title: SNP mapping and candidate gene sequencing in the class I region of the HLA complex: searching for multiple sclerosis susceptibility genes in Tasmanians.
abstract: This study is an extension to previously published work that has linked variation in the human leukocyte antigen (HLA) class I region with susceptibility to multiple sclerosis (MS) in Australians from the Island State of Tasmania. Single nucleotide polymorphism (SNP) mapping was performed on an 865-kb candidate region (D6S1683-D6S265) in 166 Tasmanian MS families, and seven candidate genes [ubiquitin D (UBD), olfactory receptor 2H3 (OR2H3), gamma-aminobutyric acid B receptor 1 (GABBR1), myelin oligodendrocyte glycoprotein (MOG), HLA-F, HLA complex group 4 (HCG4) and HLA-G] were resequenced. SNPs tagging the extended MS susceptibility haplotype were genotyped in an independent sample of 356 Australian MS trios and SNPs in the MOG gene were significantly over-transmitted to MS cases. We identified significant effects on MS susceptibility of HLA-A*2 (OR: 0.51; P = 0.05) and A*3 (OR: 2.85; P = 0.005), and two coding polymorphisms in the MOG gene (V145I: P = 0.01, OR: 2.2; V142L: P = 0.04, OR: 0.45) after full conditioning on HLA-DRB1. We have therefore identified plausible candidates for the causal MS susceptibility allele, and although not conclusive at this stage, our data provide suggestive evidence for multiple class I MS susceptibility genes.
authors.affiliation: Howard Florey Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: R K
authors.initials: RK
authors.lastname: Burfoot
authors.forename: C J
authors.initials: CJ
authors.lastname: Jensen
authors.forename: J
authors.initials: J
authors.lastname: Field
authors.forename: J
authors.initials: J
authors.lastname: Stankovich
authors.forename: M D
authors.initials: MD
authors.lastname: Varney
authors.forename: L J
authors.initials: LJ
authors.lastname: Johnson
authors.forename: H
authors.initials: H
authors.lastname: Butzkueven
authors.forename: D
authors.initials: D
authors.lastname: Booth
authors.forename: M
authors.initials: M
authors.lastname: Bahlo
authors.forename: B D
authors.initials: BD
authors.lastname: Tait
authors.forename: B V
authors.initials: BV
authors.lastname: Taylor
authors.forename: T P
authors.initials: TP
authors.lastname: Speed
authors.forename: R
authors.initials: R
authors.lastname: Heard
authors.forename: G J
authors.initials: GJ
authors.lastname: Stewart
authors.forename: S J
authors.initials: SJ
authors.lastname: Foote
authors.forename: T J
authors.initials: TJ
authors.lastname: Kilpatrick
authors.forename: J P
authors.initials: JP
authors.lastname: Rubio
mesh_terms: D016022:Case-Control Studies; D002874:Chromosome Mapping; D005260:Female; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics*; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013648:Tasmania
chemical_list: D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I