreix) for the collection of samples for this study.

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Author notes

  1. S Johansson and B A Lie: These authors contributed equally.

Authors and Affiliations

  1. Institute of Immunology, Rikshospitalet University Hospital, Norway

    S Johansson, B A Lie, H E Akselsen, E Thorsby & D E Undlien

  2. JDRF/WT Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, UK

    J A Todd

  3. Steno Diabetes Center, Gentofte, Denmark

    F Pociot & J Nerup

  4. Inserm U 558, Toulouse, France

    A Cambon-Thomsen

  5. Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

    I Kockum

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  1. S Johansson
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Correspondence to S Johansson.

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Johansson, S., Lie, B., Todd, J. et al. Evidence of at least two type 1 diabetes susceptibility genes in the HLA complex distinct from HLA-DQB1, -DQA1 and –DRB1. Genes Immun 4, 46–53 (2003). https://doi.org/10.1038/sj.gene.6363917

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