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
Article first published online: 7 JAN 2005
Copyright © 2005 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 52, Issue 1, pages 212–218, January 2005
How to Cite
Yasuda, S., Atsumi, T., Matsuura, E., Kaihara, K., Yamamoto, D., Ichikawa, K. and Koike, T. (2005), 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. Arthritis & Rheumatism, 52: 212–218. doi: 10.1002/art.20741
- Issue published online: 7 JAN 2005
- Article first published online: 7 JAN 2005
- Manuscript Accepted: 27 SEP 2004
- Manuscript Received: 10 MAY 2004
To clarify the consequences of the valine/leucine polymorphism at position 247 of the β2-glycoprotein 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.
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.
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 Leu247 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.
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.