title: Evidence of at least two type 1 diabetes susceptibility genes in the HLA complex distinct from HLA-DQB1, -DQA1 and -DRB1.
abstract: Susceptibility to, and protection against development of type 1 diabetes (T1D) are primarily associated with the highly polymorphic exon 2 sequences of the HLA class II genes: DQB1, DQA1 and DRB1. However, several studies have also suggested that additional genes in the HLA complex influence T1D risk, albeit to a lesser degree than the class II genes. We have previously shown that allele 3 of microsatellite marker D6S2223, 4.9 Mb telomeric of DQ in the extended class I region, is associated with a reduction in risk conferred by the DQ2-DR3 haplotype. Here we replicate this finding in two populations from Sweden and France. We also show that markers in the HLA class II, III and centromeric class I regions contribute to the DQ2-DR3 associated risk of T1D, independently of linkage disequilibrium (LD) with both the DQ/DR genes and the D6S2223 associated gene. The associated marker alleles are carried on the DQ2-DR3-B18 haplotype in a region of strong LD. By haplotype mapping, we have located the most likely location for this second DQ2-DR3 haplotype-modifying locus to the 2.35 Mb region between HLA-DOB and marker D6S2702, located 970 kb telomeric of HLA-B.
authors.affiliation: Institute of Immunology, Rikshospitalet, University Hospital, Norway. stefan.johansson@labmed.uio.no
authors.forename: S
authors.initials: S
authors.lastname: Johansson
authors.forename: B A
authors.initials: BA
authors.lastname: Lie
authors.forename: J A
authors.initials: JA
authors.lastname: Todd
authors.forename: F
authors.initials: F
authors.lastname: Pociot
authors.forename: J
authors.initials: J
authors.lastname: Nerup
authors.forename: A
authors.initials: A
authors.lastname: Cambon-Thomsen
authors.forename: I
authors.initials: I
authors.lastname: Kockum
authors.forename: H E
authors.initials: HE
authors.lastname: Akselsen
authors.forename: E
authors.initials: E
authors.lastname: Thorsby
authors.forename: D E
authors.initials: DE
authors.lastname: Undlien
mesh_terms: D016009:Chi-Square Distribution; D016001:Confidence Intervals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics*; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D016017:Odds Ratio
chemical_list: D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains