Genetic variation in apolipoprotein H (beta2-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 (APA). In this study we have examined whether genetic variation in the APOH gene affects variation in risk for systemic lupus erythematosus (SLE), occurrence of antiphospholipid antibodies (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 by 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 associated with variation in risk for SLE. The codons 306 and 316 polymorphisms 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 anti-apoH status and APOH polymorphisms or plasma apoH levels. However, plasma apoH concentrations were significantly higher in patients positive for APA 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 different between the APA-positive and APA-negative groups. The frequency of the mutant allele (Ser316) was significantly lower in the APA-positive group 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 dependent APA. Our data indicate that common genetic variation in the APOH gene is a significant determinant of plasma apoH variation in SLE patients, and the Trp316Ser polymorphism appears to provide protection against the production of APA in SLE patients.