title: Significance of valine/leucine247 polymorphism of beta2-glycoprotein I in antiphospholipid syndrome: increased reactivity of anti-beta2-glycoprotein I autoantibodies to the valine247 beta2-glycoprotein I variant.
abstract: OBJECTIVE
  To clarify the consequences of the valine/leucine polymorphism at position 247 of the beta(2)-glycoprotein I (beta(2)GPI) gene in patients with antiphospholipid syndrome (APS), by investigating the correlation between genotypes and the presence of anti-beta(2)GPI antibody. The reactivity of anti-beta(2)GPI antibodies was characterized using recombinant Val(247) and Leu(247) beta(2)GPI.
  
  
  METHODS
  Sixty-five Japanese patients with APS and/or systemic lupus erythematosus who were positive for antiphospholipid antibodies and 61 controls were analyzed for the presence of the Val/Leu(247) polymorphism of beta(2)GPI. Polymorphism assignment was determined by polymerase chain reaction followed by restriction enzyme digestion. Recombinant Val(247) and Leu(247) beta(2)GPI were established to compare the reactivity of anti-beta(2)GPI antibodies to beta(2)GPI between these variants. The variants were prepared on polyoxygenated plates or cardiolipin-coated plates, and the reactivity of a series of anti-beta(2)GPI antibodies (immunized anti-human beta(2)GPI monoclonal antibodies [Cof-19-21] and autoimmune anti-beta(2)GPI monoclonal antibodies [EY1C8, EY2C9, and TM1G2]) and IgGs purified from patient sera was investigated.
  
  
  RESULTS
  A positive correlation between the Val(247) allele and the presence of anti-beta(2)GPI antibodies was observed in the patient group. Human monoclonal/polyclonal anti-beta(2)GPI autoantibodies showed higher binding to recombinant Val(247) beta(2)GPI than to Leu(247) beta(2)GPI, although no difference in the reactivity of the immunized anti-beta(2)GPI between these variants was observed. Conformational optimization showed that the replacement of Leu(247) by Val(247) led to a significant alteration in the tertiary structure of domain V and/or the domain IV-V interaction.
  
  
  CONCLUSIONS
  The Val(247) beta(2)GPI allele was associated with both a high frequency of anti-beta(2)GPI antibodies and stronger reactivity with anti-beta(2)GPI antibodies compared with the Leu(247) beta(2)GPI allele, suggesting that the Val(247) beta(2)GPI allele may be one of the genetic risk factors for development of APS.
authors.affiliation: Medicine II, Hokkaido University Graduate School of Medicine, N15 W7, Kita-ku, Sapporo 060-8638, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Yasuda
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Atsumi
authors.forename: Eiji
authors.initials: E
authors.lastname: Matsuura
authors.forename: Keiko
authors.initials: K
authors.lastname: Kaihara
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamamoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Ichikawa
authors.forename: Takao
authors.initials: T
authors.lastname: Koike
mesh_terms: D000328:Adult; D000368:Aged; D017153:Antibodies, Anticardiolipin / Q000097:blood; D016736:Antiphospholipid Syndrome / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D005260:Female; D006023:Glycoproteins / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007930:Leucine; D008297:Male; D008875:Middle Aged; D008968:Molecular Conformation; D011110:Polymorphism, Genetic; D014633:Valine; D053482:beta 2-Glycoprotein I
chemical_list: D017153:Antibodies, Anticardiolipin; D001323:Autoantibodies; D006023:Glycoproteins; D053482:beta 2-Glycoprotein I; D007930:Leucine; D014633:Valine