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Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus

Abstract

As a result of genome-wide association studies in larger sample sets, there has been an increase in identifying genes that influence susceptibility to individual immune-mediated diseases, as well as evidence that some genes are associated with more than one disease. In this study, we tested 17 single nucleotide polymorphisms (SNP) from 16 gene regions that have been reported in several autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), ankylosing spondylitis (AS) and Crohn's disease (CD) to determine whether the variants are also associated with type 1 diabetes (T1D). In up to 8010 cases and 9733 controls we found some evidence for an association with T1D in the regions containing genes: 2q32/STAT4, 17q21/STAT3, 5p15/ERAP1 (ARTS1), 6q23/TNFAIP3 and 12q13/KIF5A/PIP4K2C with allelic P-values ranging from 3.70 × 10−3 to 3.20 × 10−5. These findings extend our knowledge of susceptibility locus sharing across different autoimmune diseases, and provide convincing evidence that the RA/SLE locus 6q23/TNFAIP3 is a newly identified T1D locus.

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References

  1. 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: 857–864.

    Article  CAS  Google Scholar 

  2. Concannon P, Onengut-Gumuscu S, Todd JA, Smyth DJ, Pociot F, Bergholdt R et al. A human type 1 diabetes susceptibility locus maps to chromosome 21q22.3. Diabetes 2008; 57: 2858–2861.

    Article  CAS  Google Scholar 

  3. Cooper JD, Smyth DJ, Smiles AM, Plagnol V, Walker NM, Allen JE et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes loci. Nat Genet 2008; 40: 1399–1401.

    Article  CAS  Google Scholar 

  4. 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: 887–892.

    Article  CAS  Google Scholar 

  5. Hunt KA, Zhernakova A, Turner G, Heap GA, Franke L, Bruinenberg M et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 2008; 40: 395–402.

    Article  CAS  Google Scholar 

  6. Smyth D, Cooper JD, Collins JE, Heward JM, Franklyn JA, Howson JM et al. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 2004; 53: 3020–3023.

    Article  CAS  Google Scholar 

  7. Wellcome Trust Case Control Consortium. Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 2007; 447: 661–678.

    Article  Google Scholar 

  8. Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007; 357: 851–862.

    Article  CAS  Google Scholar 

  9. Harley JB, Alarcón-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 2008; 40: 204–210.

    Article  CAS  Google Scholar 

  10. Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med 2008; 358: 900–909.

    Article  CAS  Google Scholar 

  11. Kozyrev SV, Abelson AK, Wojcik J, Zaghlool A, Linga Reddy MV, Sanchez E et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet 2008; 40: 211–216.

    Article  CAS  Google Scholar 

  12. Kurreeman FA, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, Stoeken-Rijsbergen G et al. A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis. PLoS Med 2007; 4: e278.

    Article  Google Scholar 

  13. Plenge RM, Cotsapas C, Davies L, Price AL, de Bakker PI, Maller J et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet 2007; 39: 1477–1482.

    Article  CAS  Google Scholar 

  14. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007; 357: 977–986.

    Article  CAS  Google Scholar 

  15. Sims AM, Timms AE, Bruges-Armas J, Burgos-Vargas R, Chou CT, Doan T et al. Prospective meta-analysis of interleukin 1 gene complex polymorphisms confirms associations with ankylosing spondylitis. Ann Rheum Dis 2008; 67: 1305–1309.

    Article  Google Scholar 

  16. Thomson W, Barton A, Ke X, Eyre S, Hinks A, Bowes J et al. Rheumatoid arthritis association at 6q23. Nat Genet 2007; 39: 1431–1433.

    Article  CAS  Google Scholar 

  17. Wellcome Trust Case Control Consortium and The Australo-Anglo-American Spondylitis Consortium. Association scan of 14 500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 2007; 39: 1329–1337.

    Article  Google Scholar 

  18. Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K et al. Shared and Distinct Genetic Variants in Type 1 Diabetes and Celiac Disease. N Engl J Med 2008; 359: 2767–2777.

    Article  CAS  Google Scholar 

  19. Raychaudhuri S, Remmers EF, Lee AT, Hackett R, Guiducci C, Burtt NP et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat Genet 2008; 40: 1216–1223.

    Article  CAS  Google Scholar 

  20. Nath SK, Han S, Kim-Howard X, Kelly JA, Viswanathan P, Gilkeson GS et al. A nonsynonymous functional variant in integrin-alpha(M) (encoded by ITGAM) is associated with systemic lupus erythematosus. Nat Genet 2008; 40: 152–154.

    Article  CAS  Google Scholar 

  21. Graham RR, Cotsapas C, Davies L, Hackett R, Lessard CJ, Leon JM et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet 2008; 40: 1059–1061.

    Article  CAS  Google Scholar 

  22. Musone SL, Taylor KE, Lu TT, Nititham J, Ferreira RC, Ortmann W et al. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat Genet 2008; 40: 1062–1064.

    Article  CAS  Google Scholar 

  23. Zervou MI, Mamoulakis D, Panierakis C, Boumpas DT, Goulielmos GN . STAT4: A risk factor for type 1 diabetes? Hum Immunol 2008; 69: 647–650.

    Article  CAS  Google Scholar 

  24. Monsuur AJ, de Bakker PI, Zhernakova A, Pinto D, Verduijn W, Romanos J et al. Effective detection of human leukocyte antigen risk alleles in celiac disease using tag single nucleotide polymorphisms. PLoS ONE 2008; 3: e2270.

    Article  Google Scholar 

  25. Saric T, Chang SC, Hattori A, York IA, Markant S, Rock KL et al. An IFN-gamma-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides. Nat Immunol 2002; 3: 1169–1176.

    Article  CAS  Google Scholar 

  26. Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP et al. Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 2000; 289: 2350–2354.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was funded by Juvenile Diabetes Research Foundation International (JDRF), the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre; and the CIMR is in receipt of a Wellcome Trust Strategic Award (079895). Erik Fung was funded by the Prince Philip Graduate Exhibition from the Cambridge Overseas Trust and by the JDRF. Linda Wicker is a Juvenile Diabetes Research Foundation/Wellcome Trust Principal Research Fellow. We acknowledge use of the DNA from the British 1958 Birth Cohort collection, funded by the Medical Research Council and Wellcome Trust. We thank the Avon Longitudinal Study of Parents and Children laboratory in Bristol and the British 1958 Birth Cohort team, including S Ring, R Jones, M Pembrey, W McArdle, D Strachan and P Burton for preparing and providing the control DNA samples.

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Correspondence to J A Todd.

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Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

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Fung, E., Smyth, D., Howson, J. et al. Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus. Genes Immun 10, 188–191 (2009). https://doi.org/10.1038/gene.2008.99

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