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Progress in Understanding Type 1 Diabetes Through Its Genetic Overlap with Other Autoimmune Diseases

  • Genetics (AP Morris, Section Editor)
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Abstract

Type 1 diabetes mellitus (T1DM) is the most common autoimmune disease in pediatrics with a prevalence of roughly 1 in 500 children in the USA. Genome-wide association studies have identified more than 50 variants associated with increased risk for type 1 diabetes. Comparison of these variants with those identified in other autoimmune diseases reveals three important findings: (1) there is a high degree of overlap in implicated variants in diseases with similar pathophysiology, (2) in diseases with differing pathophysiology the same variants are often implicated in opposite roles, (3) in diseases with differing pathophysiology that have many non-overlapping or oppositely implicated variants there are still several variants which are overlapping or shared. Thus, the genetic overlap between T1DM and other autoimmune diseases forms the basis for our understanding of druggable targets in type 1 diabetes.

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References

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

  1. Dabelea D, Mayer-Davis EJ, Saydah S, et al. Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA. 2014;311(17):1778–86. doi:10.1001/jama.2014.3201. Recent work describing the increasing prevalence of diabetes (both type 1 and type 2) in the pediatric population from 2001–2009.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Dassau E, Brown SA, Basu A, et al. Adjustment of open-loop settings to improve closed-loop results in type 1 diabetes: a multicenter randomized trial. J Clin Endocrinol Metab. 2015. doi:10.1210/jc.2015-2081.

    PubMed  Google Scholar 

  3. Gingras V, Rabasa-Lhoret R, Messier V, et al. Efficacy of dual-hormone artificial pancreas to alleviate the carbohydrate-counting burden of type 1 diabetes: A randomized crossover trial. Diabete Metab. 2015. doi:10.1016/j.diabet.2015.05.001.

    PubMed  Google Scholar 

  4. Pagliuca FW, Millman JR, Gurtler M, et al. Generation of functional human pancreatic beta cells in vitro. Cell. 2014;159(2):428–39. doi:10.1016/j.cell.2014.09.040.

    Article  CAS  PubMed  Google Scholar 

  5. Khosravi-Maharlooei M, Hajizadeh-Saffar E, Tahamtani Y, et al. Islet transplantation for type 1 diabetes: so close and yet so far away. Eur J Endocrinol. 2015. doi:10.1530/eje-15-0094.

    PubMed  Google Scholar 

  6. Tomei AA, Villa C, Ricordi C. Development of an encapsulated stem cell-based therapy for diabetes. Expert Opin Biol Ther. 2015:1-16. doi:10.1517/14712598.2015.1055242.

  7. Lehmann R, Graziano J, Brockmann J, et al. Glycemic control in simultaneous islet-kidney versus pancreas-kidney transplantation in type 1 diabetes: a prospective 13-year follow-up. Diabetes Care. 2015;38(5):752–9. doi:10.2337/dc14-1686.

    Article  CAS  PubMed  Google Scholar 

  8. Park KT, Jun H, Kim MG, et al. Simultaneous pancreas-kidney transplantation from living donor using hand-assisted laparoscopic donor surgery: single-center experience. Transplant Proc. 2015;47(4):1096–8. doi:10.1016/j.transproceed.2014.10.063.

    Article  PubMed  Google Scholar 

  9. Polychronakos C, Li Q. Understanding type 1 diabetes through genetics: advances and prospects. Nat Rev Genet. 2011;12(11):781–92. doi:10.1038/nrg3069.

    Article  CAS  PubMed  Google Scholar 

  10. Tomlinson MJ, Pitsillides A, Pickin R, et al. Fine mapping and functional studies of risk variants for type 1 diabetes at chromosome 16p13.13. Diabetes. 2014;63(12):4360–8. doi:10.2337/db13-1785.

