title: Replication and further characterization of a Type 1 diabetes-associated locus at the telomeric end of the major histocompatibility complex.
abstract: BACKGROUND
  We recently reported an association between Type 1 diabetes and the telomeric major histocompatibility complex (MHC) single nucleotide polymorphism (SNP) rs1233478. As further families have been analyzed in the Type 1 Diabetes Genetics Consortium (T1DGC), we tested replication of the association and, with more data, analyzed haplotypic associations.
  
  
  METHODS
  An additional 2717 case and 1315 control chromosomes have been analyzed from the T1DGC, with human leukocyte antigen (HLA) typing and data for 2837 SNPs across the MHC region.
  
  
  RESULTS
  We confirmed the association of rs1233478 (new data only: P=2.2E-5, OR=1.4). We also found two additional SNPs nearby that were significantly associated with Type 1 diabetes (new data only rs3131020: P=8.3E-9, OR=0.65; rs1592410: P=2.2E-8, OR=1.5). For studies of Type 1 diabetes in the MHC region, it is critical to account for linkage disequilibrium with the HLA genes. Logistic regression analysis of these new data indicated that the effects of rs3131020 and rs1592410 on Type 1 diabetes risk are independent of HLA alleles (rs3131020: P=2.3E-3, OR=0.73; rs1592410: P=2.1E-3, OR=1.4). Haplotypes of 12 SNPs (including the three highly significant SNPs) stratify diabetes risk (high risk, protective, and neutral), with high-risk haplotypes limited to approximately 20,000 bp in length. The 20,000-bp region is telomeric of the UBD gene and contains LOC729653, a hypothetical gene.
  
  
  CONCLUSIONS
  We believe that polymorphisms of the telomeric MHC locus LOC729653 may confer risk for Type 1 diabetes.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado-Denver, 1775 Aurora Ct., Aurora, CO 80045, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Baschal
authors.forename: Suparna A
authors.initials: SA
authors.lastname: Sarkar
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Boyle
authors.forename: Janet C
authors.initials: JC
authors.lastname: Siebert
authors.forename: Jean M
authors.initials: JM
authors.lastname: Jasinski
authors.forename: Katharine R
authors.initials: KR
authors.lastname: Grabek
authors.forename: Taylor K
authors.initials: TK
authors.lastname: Armstrong
authors.forename: Sunanda R
authors.initials: SR
authors.lastname: Babu
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Fain
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Steck
authors.forename: Marian J
authors.initials: MJ
authors.lastname: Rewers
authors.forename: George S
authors.initials: GS
authors.lastname: Eisenbarth
mesh_terms: D001483:Base Sequence; D004261:DNA Replication; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D056426:Genetic Loci / Q000235:genetics; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D016615:Telomere / Q000235:genetics; D014452:Ubiquitins / Q000235:genetics
chemical_list: D006680:HLA Antigens; C109184:UBD protein, human; D014452:Ubiquitins