Genetic variation in apolipoprotein H (beta 2-glycoprotein I) affects the occurrence of antiphospholipid antibodies and apolipoprotein H concentrations in systemic lupus erythematosus

Apolipoprotein H (apoH, protein; APOH gene) is a required cofactor for the production of antiphospholipid antibodies (AP). In this study we have exami ned whether genetic variation in the APOH gene affects variation in risk fo r systemic lupus erythematosus (SLE), occurrence of antiphospholipid antibo dies (APA), anti-apoH, and plasma apoH concentrations. A total of 222 white SLE women were screened for four APOH polymorphisms (codons 88, 247, 306, and 316) by polymerase chain reaction, and for plasma apoH concentrations b y ELISA. Of these, 29.3% were positive for APA (APA-positive group) and 31. 1% for anti-apoH. None of the four APOH polymorphisms were significantly as sociated with variation in risk for SLE. The codons 306 and 316 polymorphis ms showed significant, gene-dosage effects on plasma apoH concentrations (P <0.0001) and explained 30% and 13%, respectively, of the residual variation in apoH concentrations. No significant association was observed between an ti-apoH status and,APOH polymorphisms or plasma apoW levels. However, plasm a apoH concentrations were significantly higher in patients positive for AP A than in patients negative for APA (18.5+/-4.0 mg/dl vs 17.1+/-3.8 mg/dl; P=0.02). The distribution of the Trp316Ser polymorphism was significantly d ifferent between the APA-positive and APA-negative groups. The frequency of the mutant allele (Ser316) was significantly lower in the APA-positive gro up than the APA-negative group (3.1% vs 12.1% P<0.04), indicating that the Ser316 mutation is protective against the production of phospholipid-apoH d ependent APA. Our data indicate that common generic variation in the APOH g ene is a significant determinant of plasma apoW variation in SLE patients, and the Trp316Ser polymorphism appears to provide protection against the pr oduction of APA in SLE patients.