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A human type 1 diabetes susceptibility locus maps to chromosome 21q22.3

¹Department of Biochemistry and Molecular Genetics,
²Center for Public Health Genomics, and
³Department of Medicine, Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, Virginia, USA
⁴Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
⁵Steno Diabetes Center, Gentofte, Denmark
⁶Division of Diabetes, Endocrinology, and Metabolic Diseases, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD
⁷Roche Molecular Systems, Alameda, CA, USA
⁸Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, USA
⁹Inserm U730 et CEA, Institut de Génomique Centre National de Génotypage, Evry, France
¹⁰Centre for Diabetes Research, The Western Australian Institute for Medical Research, and Centre for Medical Research, University of Western Australia, Australia
¹¹Juvenile Diabetes Research Foundation, New York, NY, USA
¹²Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, VA, USA

Objective.: The Type 1 Diabetes Genetics Consortium (T1DGC) has assembled and genotyped a large collection of multiplex families for the purpose of mapping genomic regions linked to type 1 diabetes. In the current study, we tested for evidence of loci associated with type 1 diabetes utilizing genome-wide linkage scan data and family-based association methods.

Research Design and Methods: A total of 2,496 multiplex type 1 diabetes families were genotyped with a panel of 6,090 SNPs. Evidence of association to disease was evaluated by the pedigree disequilibrium test (PDT). Significant results were followed up by genotyping and analyses in two independent sets of samples: 2,214 parent-affected child trio families and a panel of 7,721 cases and 9,679 controls.

Results: Three of the SNPs most strongly associated with type 1 diabetes localized to previously identified type 1 diabetes risk loci: INS, IFIH1, and KIAA0350. A fourth strongly associated SNP, rs876498 (P=1.0x10^-4) occurred in the sixth intron of the UBASH3A locus at chromosome 21q22.3. Support for this disease association was obtained in two additional independent sample sets, type 1 diabetes families (OR=1.06, 95%CI=1.00-1.11, P=0.023) and cases and controls (OR=1.14, 95%CI=1.09-1.19, P=7.5x10^-8).

Conclusions: The T1DGC 6K SNP scan and follow-up studies reported here confirm previously reported type 1 diabetes associations at INS, IFIH1 and KIAA0350 and identify an additional disease association on chromosome 21q22.3 in the UBASH3A locus (OR=1.10, 95% CI=1.07-1.13, P=4.4x10^-12). This gene and its flanking regions are now validated targets for further re-sequencing, genotyping and functional studies in type 1 diabetes.

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