title: Epistasis between HLA-DRB1 parental alleles in a Spanish cohort with multiple sclerosis.
abstract: OBJECTIVE
  Multiple sclerosis (MS) has been consistently associated with the HLA-DR2 haplotype and particularly with the HLA-DRB1*15 allele. Epistatic interactions between both parental alleles in the DRB1 loci have been shown to modify the MS susceptibility risk. This study investigated the frequencies of various HLA-DRB1 genotypes, their impact on MS susceptibility and their correlation with the clinical severity in a Spanish population.
  
  
  METHODS
  A genotype was considered as the combination of the two parental DRB1 alleles. We compared the frequencies of the genotypes in a sporadic MS population (n=380) with those of an unrelated healthy control cohort (n=1088). We correlated the different genotypes with the age at onset, gender distribution, symptoms at onset, course of the disease and progression severity by means of the time to reach the progressive phase and EDSS scores of 3 and 6.
  
  
  RESULTS
  We found 81 different genotypes. There were four different MS-predisposing genotypes. Three of them contained the DRB1*15 allele (DRB1*03/15, DRB1*04/15, and DRB1*08/15) and the fourth was homozygote for the DRB1*03 allele. The highest odds ratio was found with the genotype DRB1*08/15 (OR=3.88, 95% CI=1.83-8.26, p<0.01), followed by DRB1*03/03 (OR=3.15, 95% CI=1.93-5.14, p<0.01), DRB1*03/15 (OR=2.72, 95% CI=1.88-3.94, p<0.01) and DRB1*04/15 (OR=2.54, 95% CI=1.64-3.98, p<0.01). The DRB1*01/04 and the DRB1*15/15 genotypes were associated with a shorter time to reach an EDSS score of 6.
  
  
  CONCLUSIONS
  Our results show the importance of epistatic interactions among the HLA-DRB1 alleles, modifying the risk for MS as well as its clinical severity.
authors.affiliation: Multiple Sclerosis Unit, Neurology Department, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Romero-Pinel
authors.forename: Josep María
authors.initials: JM
authors.lastname: Pujal
authors.forename: Sergio
authors.initials: S
authors.lastname: Martínez-Yélamos
authors.forename: Laura
authors.initials: L
authors.lastname: Gubieras
authors.forename: Elisabet
authors.initials: E
authors.lastname: Matas
authors.forename: Laura
authors.initials: L
authors.lastname: Bau
authors.forename: Marta
authors.initials: M
authors.lastname: Torrabadella
authors.forename: Carmen
authors.initials: C
authors.lastname: Azqueta
authors.forename: Txomin
authors.initials: T
authors.lastname: Arbizu
mesh_terms: D000328:Adult; D017668:Age of Onset; D015331:Cohort Studies; D004185:Disability Evaluation; D018450:Disease Progression; D004843:Epistasis, Genetic / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D016017:Odds Ratio; D011379:Prognosis; D017678:Sex Distribution; D013030:Spain / Q000453:epidemiology
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains