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Influence of Type 1 Diabetes Genes on Disease Progression: Similarities and Differences Between Countries

  • Pathogenesis of Type 1 Diabetes (AG Ziegler, Section Editor)
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Abstract

Type 1 diabetes (T1D) is an autoimmune disease causing the destruction of pancreatic beta cells. The onset of clinical T1D is preceded by a time period called pre-diabetes, the duration of which varies widely. However, not all subjects developing beta-cell autoimmunity progress to clinical T1D. The inherited risk for T1D is determined by the human leukocyte antigen (HLA) class II genes, HLA class I genes, and several loci outside the HLA area. Although the role of the genetic risk variants in disease pathogenesis is not completely understood, some of the variants affecting disease risk are thought to influence the initiation of beta-cell autoimmunity whereas others seem to play a role during the later stages of the autoimmune process. In this review we describe the current knowledge on the genetic factors mediating the fate of already-established beta-cell autoimmunity and the rate of beta-cell destruction.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Knip M. Natural course of preclinical type 1 diabetes. Horm Res. 2002;57 Suppl 1:6–11.

    Article  PubMed  CAS  Google Scholar 

  2. Noble JA, Valdes AM, Cook M, Klitz W, Thomson G, Erlich HA. The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. Am J Hum Genet. 1996;59:1134–48.

    PubMed  CAS  Google Scholar 

  3. Noble JA, Valdes AM, Varney MD, Carlson JA, Moonsamy P, Fear AL, et al. HLA class I and genetic susceptibility to type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium. Diabetes. 2010;59:2972–79.

    Article  PubMed  CAS  Google Scholar 

  4. Valdes AM, Erlich HA, Noble JA. Human leukocyte antigen class I B and C loci contribute to Type 1 Diabetes (T1D) susceptibility and age at T1D onset. Hum Immunol. 2005;66:301–13.

    Article  PubMed  CAS  Google Scholar 

  5. Nejentsev S, Howson JM, Walker NM, Szeszko J, Field SF, Stevens HE, et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature. 2007;450:887–92.

    Article  PubMed  CAS  Google Scholar 

  6. Bell GI, Horita S, Karam JH. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes. 1984;33:176–83.

    Article  PubMed  CAS  Google Scholar 

  7. Nistico L, Buzzetti R, Pritchard LE, Van der Auwera B, Giovannini C, Bosi E, et al. The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. Hum Mol Genet. 1996;5:1075–80.

    Article  PubMed  CAS  Google Scholar 

  8. Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, et al. Functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004;36:337–8.

    Article  PubMed  CAS  Google Scholar 

  9. Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V, et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet. 2007;39:857–64.

    Article  PubMed  CAS  Google Scholar 

  10. Tait BD, Colman PG, Morahan G, Marchinovska L, Dore E, Gellert S, et al. HLA genes associated with autoimmunity and progression to disease in type 1 diabetes. Tissue Antigens. 2003;61:146–53.

    Article  PubMed  CAS  Google Scholar 

  11. Pociot F, Akolkar B, Concannon P, Erlich HA, Julier C, Morahan G, et al. Genetics of type 1 diabetes: what's next? Diabetes. 2010;59:1561–71.

    Article  PubMed  CAS  Google Scholar 

  12. Michels AW, Gottlieb PA. Autoimmune polyglandular syndromes. Nat Rev Endocrinol. 2010;6:270–7.

    Article  PubMed  CAS  Google Scholar 

  13. Todd JA. Etiology of type 1 diabetes. Immunity. 2010;32:457–67.

    Article  PubMed  CAS  Google Scholar 

  14. Ziegler AG, Standl E, Albert E, Mehnert H. HLA-associated insulin autoantibody formation in newly diagnosed type I diabetic patients. Diabetes. 1991;40:1146–9.

    Article  PubMed  CAS  Google Scholar 

  15. Sabbah E, Savola K, Kulmala P, Reijonen H, Veijola R, Vahasalo P, et al. Disease-associated autoantibodies and HLA-DQB1 genotypes in children with newly diagnosed insulin-dependent diabetes mellitus (IDDM). The Childhood Diabetes in Finland Study Group. Clin Exp Immunol. 1999;116:78–83.

    Article  PubMed  CAS  Google Scholar 

  16. Howson JM, Rosinger S, Smyth DJ, Boehm BO, Todd JA. Genetic analysis of adult-onset autoimmune diabetes. Diabetes. 2011;60:2645–53.

    Article  PubMed  CAS  Google Scholar 

  17. Vandewalle CL, Decraene T, Schuit FC, De Leeuw IH, Pipeleers DG, Gorus FK. Insulin autoantibodies and high titre islet cell antibodies are preferentially associated with the HLA DQA1*0301-DQB1*0302 haplotype at clinical type 1 (insulin-dependent) diabetes mellitus before age 10 years, but not at onset between age 10 and 40 years. The Belgian Diabetes Registry. Diabetologia. 1993;36:1155–62.

    Article  PubMed  CAS  Google Scholar 

  18. Brorsson C, Tue Hansen N, Bergholdt R, Brunak S, Pociot F. The type 1 diabetes - HLA susceptibility interactome–identification of HLA genotype-specific disease genes for type 1 diabetes. PLoS One. 2010;5:e9576.

    Article  PubMed  Google Scholar 

  19. Graham J, Hagopian WA, Kockum I, Li LS, Sanjeevi CB, Lowe RM, et al. Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes. Diabetes. 2002;51:1346–55.

    Article  PubMed  CAS  Google Scholar 

  20. Siljander HT, Simell S, Hekkala A, Lähde J, Simell T, Vahasalo P, et al. Predictive characteristics of diabetes-associated autoantibodies among children with HLA-conferred disease susceptibility in the general population. Diabetes. 2009;58:2835–42.

    Article  PubMed  CAS  Google Scholar 

  21. Marciulionyte D, Williams AJ, Bingley PJ, Urbonaite B, Gale EA. A comparison of the prevalence of islet autoantibodies in children from two countries with differing incidence of diabetes. Diabetologia. 2001;44:16–21.

    Article  PubMed  CAS  Google Scholar 

  22. Kondrashova A, Viskari H, Kulmala P, Romanov A, Ilonen J, Hyöty H, et al. Signs of beta-cell autoimmunity in nondiabetic schoolchildren: a comparison between Russian Karelia with a low incidence of type 1 diabetes and Finland with a high incidence rate. Diabetes Care. 2007;30:95–100.

    Article  PubMed  CAS  Google Scholar 

  23. Schlosser M, Strebelow M, Wassmuth R, Arnold ML, Breunig I, Rjasanowski I, et al. The Karlsburg type 1 diabetes risk study of a normal schoolchild population: association of beta-cell autoantibodies and human leukocyte antigen-DQB1 alleles in antibody-positive individuals. J Clin Endocrinol Metab. 2002;87:2254–61.

    Article  PubMed  CAS  Google Scholar 

  24. Kukko M, Kimpimäki T, Kupila A, Korhonen S, Kulmala P, Savola K, et al. Signs of beta-cell autoimmunity and HLA-defined diabetes susceptibility in the Finnish population: the sib cohort from the Type 1 Diabetes Prediction and Prevention Study. Diabetologia. 2003;46:65–70.

    PubMed  CAS  Google Scholar 

  25. Gardner SG, Gale EA, Williams AJ, Gillespie KM, Lawrence KE, Bottazzo GF, et al. Progression to diabetes in relatives with islet autoantibodies. Is it inevitable? Diabetes Care. 1999;22:2049–54.

    Article  PubMed  CAS  Google Scholar 

  26. Butty V, Campbell C, Mathis D, Benoist C. Impact of diabetes susceptibility loci on progression from pre-diabetes to diabetes in at-risk individuals of the diabetes prevention trial-type 1 (DPT-1). Diabetes. 2008;57:2348–59.

    Article  PubMed  CAS  Google Scholar 

  27. •• Lipponen K, Gombos Z, Kiviniemi M, Siljander H, Lempainen J, Hermann R et al. Effect of HLA class I and class II alleles on progression from autoantibody positivity to overt type 1 diabetes in children with risk-associated class II genotypes. Diabetes. 2010;59:3253–6. This paper from the Finnish DIPP study demonstrated that the HLA class I alleles A*03 and B*39 affect the rate of progression to clinical T1D after the initiation of beta-cell autoimmunity.

  28. Noble JA, Valdes AM, Bugawan TL, Apple RJ, Thomson G, Erlich HA. The HLA class I A locus affects susceptibility to type 1 diabetes. Hum Immunol. 2002;63:657–64.

    Article  PubMed  CAS  Google Scholar 

  29. Reijonen H, Nejentsev S, Tuokko J, Koskinen S, Tuomilehto-Wolf E, Åkerblom HK, 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;24:357–63.

    Article  PubMed  CAS  Google Scholar 

  30. Honeyman MC, Harrison LC, Drummond B, Colman PG, Tait BD. Analysis of families at risk for insulin-dependent diabetes mellitus reveals that HLA antigens influence progression to clinical disease. Mol Med. 1995;1:576–82.

    PubMed  CAS  Google Scholar 

  31. •• Steck AK, Zhang W, Bugawan TL, Barriga KJ, Blair A, Erlich HA et al. Do non-HLA genes influence development of persistent islet autoimmunity and type 1 diabetes in children with high-risk HLA-DR,DQ genotypes? Diabetes. 2009;58:1028–33. This paper from the DAISY study, Colorado, U.S. analyzed the effect of non-HLA polymorphisms on disease progression after signs of beta-cell autoimmunity. No effect of the snps analyzed on disease progression was observed.

  32. •• Winkler C, Lauber C, Adler K, Grallert H, Illig T, Ziegler AG, et al. An interferon-induced helicase (IFIH1) gene polymorphism associates with different rates of progression from autoimmunity to type 1 diabetes. Diabetes. 2011;60:685–90. This paper from the German BABYDIAB study reports the accelerating effect of the IFIH1 gene snp on the progression of beta-cell destruction after the appearance of islet autoimmunity.

  33. •• Lempainen J, Hermann R, Veijola R, Simell O, Knip M, Ilonen J. Effect of the PTPN22 and INS risk genotypes on the progression to clinical type 1 diabetes after the initiation of beta-cell autoimmunity. Diabetes. 2012;61:963–6. This paper from the Finnish DIPP study reports the enhancing effect of the PTPN22 gene polymorphism on progression to clinical T1D after the establishment of beta-cell autoimmunity.

  34. Gregersen PK, Lee HS, Batliwalla F, Begovich AB. PTPN22: setting thresholds for autoimmunity. Semin Immunol. 2006;18:214–23.

    Article  PubMed  CAS  Google Scholar 

  35. Vang T, Congia M, Macis MD, Musumeci L, Orru V, Zavattari P, et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet. 2005;37:1317–9.

    Article  PubMed  CAS  Google Scholar 

  36. Rieck M, Arechiga A, Onengut-Gumuscu S, Greenbaum C, Concannon P, Buckner JH. Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. J Immunol. 2007;179:4704–10.

    PubMed  CAS  Google Scholar 

  37. Aarnisalo J, Treszl A, Svec P, Marttila J, Öling V, Simell O, et al. Reduced CD4(+)T cell activation in children with type 1 diabetes carrying the PTPN22/Lyp 620Trp variant. J Autoimmun. 2008;31:13–21.

    Article  PubMed  CAS  Google Scholar 

  38. Burn GL, Svensson L, Sanchez-Blanco C, Saini M, Cope AP. Why is PTPN22 a good candidate susceptibility gene for autoimmune disease? FEBS Lett. 2011;585:3689–98.

    Article  PubMed  CAS  Google Scholar 

  39. Petrone A, Galgani A, Spoletini M, Alemanno I, Di Cola S, Bassotti G, et al. Residual insulin secretion at diagnosis of type 1 diabetes is independently associated with both, age of onset and HLA genotype. Diabetes Metab Res Rev. 2005;21:271–5.

    Article  PubMed  CAS  Google Scholar 

  40. Nielsen LB, Porksen S, Andersen ML, Fredheim S, Svensson J, Hougaard P, et al. The PTPN22 C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes. BMC Med Genet. 2011;12:41.

    Article  PubMed  CAS  Google Scholar 

  41. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006;441:101–5.

    Article  PubMed  CAS  Google Scholar 

  42. Nejentsev S, Walker N, Riches D, Egholm M, Todd JA. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science. 2009;324:387–9.

    Article  PubMed  CAS  Google Scholar 

  43. Smyth DJ, Cooper JD, Bailey R, Field S, Burren O, Smink LJ, et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet. 2006;38:617–9.

    Article  PubMed  CAS  Google Scholar 

  44. Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA, et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet. 2009;41:703–7.

    Article  PubMed  CAS  Google Scholar 

  45. Liu S, Wang H, Jin Y, Podolsky R, Reddy MV, Pedersen J, et al. IFIH1 polymorphisms are significantly associated with type 1 diabetes and IFIH1 gene expression in peripheral blood mononuclear cells. Hum Mol Genet. 2009;18:358–65.

    Article  PubMed  CAS  Google Scholar 

  46. Andrejeva J, Childs KS, Young DF, Carlos TS, Stock N, Goodbourn S, et al. The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. Proc Natl Acad Sci U S A. 2004;101:17264–9.

    Article  PubMed  CAS  Google Scholar 

  47. Yeung WC, Rawlinson WD, Craig ME. Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. BMJ. 2011;342:d35.

    Article  PubMed  Google Scholar 

  48. Barratt BJ, Payne F, Lowe CE, Hermann R, Healy BC, Harold D, et al. Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes. 2004;53:1884–9.

    Article  PubMed  CAS  Google Scholar 

  49. Walter M, Albert E, Conrad M, Keller E, Hummel M, Ferber K, et al. IDDM2/insulin VNTR modifies risk conferred by IDDM1/HLA for development of Type 1 diabetes and associated autoimmunity. Diabetologia. 2003;46:712–20.

    Article  PubMed  CAS  Google Scholar 

  50. Hermann R, Laine AP, Veijola R, Vahlberg T, Simell S, Lähde J, et al. The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity. Diabetologia. 2005;48:1766–75.

    Article  PubMed  CAS  Google Scholar 

  51. Steck AK, Bugawan TL, Valdes AM, Emery LM, Blair A, Norris JM, et al. Association of non-HLA genes with type 1 diabetes autoimmunity. Diabetes. 2005;54:2482–6.

    Article  PubMed  CAS  Google Scholar 

  52. Ziegler AG, Hummel M, Schenker M, Bonifacio E. Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. Diabetes. 1999;48:460–8.

    Article  PubMed  CAS  Google Scholar 

  53. Kukko M, Kimpimäki T, Korhonen S, Kupila A, Simell S, Veijola R, et al. Dynamics of diabetes-associated autoantibodies in young children with human leukocyte antigen-conferred risk of type 1 diabetes recruited from the general population. J Clin Endocrinol Metab. 2005;90:2712–7.

    Article  PubMed  CAS  Google Scholar 

  54. Pugliese A. Central and peripheral autoantigen presentation in immune tolerance. Immunology. 2004;111:138–46.

    Article  PubMed  CAS  Google Scholar 

  55. Pugliese A, Zeller M, Fernandez Jr A, Zalcberg LJ, Bartlett RJ, Ricordi C, et al. The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet. 1997;15:293–7.

    Article  PubMed  CAS  Google Scholar 

  56. Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet. 1997;15:289–92.

    Article  PubMed  CAS  Google Scholar 

  57. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003;423:506–11.

    Article  PubMed  CAS  Google Scholar 

  58. Marron MP, Raffel LJ, Garchon HJ, Jacob CO, Serrano-Rios M, Martinez Larrad MT, et al. Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups. Hum Mol Genet. 1997;6:1275–82.

    Article  PubMed  CAS  Google Scholar 

  59. Kavvoura FK, Ioannidis JP. CTLA-4 gene polymorphisms and susceptibility to type 1 diabetes mellitus: a HuGE Review and meta-analysis. Am J Epidemiol. 2005;162:3–16.

    Article  PubMed  Google Scholar 

  60. Kouki T, Sawai Y, Gardine CA, Fisfalen ME, Alegre ML, DeGroot LJ. CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves' disease. J Immunol. 2000;165:6606–11.

    PubMed  CAS  Google Scholar 

  61. Hermann R, Knip M, Veijola R, Simell O, Laine AP, Åkerblom HK, et al. Temporal changes in the frequencies of HLA genotypes in patients with Type 1 diabetes–indication of an increased environmental pressure? Diabetologia. 2003;46:420–5.

    PubMed  CAS  Google Scholar 

  62. Gillespie KM, Bain SC, Barnett AH, Bingley PJ, Christie MR, Gill GV, et al. The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes. Lancet. 2004;364:1699–700.

    Article  PubMed  Google Scholar 

  63. Lempainen J, Vaarala O, Mäkela M, Veijola R, Simell O, Knip M, et al. Interplay between PTPN22 C1858T polymorphism and cow's milk formula exposure in type 1 diabetes. J Autoimmun. 2009;33:155–64.

    Article  PubMed  CAS  Google Scholar 

  64. Stene LC, Ronningen KS, Undlien DE, Joner G. Does the relative risk for type 1 diabetes conferred by HLA-DQ, INS, and PTPN22 polymorphisms vary with maternal age, birth weight, or cesarean section? Pediatr Diabetes. 2011;12:91–4.

    Article  PubMed  Google Scholar 

  65. Bonifacio E, Warncke K, Winkler C, Wallner M, Ziegler AG. Cesarean section and interferon-induced helicase gene polymorphisms combine to increase childhood type 1 diabetes risk. Diabetes. 2011;60:3300–6.

    Article  PubMed  CAS  Google Scholar 

  66. Nakanishi K, Kobayashi T, Murase T, Nakatsuji T, Inoko H, Tsuji K, et al. Association of HLA-A24 with complete beta-cell destruction in IDDM. Diabetes. 1993;42:1086–93.

    Article  PubMed  CAS  Google Scholar 

  67. Nakanishi K, Kobayashi T, Inoko H, Tsuji K, Murase T, Kosaka K. Residual beta-cell function and HLA-A24 in IDDM. Markers of glycemic control and subsequent development of diabetic retinopathy. Diabetes. 1995;44:1334–9.

    Article  PubMed  CAS  Google Scholar 

  68. Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JH, et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med. 2008;359:2767–77.

    Article  PubMed  CAS  Google Scholar 

  69. Mlynarski WM, Placha GP, Wolkow PP, Bochenski JP, Warram JH, Krolewski AS. Risk of diabetic nephropathy in type 1 diabetes is associated with functional polymorphisms in RANTES receptor gene (CCR5): a sex-specific effect. Diabetes. 2005;54:3331–5.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Academy of Finland, the Sigrid Jusélius Foundation and the Finnish Medical Foundation.

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Correspondence to Johanna Lempainen.

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Lempainen, J., Ilonen, J. Influence of Type 1 Diabetes Genes on Disease Progression: Similarities and Differences Between Countries. Curr Diab Rep 12, 447–455 (2012). https://doi.org/10.1007/s11892-012-0310-7

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