title: CRYAB promoter polymorphisms: influence on multiple sclerosis susceptibility and clinical presentation.
abstract: BACKGROUND
  alphaB-crystallin is a molecular chaperone and potential myelin antigen, up-regulated in the earlier stages of multiple sclerosis (MS) lesions. In the alphaB-crystallin gene (CRYAB), single nucleotide polymorphisms (SNPs) have been associated with MS susceptibility (g.CRYAB-652A>G) and a rapidly progressive clinical course (g.CRYAB-650C>G).
  
  
  METHODS
  CRYAB was screened for mutations in 233 MS patients and 96 controls. Genomic DNA was extracted and the coding and 3' and 5' untranslated regions were amplified by PCR. Subsequently, the products were analysed by Single Strand Conformation Polymorphism technique followed by DNA sequencing of aberrant conformers.
  
  
  RESULTS
  In CRYAB (Genbank ) no mutations were found but SNPs were identified in the promoter region (g.CRYAB-249C>G, g.CRYAB-650C>G and g.CRYAB-652A>G), and intronic region (g.CRYAB.2398T>G). The g.CRYAB-249C>G genotype distribution was significantly different between groups (chi(2), p=0.01), caused by differences between Relapsing Remitting MS (RRMS) and controls (chi(2), p=0.025) and Secondary Progressive MS (SPMS) and controls (chi(2), p=0.05). In addition, a significant difference was observed in the g.CRYAB-249C>G allele distribution (chi(2), p=0.04), caused by a difference between SPMS and controls (chi(2), p=0.01). In RRMS and SPMS a tendency of the g.CRYAB-249GG genotype being associated with an earlier age of onset (p=0.05) and a slowly progressive cause (p=0.07) was found. Multiple sequence alignment showed conservation of the g.CRYAB-249*C between mammalian CRAYB genes and within the small heat shock protein gene family.
  
  
  CONCLUSIONS
  CRYAB polymorphisms may be involved in the pathogenesis of MS by mechanisms that could involve increased expression of the superantigen alphaB-crystallin and modulation of the immune response. CRYAB polymorphisms should be included in future multivariate biomaker studies in MS.
authors.affiliation: Department of Clinical Biochemistry, Statens Serum Institut, 5 Artillerivej, DK 2300 S, Copenhagen, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Stoevring
authors.forename: Jette L
authors.initials: JL
authors.lastname: Frederiksen
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers; D016022:Case-Control Studies; D003718:Denmark / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D038203:alpha-Crystallin B Chain / Q000235:genetics*
chemical_list: D015415:Biomarkers; C059215:CRYAB protein, human; D038203:alpha-Crystallin B Chain