Current Diabetes Reports

, 11:445

The Past, Present, and Future of Genetic Associations in Type 1 Diabetes

Article

Abstract

Type 1 diabetes mellitus (T1DM) is an autoimmune disease affecting approximately one in 300 individuals in the United States. The majority of genetic research to date has focused on the heritability that predisposes to islet autoimmunity and T1DM. The evidence so far points to T1DM being a polygenic, common, complex disease with major susceptibility lying in the major histocompatibility complex (MHC) on chromosome 6 with other smaller effects seen in loci outside of the MHC. With recent advances in technology, novel means of exploring the human genome have given way to new information in the development of T1DM. The newest technologies, namely high-throughput polymorphism typing and sequencing, have led to a paradigm shift in studying common diseases such as T1DM. In this review we highlight the advances in genetic associations in T1DM in the last several decades and how they have led to a better understanding of T1DM pathogenesis.

Keywords

Type 1 diabetes Autoimmune diseases Major histocompatibility complex Human leukocyte antigen Genetic association study Linkage study Candidate gene Extended haplotype Single nucleotide polymorphism Genome-wide association study Whole exome sequencing 

References

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

  1. 1.
    Horton R, Wilming L, Rand V, et al. Gene map of the extended human MHC. Nat Rev Genet. 2004;5:889–99.PubMedCrossRefGoogle Scholar
  2. 2.
    Anonymous. Complete sequence and gene map of a human major histocompatibility complex. The MHC sequencing consortium. Nature. 1999;401:921–3.CrossRefGoogle Scholar
  3. 3.
    Park Y, She JX, Wang CY, et al. Common susceptibility and transmission pattern of human leukocyte antigen DRB1-DQB1 haplotypes to Korean and Caucasian patients with type 1 diabetes. J Clin Endocrinol Metab. 2000;85:4538–42.PubMedCrossRefGoogle Scholar
  4. 4.
    She J-X. Susceptibility to type I diabetes: HLA-DQ and DR revisited. Immunol Today. 1996;17:323–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Rewers M, Bugawan TL, Norris JM, et al. Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY). Diabetol. 1996;39:807–12.CrossRefGoogle Scholar
  6. 6.
    Aly TA, Ide A, Jahromi MM, et al. Extreme genetic risk for type 1A diabetes. Proc Natl Acad Sci USA. 2006;103:14074–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Bonifacio E, Hummel M, Walter M, Schmid S, Ziegler AG. IDDM1 and multiple family history of type 1 diabetes combine to identify neonates at high risk for type 1 diabetes. Diabetes Care. 2004;27:2695–700.PubMedCrossRefGoogle Scholar
  8. 8.
    Erlich H, Valdes AM, Noble J, et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes. 2008;57:1084–92.PubMedCrossRefGoogle Scholar
  9. 9.
    Pugliese A, Gianani R, Moromisato R, et al. HLA-DQB1*0602 is associated with dominant protection from diabetes even among islet cell antibody-positive first-degree relatives of patients with IDDM. Diab. 1995;44:608–13.CrossRefGoogle Scholar
  10. 10.
    Aly TA, Baschal EE, Jahromi MM, et al. Analysis of single nucleotide polymorphisms identifies major type 1A diabetes locus telomeric of the major histocompatibility complex. Diabetes. 2008;57:770–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Cruz TD, Valdes AM, Santiago A, et al. DPB1 alleles are associated with type 1 diabetes susceptibility in multiple ethnic groups. Diabetes. 2004;53:2158–63.PubMedCrossRefGoogle Scholar
  12. 12.
    Baschal EE, Aly TA, Babu SR, et al. HLA-DPB1*0402 protects against type 1A diabetic autoimmunity in the highest risk DR3-DQB1*0201/DR4-DQB1*0302 DAISY population. Diabetes. 2007;56:2405–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Varney MD, Valdes AM, Carlson JA, et al. HLA DPA1, DPB1 alleles and haplotypes contribute to the risk associated with type 1 diabetes: analysis of the type 1 diabetes genetics consortium families. Diab. 2010;59:2055–62.CrossRefGoogle Scholar
  14. 14.
    Steck AK, Armstrong TK, Babu SR, Eisenbarth GS. Stepwise or linear decrease in penetrance of type 1 diabetes with lower-risk HLA genotypes over the past 40 years. Diab. 2011.Google Scholar
  15. 15.
    Noble JA, Valdes AM, Varney MD, et al. HLA class I and genetic susceptibility to type 1 diabetes: results from the type 1 diabetes genetics consortium. Diab. 2010;59:2972–9.CrossRefGoogle Scholar
  16. 16.
    Lipponen K, Gombos Z, Kiviniemi M, 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. Diab. 2010;59:3253–6.CrossRefGoogle Scholar
  17. 17.
    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.PubMedCrossRefGoogle Scholar
  18. 18.
    Nejentsev S, Howson JM, Walker NM, et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature. 2007;450:887–92.PubMedCrossRefGoogle Scholar
  19. 19.
    Baschal EE, Baker PR, Eyring KR, Siebert JC, Jasinski JM, Eisenbarth GS. The HLA-B*3906 allele imparts high diabetes risk only on specific HLA-DR/DQ haplotypes. Diabetalogia 2011, In Press.Google Scholar
  20. 20.
    Brown WM, Pierce J, Hilner JE, et al. Overview of the MHC fine mapping data. Diabetes Obes Metab. 2009;11 Suppl 1:2–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Alper CA, Larsen CE, Dubey DP, Awdeh ZL, Fici DA, Yunis EJ. The haplotype structure of the human major histocompatibility complex. Hum Immunol. 2006;67:73–84.PubMedCrossRefGoogle Scholar
  22. 22.
    Bilbao JR, Calvo B, Aransay AM, et al. Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease. Genes Immun. 2006;7:550–4.PubMedCrossRefGoogle Scholar
  23. 23.
    Baschal EE, Aly TA, Jasinski JM, et al. The frequent and conserved DR3-B8-A1 extended haplotype confers less diabetes risk than other DR3 haplotypes. Diabetes Obes Metab. 2009;11 Suppl 1:25–30.PubMedCrossRefGoogle Scholar
  24. 24.
    Steck AK, Zhang W, Bugawan TL, 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? Diab. 2009;58:1028–33.CrossRefGoogle Scholar
  25. 25.
    • Barrett JC, Clayton DG, Concannon P, et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet. 2009. This is a high-powered study analyzing previously published GWAS-implicated loci outside of the MHC. It reveals many loci not previously described and verifies several important findings from previous GWAS. Google Scholar
  26. 26.
    Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med. 2009;360:1646–54.PubMedCrossRefGoogle Scholar
  27. 27.
    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.PubMedCrossRefGoogle Scholar
  28. 28.
    Hanahan D. Peripheral-antigen-expressing cells in thymic medulla: factors in self- tolerance and autoimmunity. Curr Opin Immunol. 1998;10:656–62.PubMedCrossRefGoogle Scholar
  29. 29.
    Chentoufi AA, Polychronakos C. Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes. Diabetes. 2002;51:1383–90.PubMedCrossRefGoogle Scholar
  30. 30.
    Barratt BJ, Payne F, Lowe CE, et al. Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes. 2004;53:1884–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Bottini N, Musumeci L, Alonso A, et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004;36:337–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Steck AK, Baschal EE, Jasinski JM, et al. rs2476601 T allele (R620W) defines high-risk PTPN22 type I diabetes-associated haplotypes with preliminary evidence for an additional protective haplotype. Genes Immun. 2009;10 Suppl 1:S21–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Kristiansen OP, Larsen ZM, Pociot F. CTLA-4 in autoimmune diseases–a general susceptibility gene to autoimmunity? Genes Immun. 2000;1:170–84.PubMedCrossRefGoogle Scholar
  34. 34.
    Nistico L, Buzzetti R, Pritchard LE, et al. The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Hum Mol Genet. 1996;5:1075–80.PubMedCrossRefGoogle Scholar
  35. 35.
    Anjos SM, Tessier MC, Polychronakos C. Association of the cytotoxic T lymphocyte-associated antigen 4 gene with type 1 diabetes: evidence for independent effects of two polymorphisms on the same haplotype block. J Clin Endocrinol Metab. 2004;89:6257–65.PubMedCrossRefGoogle Scholar
  36. 36.
    Bergman ML, Cilio CM, Penha-Goncalves C, et al. CTLA-4−/− mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice. J Autoimmun. 2001;16:105–13.PubMedCrossRefGoogle Scholar
  37. 37.
    Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3:541–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Howson JM, Dunger DB, Nutland S, Stevens H, Wicker LS, Todd JA. A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene. Diabetologia. 2007;50:741–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Vella A, Cooper JD, Lowe CE, et al. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am J Hum Genet. 2005;76:773–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Salomon B, Lenschow DJ, Rhee L, et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity. 2000;12:431–40.PubMedCrossRefGoogle Scholar
  41. 41.
    Dendrou CA, Wicker LS. The IL-2/CD25 pathway determines susceptibility to T1D in humans and NOD mice. J Clin Immunol. 2008;28:685–96.PubMedCrossRefGoogle Scholar
  42. 42.
    Lowe CE, Cooper JD, Brusko T, et al. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet. 2007;39:1074–82.PubMedCrossRefGoogle Scholar
  43. 43.
    WTCCC. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–78.CrossRefGoogle Scholar
  44. 44.
    Cooper JD, Smyth DJ, Smiles AM, et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat Genet. 2008;40:1399–401.PubMedCrossRefGoogle Scholar
  45. 45.
    Concannon P, Erlich HA, Julier C, et al. Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families. Diabetes. 2005;54:2995–3001.PubMedCrossRefGoogle Scholar
  46. 46.
    Smyth DJ, Plagnol V, Walker NM, et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med. 2008;359:2767–77.PubMedCrossRefGoogle Scholar
  47. 47.
    Hakonarson H, Grant SF. Genome-wide association studies in type 1 diabetes, inflammatory bowel disease and other immune-mediated disorders. Semin Immunol. 2009;21:355–62.PubMedCrossRefGoogle Scholar
  48. 48.
    Heinig M, Petretto E, Wallace C, et al. A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature. 2010;467:460–4.PubMedCrossRefGoogle Scholar
  49. 49.
    Wallace C, Smyth DJ, Maisuria-Armer M, Walker NM, Todd JA, Clayton DG. The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes. Nat Genet. 2010;42:68–71.PubMedCrossRefGoogle Scholar
  50. 50.
    • Burren OS, Adlem EC, Achuthan P, Christensen M, Coulson RM, Todd JA. T1DBase: update 2011, organization and presentation of large-scale data sets for type 1 diabetes research. Nucleic Acids Res. 2011; 39:D997–1001. This is an update detailing a web-based platform with publically accessible information on genetic, genomic, and expression data relevant toT1DM research across mouse, rat, and humans. Provides full datasets and tools for TIDM data analysis with meticulous curation and regular updates. Integrates and consolidates the plethora of information being created by new genetic study methods. PubMedCrossRefGoogle Scholar
  51. 51.
    Pritchard JK, Cox NJ. The allelic architecture of human disease genes: common disease-common variant…or not? Hum Mol Genet. 2002;11:2417–23.PubMedCrossRefGoogle Scholar
  52. 52.
    Anonymous. The international HapMap project. Nature. 2003;426:789–96.CrossRefGoogle Scholar
  53. 53.
    Plomin R, Haworth CM, Davis OS. Common disorders are quantitative traits. Nat Rev Genet. 2009;10:872–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Pociot F, Akolkar B, Concannon P, et al. Genetics of type 1 diabetes: what’s next? Diab. 2010;59:1561–71.CrossRefGoogle Scholar
  55. 55.
    Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB. Rare variants create synthetic genome-wide associations. PLoS Biol. 2010;8:e1000294.PubMedCrossRefGoogle Scholar
  56. 56.
    Todd JA, Walker NM, Cooper JD, et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet. 2007;39:857–64.PubMedCrossRefGoogle Scholar
  57. 57.
    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.PubMedCrossRefGoogle Scholar
  58. 58.
    Reich DE, Lander ES. On the allelic spectrum of human disease. Trends Genet. 2001;17:502–10.PubMedCrossRefGoogle Scholar
  59. 59.
    Pritchard JK. Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet. 2001;69:124–37.PubMedCrossRefGoogle Scholar
  60. 60.
    • Ng SB, Turner EH, Robertson PD, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 2009; 461:272–6. This is the first study to use whole-exome sequencing to determine the genetic cause of a rare mendelian condition. PubMedCrossRefGoogle Scholar
  61. 61.
    Ng SB, Buckingham KJ, Lee C, et al. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 2010;42:30–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Hagopian WA, Lernmark A, Rewers MJ, et al. TEDDY–The Environmental Determinants of Diabetes in the Young: an observational clinical trial. Ann N Y Acad Sci. 2006;1079(320–6):320–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.The Barbara Davis Center for Childhood DiabetesUniversity of Colorado DenverAuroraUSA
  2. 2.The Barbara Davis Center for Childhood DiabetesUniversity of Colorado DenverAuroraUSA

Personalised recommendations