A role for the polymorphism at position 247 of the β2-glycoprotein I gene in the generation of anti-β2-glycoprotein I antibodies in the antiphospholipid syndrome

Objective. To determine the frequencies at which either a valine or leucine occurs at position 247 in the beta(2)-glycoprotein I (beta(2)GPI) gene of normal individuals of the Caucasian, African American, and Asian ethnic groups and to compare these data with those in patients with the antiphospholipid syndrome (APS), with and without anti-beta(2)GPI antibodies. Methods. The DNA segment containing the position-247 polymorphism was amplified by semi-nested polymerase chain reaction, and the polymorphism was detected by restriction endonuclease digestion. DNA samples from 370 healthy controls of different racial backgrounds were analyzed, and the results were compared with those from 149 APS patients (66 primary; 83 secondary), Allele and genotype frequencies were compared using Fisher's exact test. When significant differences were detected, pairwise comparisons were made using Fisher's exact test,vith a Bonferroni adjustment. Results. Allele and genotype expression was significantly different (P < 0.0001 for both) among the 3 races, with the V allele and the VV genotype occurring most often among Caucasians, less among African Americans, and least among Asians. Conversely, the V allele and the VV genotype were found more frequently among Asian APS patients than among controls (P = 0.0028 and P = 0.0023, respectively). No significant differences in allele or genotype frequencies were seen in comparisons of the Caucasian or the African American patients with appropriate controls, The differences in allele and genotype frequencies seen in the Asian APS patients were restricted to the anti-beta(2)GPI-positive patients (P = 0.0018 and P = 0.0005, respectively). Conclusion. In Asian patients with APS, expression of a V at position 247, especially in the homozygous state, is significantly associated with the presence of anti-beta(2)GPI antibodies and, therefore, can be viewed as a major risk factor in this ethnic group (odds ratio 9.19 and 16.33, respectively).