title: Influence of HLA-DRB1 allele heterogeneity on disease risk and clinical course in a West Australian MS cohort: a high-resolution genotyping study.
abstract: BACKGROUND
  Previous studies on the influence of HLA-DRB1 alleles on multiple sclerosis (MS) susceptibility and clinical course have mostly employed the 2-point genotyping method.
  
  
  OBJECTIVE
  To assess the influence of HLA-DRB1 alleles and allele interactions on disease risk and clinical course in a large West Australian MS patient cohort using high-resolution genotyping.
  
  
  METHODS
  Four digit HLA-DRB1 genotyping was performed on a group of 466 clinically definite or probable MS patients from the Perth Demyelinating Diseases Database and 189 healthy Caucasian controls from the Busselton Community Health Study.
  
  
  RESULTS
  In addition to the known risk allele HLA-DRB1*1501, evidence of increased susceptibility to MS was found for three additional alleles, DRB1*0405, DRB1*1104 and DRB1*1303, though the power was insufficient to sustain significance for these when crudely Bonferroni corrected over all alleles considered. DRB1*0701 was found to be protective even after correction for multiple comparisons. In addition we found evidence that the DRB1*04 sub-allele HLA-DRB1*0407 and HLA-DRB1*0901 may be protective. Among the diplotypes, the highest estimated risk was in HLA-DRB1*1501/*0801 heterozygotes and DRB1*1501 homozygotes and the lowest in HLA-DRB1*0701/*0101 heterozygotes. There was no significant gender association with HLA-DRB1*1501 overall, but the HLA-DRB1*1501/*1104 risk genotype was significantly associated with female gender. HLA-DRB1*1501 was the strongest risk allele in both primary progressive MS and relapsing-remitting MS.
  
  
  CONCLUSIONS
  Our results demonstrate the advantages of high-resolution HLA genotyping in recognizing risk-modifying alleles and allele combinations in this patient cohort and in recognizing the differential effects of HLA-DRB1*04 and DRB1*11 sub-alleles.
authors.affiliation: Centre of Neuromuscular and Neurological Disorders, University of Western Australia, and Department of Neurology, Sir Charles Gairdner Hospital, Queen Elizabeth Medical Centre, Perth, Western Australia, Australia.
authors.forename: Jing-Shan
authors.initials: JS
authors.lastname: Wu
authors.forename: Ian
authors.initials: I
authors.lastname: James
authors.lastname: Wei Qiu
authors.forename: Alison
authors.initials: A
authors.lastname: Castley
authors.forename: Frank T
authors.initials: FT
authors.lastname: Christiansen
authors.forename: William M
authors.initials: WM
authors.lastname: Carroll
authors.forename: Frank L
authors.initials: FL
authors.lastname: Mastaglia
authors.forename: Allan G
authors.initials: AG
authors.lastname: Kermode
mesh_terms: D017668:Age of Onset; D000483:Alleles; D001315:Australia; D018450:Disease Progression; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics*; D012307:Risk Factors
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains