A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene

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Abstract

Type 1 diabetes (T1D) in children results from autoimmune destruction of pancreatic beta cells, leading to insufficient production of insulin1. A number of genetic determinants of T1D have already been established through candidate gene studies, primarily within the major histocompatibility complex2,3,4 but also within other loci5,6,7,8,9,10,11,12. To identify new genetic factors that increase the risk of T1D, we performed a genome-wide association study in a large paediatric cohort of European descent. In addition to confirming previously identified loci2,3,4,5,6,7,8,9, we found that T1D was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13. This region contains KIAA0350, the gene product of which is predicted to be a sugar-binding, C-type lectin. Three common non-coding variants of the gene (rs2903692, rs725613 and rs17673553) in strong linkage disequilibrium reached genome-wide significance for association with T1D. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. These results indicate that KIAA0350 might be involved in the pathogenesis of T1D and demonstrate the utility of the genome-wide association approach in the identification of previously unsuspected genetic determinants of complex traits.

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Figure 1: Pairwise linkage disequilibrium diagram of the KIAA0350 locus on 16p13.13.

References

  1. 1

    Devendra, D., Liu, E. & Eisenbarth, G. S. Type 1 diabetes: recent developments. Br. Med. J. 328, 750–754 (2004)

  2. 2

    Cucca, F. et al. A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins. Hum. Mol. Genet. 10, 2025–2037 (2001)

  3. 3

    Nerup, J. et al. HL-A antigens and diabetes mellitus. Lancet 2, 864–866 (1974)

  4. 4

    Noble, J. A. et al. The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. Am. J. Hum. Genet. 59, 1134–1148 (1996)

  5. 5

    Bell, G. I., Horita, S. & Karam, J. H. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33, 176–183 (1984)

  6. 6

    Bennett, S. T. et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nature Genet. 9, 284–292 (1995)

  7. 7

    Vafiadis, P. et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nature Genet. 15, 289–292 (1997)

  8. 8

    Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nature Genet. 36, 337–338 (2004)

  9. 9

    Smyth, D. 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 53, 3020–3023 (2004)

  10. 10

    Kristiansen, O. P., Larsen, Z. M. & Pociot, F. CTLA-4 in autoimmune diseases—a general susceptibility gene to autoimmunity? Genes Immun. 1, 170–184 (2000)

  11. 11

    Ueda, H. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003)

  12. 12

    Anjos, S. M., Tessier, M. C. & 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. 89, 6257–6265 (2004)

  13. 13

    Vella, A. 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. 76, 773–779 (2005)

  14. 14

    Smyth, D. J. et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nature Genet. 38, 617–619 (2006)

  15. 15

    Guo, D. et al. A functional variant of SUMO4, a new IκBα modifier, is associated with type 1 diabetes. Nature Genet. 36, 837–841 (2004)

  16. 16

    Mirel, D. B. et al. Association of IL4R haplotypes with type 1 diabetes. Diabetes 51, 3336–3341 (2002)

  17. 17

    Biason-Lauber, A. et al. Association of childhood type 1 diabetes mellitus with a variant of PAX4: possible link to beta cell regenerative capacity. Diabetologia 48, 900–905 (2005)

  18. 18

    Davies, J. L. et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371, 130–136 (1994)

  19. 19

    Concannon, P. et al. A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus. Nature Genet. 19, 292–296 (1998)

  20. 20

    Mein, C. A. et al. A search for type 1 diabetes susceptibility genes in families from the United Kingdom. Nature Genet. 19, 297–300 (1998)

  21. 21

    Cucca, F. et al. A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients. Nature Genet. 19, 301–302 (1998)

  22. 22

    Gunderson, K. L., Steemers, F. J., Lee, G., Mendoza, L. G. & Chee, M. S. A genome-wide scalable SNP genotyping assay using microarray technology. Nature Genet. 37, 549–554 (2005)

  23. 23

    Fisher, R. A. Statistical Methods for Research Workers edn 13 (Hafner, New York, 1958)

  24. 24

    de Bakker, P. I. et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nature Genet. 38, 1166–1172 (2006)

  25. 25

    Hirschhorn, J. N., Lohmueller, K., Byrne, E. & Hirschhorn, K. A comprehensive review of genetic association studies. Genet. Med. 4, 45–61 (2002)

  26. 26

    Price, A. L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nature Genet. 38, 904–909 (2006)

  27. 27

    Poirot, L., Benoist, C. & Mathis, D. Natural killer cells distinguish innocuous and destructive forms of pancreatic islet autoimmunity. Proc. Natl Acad. Sci. USA 101, 8102–8107 (2004)

  28. 28

    Rodacki, M. et al. Altered natural killer cells in type 1 diabetic patients. Diabetes 56, 177–185 (2007)

  29. 29

    Finn, R. D. et al. Pfam: clans, web tools and services. Nucleic Acids Res. 34, D247–D251 (2006)

  30. 30

    Cambi, A. & Figdor, C. G. Levels of complexity in pathogen recognition by C-type lectins. Curr. Opin. Immunol. 17, 345–351 (2005)

  31. 31

    Todd, J. A. et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Genet. advance online publication, doi: 10.1038/ng2068 (6 June 2007)

  32. 32

    The Wellcome Trust Case Control Consortium Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007)

  33. 33

    Steemers, F. J. et al. Whole-genome genotyping with the single-base extension assay. Nature Methods 3, 31–33 (2006)

  34. 34

    Purcell, S. et al. PLINK: a toolset for whole-genome association and population-based linkage analysis. Am. J. Hum. Genet. (in the press)

  35. 35

    Barrett, J. C., Fry, B., Maller, J. & Daly, M. J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005)

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Acknowledgements

We acknowledge the use of DNA samples from the T1DGC, funded by the NIH. We thank all participating subjects and families. A. Belisle, A. W. Eckert, A. Estevez, K. Fain, R. Frechette, P. Kline, C. C. Onyiah, G. Otieno, E. Santa, J. L. Shaner, R. M. Smith, A. Thomas and L. Williams helped with genotyping or data collection and management. We thank D. Laforte and the PRUDENT team for subject recruitment and all T1DGC coordinating teams. We also thank S. Kristinsson, L. A. Hermannsson and A. Krisbjörnsson for their software design and contribution. This research was financially supported by the Children’s Hospital of Philadelphia, Genome Canada through the Ontario Genomics Institute and the Juvenile Diabetes Research Foundation.

Author Contributions H.H. and C.P. designed the study and supervised the data analysis and interpretation. S.F.A.G., J.P.B. and M.D. conducted the statistical analyses. C.E.K, T.C., E.C.F. and R.S. directed the genotyping of stage 1. H-Q.Q. and C.P. coordinated the genotyping and data analysis for stage 2. Y.L. and H-Q.Q. performed the resequencing and allelic-imbalance experiments. J.S.O. and E.F.R. carried out the work on NKT expression. J.P.B., J.T.G. and L.J.R. provided bioinformatics support. The remaining authors coordinated the studies used in stage 1 and 2. H.H., S.F.A.G., J.P.B., H-Q.Q. and C.P. drafted the manuscript.

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Correspondence to Hakon Hakonarson or Constantin Polychronakos.

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Methods, Supplementary Tables S1-S3, Supplementary Figures S1 and S2 with Legends and additional references. This file was corrected on 20 July 2007. (PDF 1101 kb)

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