title: Genetic dissection of the human leukocyte antigen region by use of haplotypes of Tasmanians with multiple sclerosis.
abstract: Association of multiple sclerosis (MS) with the human leukocyte antigen (HLA) class II haplotype DRB1*1501-DQB1*0602 is the most consistently replicated finding of genetic studies of the disease. However, the high level of linkage disequilibrium (LD) in the HLA region has hindered the identification of other loci that single-marker tests for association are unlikely to resolve. In order to address this issue, we generated haplotypes spanning 14.754 Mb (5 cM) across the entire HLA region. The haplotypes, which were inferred by genotyping relatives of 152 patients with MS and 105 unaffected control subjects of Tasmanian ancestry, define a genomic segment from D6S276 to D6S291, including 13 microsatellite markers integrated with allele-typing data for DRB1 and DQB1. Association to the DRB1*1501-DQB1*0602 haplotype was replicated. In addition, we found that the class I/extended class I region, defined by a genomic segment of approximately 400 kb between MOGCA and D6S265, harbors genes that independently increase risk of, or provide protection from, MS. Log-linear modeling analysis of constituent haplotypes that represent genomic regions containing class I (MOGCA-D6S265), class III (TNFa-TNFd-D6S273), and class II (DRB1-DQB1) genes indicated that having class I and class II susceptibility variants on the same haplotype provides an additive effect on risk. Moreover, we found no evidence for a disease locus in the class III region defined by a 150-kb genomic segment containing the TNF locus and 14 other genes. A global overview of LD performed using GOLD identified two discrete blocks of LD in the HLA region that correspond well with previous findings. We propose that the analysis of haplotypes, by use of the types of approaches outlined in the present article, should make it possible to more accurately define the contribution of the HLA to MS.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, and Cooperative Research Centre for Discovery of Genes for Common Human Diseases, Melbourne, Victoria, Australia. rubio@wehi.edu.au
authors.forename: Justin P
authors.initials: JP
authors.lastname: Rubio
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.forename: Helmut
authors.initials: H
authors.lastname: Butzkueven
authors.forename: Ingrid A F
authors.initials: IA
authors.lastname: van Der Mei
authors.forename: Michèle M
authors.initials: MM
authors.lastname: Sale
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Dickinson
authors.forename: Patricia
authors.initials: P
authors.lastname: Groom
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Johnson
authors.forename: Rex D
authors.initials: RD
authors.lastname: Simmons
authors.forename: Brian
authors.initials: B
authors.lastname: Tait
authors.forename: Mike
authors.initials: M
authors.lastname: Varney
authors.forename: Bruce
authors.initials: B
authors.lastname: Taylor
authors.forename: Terence
authors.initials: T
authors.lastname: Dwyer
authors.forename: Robert
authors.initials: R
authors.lastname: Williamson
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Gough
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Kilpatrick
authors.forename: Terence P
authors.initials: TP
authors.lastname: Speed
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Foote
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002874:Chromosome Mapping; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006680:HLA Antigens / Q000235:genetics*; D006681:HLA-D Antigens / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D015810:Linkage Disequilibrium / Q000235:genetics; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D008957:Models, Genetic; D009103:Multiple Sclerosis / Q000235:genetics*; D016017:Odds Ratio; D012984:Software; D013648:Tasmania / Q000453:epidemiology
chemical_list: D005819:Genetic Markers; D006680:HLA Antigens; D006681:HLA-D Antigens