    Article  CAS  PubMed  Google Scholar 

  11. Onengut-Gumuscu S, Chen WM, Burren O, et al. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat Genet. 2015;47(4):381–6. doi:10.1038/ng.3245. Recent study that used the overlap of finely mapped SNPs and ENCODE data to identify likely causal SNPs for T1DM and other autoimmune diseases.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Bradfield JP, Qu HQ, Wang K, et al. A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci. PLoS Genet. 2011;7(9):e1002293. doi:10.1371/journal.pgen.1002293.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Wang K, Baldassano R, Zhang H, et al. Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects. Hum Mol Genet. 2010;19(10):2059–67. doi:10.1093/hmg/ddq078. Early comparative study that identified oppositely oriented associations in T1DM and inflammatory bowel disease.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Trynka G, Hunt KA, Bockett NA, et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet. 2011;43(12):1193–201. doi:10.1038/ng.998.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Fortune MD, Guo H, Burren O, Schofield E, Walker NM, Ban M, et al. Statistical colocalization of genetic risk variants for related autoimmune diseases in the context of common controls. Nat Genet. 2015. doi:10.1038/ng.3330. Uses baysean inference to identify likely causal SNPs across several autoimmune diseases. 

    PubMed Central  Google Scholar 

  16. Eaton WW, Rose NR, Kalaydjian A, et al. Epidemiology of autoimmune diseases in Denmark. J Autoimmun. 2007;29(1):1–9. doi:10.1016/j.jaut.2007.05.002.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med. 2004;350(20):2068–79. doi:10.1056/NEJMra030158.

    Article  CAS  PubMed  Google Scholar 

  18. Yang S, Fujikado N, Kolodin D, et al. Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science. 2015;348(6234):589–94. doi:10.1126/science.aaa7017.

    Article  CAS  PubMed  Google Scholar 

  19. Aronson R, Gottlieb PA, Christiansen JS, et al. Low-dose otelixizumab anti-CD3 monoclonal antibody DEFEND-1 study: results of the randomized phase III study in recent-onset human type 1 diabetes. Diabetes Care. 2014;37(10):2746–54. doi:10.2337/dc13-0327.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Criswell LA, Pfeiffer KA, Lum RF, et al. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet. 2005;76(4):561–71. doi:10.1086/429096.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Wildin RS, Ramsdell F, Peake J, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27(1):18–20. doi:10.1038/83707.

    Article  CAS  PubMed  Google Scholar 

  22. Huber A, Menconi F, Corathers S, et al. Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis: from epidemiology to mechanisms. Endocr Rev. 2008;29(6):697–725. doi:10.1210/er.2008-0015.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Hakonarson H, Grant SF, Bradfield JP, et al. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature. 2007;448(7153):591–4. doi:10.1038/nature06010. One of the two first GWAS of T1DM.

    Article  CAS  PubMed  Google Scholar 

  24. Hakonarson H, Qu HQ, Bradfield JP, et al. A novel susceptibility locus for type 1 diabetes on Chr12q13 identified by a genome-wide association study. Diabetes. 2008;57(4):1143–6. doi:10.2337/db07-1305. Used larger sample size to identify rare risk-associated variant in T1D.

    Article  CAS  PubMed  Google Scholar 

  25. Concannon P, Onengut-Gumuscu S, Todd JA, et al. A human type 1 diabetes susceptibility locus maps to chromosome 21q22.3. Diabetes. 2008;57(10):2858–61. doi:10.2337/db08-0753.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Wellcome Trust Case Control C. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447(7145):661–78. doi:10.1038/nature05911.

    Article  Google Scholar 

  27. Grant SF, Qu HQ, Bradfield JP, et al. Follow-up analysis of genome-wide association data identifies novel loci for type 1 diabetes. Diabetes. 2009;58(1):290–5. doi:10.2337/db08-1022.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. 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(7):857–64. doi:10.1038/ng2068.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. 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;41(6):703–7. doi:10.1038/ng.381.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Qu HQ, Bradfield JP, Li Q, et al. In silico replication of the genome-wide association results of the Type 1 Diabetes Genetics Consortium. Hum Mol Genet. 2010;19(12):2534–8. doi:10.1093/hmg/ddq133.

    Article  CAS  PubMed  Google Scholar 

  31. 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(12):1399–401. doi:10.1038/ng.249.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Wallace C, Smyth DJ, Maisuria-Armer M, et al. The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes. Nat Genet. 2010;42(1):68–71. doi:10.1038/ng.493.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Wei Z, Wang K, Qu HQ, et al. From disease association to risk assessment: an optimistic view from genome-wide association studies on type 1 diabetes. PLoS Genet. 2009;5(10):e1000678. doi:10.1371/journal.pgen.1000678.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Eleftherohorinou H, Wright V, Hoggart C, et al. Pathway analysis of GWAS provides new insights into genetic susceptibility to 3 inflammatory diseases. PLoS One. 2009;4(11):e8068. doi:10.1371/journal.pone.0008068.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Tuller T, Atar S, Ruppin E, et al. Common and specific signatures of gene expression and protein-protein interactions in autoimmune diseases. Genes Immun. 2013;14(2):67–82. doi:10.1038/gene.2012.55.

    Article  CAS  PubMed  Google Scholar 

  36. Ferreira RC, Simons HZ, Thompson WS, et al. IL-21 production by CD4+ effector T cells and frequency of circulating follicular helper T cells are increased in type 1 diabetes patients. Diabetologia. 2015;58(4):781–90. doi:10.1007/s00125-015-3509-8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Dendrou CA, Plagnol V, Fung E, et al. Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nat Genet. 2009;41(9):1011–5. doi:10.1038/ng.434.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Guo H, Fortune MD, Burren OS, et al. Integration of disease association and eQTL data using a Bayesian colocalisation approach highlights six candidate causal genes in immune-mediated diseases. Hum Mol Genet. 2015;24(12):3305–13. doi:10.1093/hmg/ddv077. Integrates eQTL data to identify likely causal variants. 

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Smyth DJ, Cooper JD, Bailey R, 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(6):617–9. doi:10.1038/ng1800.

    Article  CAS  PubMed  Google Scholar 

  40. Bell GI, Horita S, Karam JH. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes. 1984;33(2):176–83.

    Article  CAS  PubMed  Google Scholar 

  41. 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(4):337–8. doi:10.1038/ng1323.

    Article  CAS  PubMed  Google Scholar 

  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(9):1074–82. doi:10.1038/ng2102.

    Article  CAS  PubMed  Google Scholar 

  43. Eyre S, Bowes J, Diogo D, et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 2012;44(12):1336–40. doi:10.1038/ng.2462.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Farh KK, Marson A, Zhu J, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2015;518(7539):337–43. doi:10.1038/nature13835. Generated and used an algorhythm (PICS) to identify likely causal variants in automimmune disease.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Hrdlickova B, Westra HJ, Franke L, Wijmenga C. Celiac disease: moving from genetic associations to causal variants. Clin Genet. 2011;80(3):203–313. doi:10.1111/j.1399-0004.2011.01707.x.

    Article  CAS  PubMed  Google Scholar 

  46. Wellcome Trust Case Control C, Maller JB, McVean G, et al. Bayesian refinement of association signals for 14 loci in 3 common diseases. Nat Genet. 2012;44(12):1294–301. doi:10.1038/ng.2435. This is an early paper looking at specific shared loci underlying auto-immunoe disease.  

    Article  Google Scholar 

  47. Andreassen OA, Desikan RS, Wang Y, et al. Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms. PLoS One. 2015;10(4):e0123057. doi:10.1371/journal.pone.0123057. Identifies common loci shared between autoimmune disease and lipid dysregulation.

    Article  PubMed Central  PubMed  Google Scholar 

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Conflict of Interest

Jeffrey D. Roizen, Jonathan P. Bradfield, and Hakon Hakonarson declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Author notes

    Authors and Affiliations

    1. Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, 34th and Civic Center Blvd. 11NW, Philadelphia, PA, 19103, USA

      Jeffrey D. Roizen

    2. The Center for Applied Genomics, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd., Suite 1014H, Philadelphia, PA, 19104, USA

      Jonathan P. Bradfield & Hakon Hakonarson

    3. Division of Pulmonary Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

      Jeffrey D. Roizen & Hakon Hakonarson

    4. Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

      Hakon Hakonarson

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    1. Jeffrey D. Roizen
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    2. Jonathan P. Bradfield
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    3. Hakon Hakonarson
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    Correspondence to Hakon Hakonarson.

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    This article is part of the Topical Collection on Genetics

    Jeffrey D. Roizen and Jonathan P. Bradfield contributed equally to this work.

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    Roizen, J.D., Bradfield, J.P. & Hakonarson, H. Progress in Understanding Type 1 Diabetes Through Its Genetic Overlap with Other Autoimmune Diseases. Curr Diab Rep 15, 102 (2015). https://doi.org/10.1007/s11892-015-0668-4

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