title: Fine mapping and functional studies of risk variants for type 1 diabetes at chromosome 16p13.13.
abstract: Single nucleotide polymorphisms (SNPs) located in the chromosomal region 16p13.13 have been previously associated with risk for several autoimmune diseases, including type 1 diabetes. To identify and localize specific risk variants for type 1 diabetes in this region and understand the mechanism of their action, we resequenced a 455-kb region in type 1 diabetic patients and unaffected control subjects, identifying 93 novel variants. A panel of 939 SNPs that included 46 of these novel variants was genotyped in 3,070 multiplex families with type 1 diabetes. Forty-eight SNPs, all located in CLEC16A, provided a statistically significant association (P < 5.32 × 10(-5)) with disease, with rs34306440 being most significantly associated (P = 5.74 × 10(-6)). The panel of SNPs used for fine mapping was also tested for association with transcript levels for each of the four genes in the region in B lymphoblastoid cell lines. Significant associations were observed only for transcript levels of DEXI, a gene with unknown function. We examined the relationship between the odds ratio for type 1 diabetes and the magnitude of the effect of DEXI transcript levels for each SNP in the region. Among SNPs significantly associated with type 1 diabetes, the common allele conferred an increased risk for disease and corresponded to lower DEXI expression. Our results suggest that the primary mechanism by which genetic variation at CLEC16A contributes to the risk for type 1 diabetes is through reduced expression of DEXI.
authors.affiliation: Department of Biochemistry and Molecular Genetics, UVA School of Medicine, University of Virginia, Charlottesville, VA Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA.
authors.forename: M Joseph
authors.initials: MJ
authors.lastname: Tomlinson
authors.affiliation: Department of Biochemistry and Molecular Genetics, UVA School of Medicine, University of Virginia, Charlottesville, VA Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA.
authors.forename: Achilleas
authors.initials: A
authors.lastname: Pitsillides
authors.affiliation: Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA Department of Public Health Sciences, UVA School of Medicine, University of Virginia, Charlottesville, VA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Pickin
authors.affiliation: Department of Biochemistry and Molecular Genetics, UVA School of Medicine, University of Virginia, Charlottesville, VA Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mika
authors.affiliation: Department of Biochemistry and Molecular Genetics, UVA School of Medicine, University of Virginia, Charlottesville, VA Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Keene
authors.affiliation: Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA Department of Public Health Sciences, UVA School of Medicine, University of Virginia, Charlottesville, VA.
authors.forename: Xuanlin
authors.initials: X
authors.lastname: Hou
authors.affiliation: Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA Department of Public Health Sciences, UVA School of Medicine, University of Virginia, Charlottesville, VA.
authors.forename: Josyf
authors.initials: J
authors.lastname: Mychaleckyj
authors.affiliation: Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA Department of Public Health Sciences, UVA School of Medicine, University of Virginia, Charlottesville, VA.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Genetics, UVA School of Medicine, University of Virginia, Charlottesville, VA Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
authors.forename: Patrick
authors.initials: P
authors.lastname: Concannon
authors.affiliation: Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA Department of Public Health Sciences, UVA School of Medicine, University of Virginia, Charlottesville, VA so4g@eservices.virginia.edu.
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
mesh_terms: D016022:Case-Control Studies; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C522505:CLEC16A protein, human; C433368:DEXI protein, human; D004268:DNA-Binding Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger