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