title: HLA-DRB1*15:01 and multiple sclerosis: a female association?
abstract: BACKGROUND
  The association between multiple sclerosis (MS) and the HLA-DRB1*15:01 haplotype has been proven to be strong, but its molecular basis remains unclear. Vitamin D receptor (VDR) gene variants and sex have been proposed to modulate this association.
  
  
  OBJECTIVE
  1) Test the association of MS with *15:01 and VDR variants; 2) check whether VDR variants and/or sex modulate the risk conferred by *15:01; 3) study whether *15:01, VDR variants and/or sex affect HLA II gene expression.
  
  
  METHODS
  Peripheral blood from 364 MS patients and 513 healthy controls was obtained and DNA and total RNA were extracted from leukocytes. HLA-DRB1, DRB5 and DQA1 gene expression measurements and *15:01 genotyping were performed by qPCR. VDR variants were genotyped by PCR-RFLP.
  
  
  RESULTS
  Our data confirms that the *15:01 haplotype confers a higher risk of suffering from MS (OR = 1.364; 95% CI = 1.107-1.681). No association was found between VDR variants and MS, but they were shown to moderately modulate the risk conferred by *15:01. Sex confers a much stronger modulation and the *15:01-MS association seems to be female specific. A higher *15:01 frequency has been observed in Basques (45.1%). *15:01 positive samples showed a significant overexpression of DRB1 (p < 0.001), DRB5 (p < 0.001) and DQA1 (p = 0.004) in patients. DRB1 (p = 0.004) and DRB5 (p < 0.001) were also overexpressed in *15:01 controls.
  
  
  CONCLUSIONS
  We confirm the *15:01-MS association and support that it is female specific. The relevance of ethnic origin on association studies has also been highlighted. HLA-DRB1*15:01 seems to be a haplotype consistently linked to high HLA II gene expression.
authors: Multiple Sclerosis Unit, Neuroscience Area, Biodonostia Health Research Institute, Donostia-San Sebastian, Spain. haritz.irizaragirre@osakidetza.net
authors: Haritz
authors: H
authors: Irizar
authors: Maider
authors: M
authors: Muñoz-Culla
authors: Olaia
authors: O
authors: Zuriarrain
authors: Estibaliz
authors: E
authors: Goyenechea
authors: Tamara
authors: T
authors: Castillo-Triviño
authors: Alvaro
authors: A
authors: Prada
authors: Matias
authors: M
authors: Saenz-Cuesta
authors: Dolores
authors: D
authors: De Juan
authors: Adolfo
authors: A
authors: Lopez de Munain
authors: Javier
authors: J
authors: Olascoaga
authors: David
authors: D
authors: Otaegui
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology; D016017:Odds Ratio; D010641:Phenotype; D016133:Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000235:genetics; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D013030:Spain
chemical_list: D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen; D018167:Receptors, Calcitriol