Molecular Genetics of Type 1 Diabetes

Yi Ye, University of Bristol, Bristol, UK
Kay L Mehers, University of Bristol, Bristol, UK
Kathleen M Gillespie, University of Bristol, Bristol, UK

Published online: September 2010

DOI: 10.1002/9780470015902.a0022432

Combinations of susceptibility genes interact with environmental modifiers to precipitate autoimmune destruction of islet beta cells and type 1 diabetes (T1D). This interaction has become increasingly penetrant in recent decades with annual increases in incidence of T1D of 3% per year and the greatest increase occurring in young children. Although the major genetic determinant the human leucocyte antigen (HLA) on chromosome 6 has been known for decades, recent advances in genetic technology coupled with deoxyribonucleic acid (DNA) collections from large cohorts of individuals with T1D and controls have resulted in an explosion of information on the genetic determinants of autoimmune diabetes. To date, more than 40 predisposing loci have been identified and hundreds are in the pipeline but the molecular effects of most remain to be determined.

Key Concepts:

  • The incidence of T1D is increasing at a rate of 3% per year.
  • Multiple susceptibility genes and environmental determinants interact to precipitate disease.
  • The HLA is currently the best genetic determinant of risk of future T1D. Improving methodologies have resulted in identification of multiple susceptibility genes.

Keywords: autoimmune; human leucocyte antigen (HLA); islet autoantibodies

Figure 1. Geographical variation in incidence of T1D.
Figure 2. The HLA region on chromosome 6.
Figure 3. Chromosomal localisation of selected T1D-associated loci.
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 References
    Aly TA, Ide A, Jahromi MM et al. (2006) Extreme genetic risk for type 1A diabetes. Proceedings of the National Academy of Sciences of the USA 103: 14074–14079.
    Bell GI, Horita S and Karam JH (1984) A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33: 176–183.
    Bennett ST, Lucassen AM, Gough SC et al. (1995) Susceptibility to human type-1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nature Genetics 9: 284–292.
    Bingley PJ, Bonifacio E, Williams AJ et al. (1997) Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers. Diabetes 46: 1701–1710.
    Bonifacio E, Hummel M, Walter M et al. (2004) IDDM1 and multiple family history of type 1 diabetes combine to identify neonates at high risk for type 1 diabetes. Diabetes Care 27: 2695–2700.
    Bottini N, Musumeci L, Alonso A et al. (2004) A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nature Genetics 36: 337–338.
    Concannon P, Erlich HA, Julier C et al. (2005) Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1435 multiplex families. Diabetes 54: 2995–3001.
    Concannon P, Onengut-Gumuscu S, Todd JA et al. (2008) A human type 1 diabetes susceptibility locus maps to chromosome 21q22.3. Type 1 Diabetes Genetics Consortium. Diabetes 57: 2858–2861.
    Cooper JD, Smyth DJ, Smiles AM et al. (2008) Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nature Genetics 40: 1399–1401.
    Cruz TD, Valdes AM, Santiago A et al. (2004) DPB1 alleles are associated with type 1 diabetes susceptibility in multiple ethnic groups. Diabetes 53: 2158–2163.
    Cudworth AG and Woodrow JC (1975) HL-A system and diabetes mellitus. Diabetes 24: 345–349.
    Dotta F, Censini S, van Halteren AG et al. (2007) Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proceedings of the National Academy of Sciences of the USA 104: 5115–5120.
    Edghill EL, Dix RJ, Flanagan SE et al. (2006) HLA genotyping supports a non-autoimmune etiology in patients diagnosed with diabetes under the age of 6 months. Diabetes 55: 1895–1898.
    Fourlanos S, Varney MD, Tait BD et al. (2008) The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes. Diabetes Care 31: 1546–1549.
    Gillespie KM, Bain SC, Barnett AH et al. (2004) The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes. Lancet 364: 1699–1700.
    Gillespie KM, Dix RJ, Williams AJ et al. (2006) Islet autoimmunity in children with Down's syndrome. Diabetes 55: 3185–3188.
    Hermann R, Knip M, Veijola R et al. (2003) Temporal changes in the frequencies of HLA genotypes in patients with type 1 diabetes – indication of an increased environmental pressure? Diabetologia 46: 420–425.
    Hyttinen V, Kaprio J, Kinnunen L et al. (2003) Genetic liability of type 1 diabetes and the onset age among 22 650 young Finnish twin pairs – a nationwide follow-up study. Diabetes 52: 1052–1055.
    Karvonen M, Viik-Kajander M, Moltchanova E et al. (2000) Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care 23: 1516–1526.
    Lambert AP, Gillespie KM, Thomson G et al. (2004) Absolute risk of childhood-onset type 1 diabetes defined by human leukocyte antigen class II genotype: a population-based study in the United Kingdom. Journal of Clinical Endocrinology and Metabolism 89: 4037–4043.
    Lowe CE, Cooper JD, Brusko T et al. (2007) Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nature Genetics 39: 1074–1082.
    Nejentsev S, Howson JM, Walker NM et al. (2007) Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450: 887–892.
    Nerup J, Platz P, Andersen OO et al. (1974) HL-A antigens and diabetes mellitus. Lancet 2: 864–866.
    Nistico L, Buzzetti R, Pritchard LE et al. (1996) The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. Human Molecular Genetics 5: 1075–1080.
    Patterson CC, Dahlquist GG, Gyürüs E et al. EURODIAB Study Group (2009) Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: a multicentre prospective registration study. Lancet 373: 2027–2033.
    Pugliese A, Zeller M, Fernandez A et al. (1997) 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. Nature Genetics 15: 293–297.
    Qu HQ, Marchand L, Grabs R et al. (2008) The association between the IFIH1 locus and type 1 diabetes. Diabetologia 51: 473–475.
    Qu HQ, Montpetit A, Ge B et al. (2007) Toward further mapping of the association between the IL2RA locus and type 1 diabetes. Diabetes 56: 1174–1176.
    Redondo MJ, Yu L, Hawa M et al. (2001) Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States. Diabetologia 44: 354–362.
    Risch N (1987) Assessing the role of HLA-linked and unlinked determinants of disease. American Journal of Human Genetics 40: 1–14.
    Roll U, Christie MR, Fuchtenbusch M et al. (1996) Perinatal autoimmunity in offspring of diabetic parents. The German multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood. Diabetes 45: 967–973.
    Singal DP and Blajchman MA (1973) Histocompatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes 22: 429–432.
    Smyth DJ, Cooper JD, Bailey R et al. (2006) A genome-wide association study of non-synonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nature Genetics 38: 617–619.
    Smyth DJ, Plagnol V, Walker NM et al. (2008) Shared and distinct genetic variants in type 1 diabetes and celiac disease. New England Journal of Medicine 359: 2767–2777.
    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. American Journal of Human Genetics 43: 799–816.
    Todd JA, Bell JI and McDevitt HO (1987) HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329: 599–604.
    Todd JA, Walker NM, Cooper JD et al. (2007) Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Genetics 39: 857–864.
    Ueda H, Howson JM, Esposito L et al. (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423: 506–511.
    Vafiadis P, Bennett ST, Todd JA et al. (1997) Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nature Genetics 15: 289–292.
    Vella A, Cooper JD, Lowe CE et al. (2005) Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. American Journal of Human Genetics 76: 773–779.
    Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 447: 661–678.
    Wenzlau JM, Juhl K, Yu L et al. (2007) The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proceedings of the National Academy of Sciences of the USA 104: 17040–17045.
    Wicker LS, Clark J, Fraser HI et al. (2005) Type 1 diabetes genes and pathways shared by humans and NOD mice. Journal of Autoimmunity 25(suppl.): 29–33.
    Ziegler AG, Hummel M, Schenker M et al. (1999) 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 48: 460–468.
 Further Reading
    Achenbach P, Barker J, Bonifacio E and Pre-POINT Study Group (2008) Modulating the natural history of type 1 diabetes in children at high genetic risk by mucosal insulin immunization. Current Diabetes Reports 8: 87–93. (review).
    other Harrison LC, Unglik G and Honeyman MC. Immunity: humoral and cellular. Encyclopaedia of Life Science Online. doi: 10.1038/npg.els.0001236.
    Ounissi-Benkalha H and Polychronakos C (2008) The molecular genetics of type 1 diabetes: new genes and emerging mechanisms. Trends in Molecular Medicine 14: 268–275.

Related Sub-Topics:

Autoimmunity | Molecular Genetics of Common and Complex Disease | Molecular Genetics of Common and Complex Disease | Linkage Analysis | Inter-Individual Variation and Polymorphism
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Article Title: Molecular Genetics of Type 1 Diabetes
 
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Ye, Yi, Mehers, Kay L, and Gillespie, Kathleen M(Sep 2010) Molecular Genetics of Type 1 Diabetes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022432]