Significance of valine/leucine247 polymorphism of β2-glycoprotein I in antiphospholipid syndrome: Increased reactivity of anti-β2-glycoprotein I autoantibodies to the valine247 β2-glycoprotein I variant

Shinsuke Yasuda, Tatsuya Atsumi, Eiji Matsuura, Keiko Kaihara, Daisuke Yamamoto, Kenji Ichikawa, Takao Koike

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Objective. To clarify the consequences of the valine/leucine polymorphism at position 247 of the β2-glycoproiein I (β2GPI) gene in patients with antiphospholipid syndrome (APS), by investigating the correlation between genotypes and the presence of anti-β2GPI antibody. The reactivity of anti-β2GPI antibodies was characterized using recombinant Val247 and Leu247 β2GPI. 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/Leu247 polymorphism of β2GPI. Polymorphism assignment was determined by polymerase chain reaction followed by restriction enzyme digestion. Recombinant Val247 and Leu247 β2GPI were established to compare the reactivity of anti-β2GPI antibodies to β2GPI between these variants. The variants were prepared on polyoxygenated plates or cardiolipin-coated plates, and the reactivity of a series of anti-β2GPI antibodies (immunized anti-human β2GPI monoclonal antibodies [Cof-19-21] and autoimmune anti-β2GPI monoclonal antibodies [EY1C8, EY2C9, and TM1G2]) and IgGs purified from patient sera was investigated. Results. A positive correlation between the Val247 allele and the presence of anti-β2GPI antibodies was observed in the patient group. Human monoclonal/ polyclonal anti-β2GPI autoantibodies showed higher binding to recombinant Val247 β2GPI than to Leu 247 β2GPI, although no difference in the reactivity of the immunized anti-β2GPI between these variants was observed. Conformational optimization showed that the replacement of Leu247 by Val247 led to a significant alteration in the tertiary structure of domain V and/or the domain IV-V interaction. Conclusion. The Val247 β2GPI allele was associated with both a high frequency of anti-β2GPI antibodies and stronger reactivity with anti-β2GPI antibodies compared with the Leu247 β2GPI allele, suggesting that the Val247 β2GPI allele may be one of the genetic risk factors for development of APS.

Original languageEnglish
Pages (from-to)212-218
Number of pages7
JournalArthritis and Rheumatism
Volume52
Issue number1
DOIs
Publication statusPublished - Jan 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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