Association between beta 2-glycoprotein I gene polymorphisms and pediatric SLE and antiphospholipid antibodies

Antibodies against phospholipids (PL) and PL-binding proteins have been causally implicated in antiphospholipid syndrome (APS). Mutations in the fifth domain of the beta(2)-glycoprotein I (beta(2)GPI) protein, a putative PL-binding site, may play a critical role in APS pathogenesis. The purpose of this study was to identify associations between beta(2)GPI mutations and both antiphospholipid antibodies (aPL) and their associated clinical manifestations in a pediatric and adolescent cohort and to search for novel mutations. Genetic analysis of beta(2)GPI was performed in 58 youths with systemic lupus erythematosus (SLE) and/or aPL, to identify known polymorphisms at amino acids 247 and 306 as well as novel mutations in exon 7 of the beta(2)GPI gene, and their association with aPL-associated clinical manifestations. Our results demonstrate an association between substitution of Val for Len at AA247 (L247V) of beta(2)GPI and both the development of aPL (P = 0.05) and aPL-associated clinical manifestations (P = 0.03) among pediatric patients. The odds ratio associated with risk of aPL-associated clinical manifestations for the homozygous VV polymorphism was 5.5 (CI 1.3-23, P = 0.03) for the overall cohort, and 4.75 (CI 0.66-55.49, P = 0.06) after adjusting for ethnicity. The association was not significant after stratifying for SLE versus non-SLE. Association between the VV genotype at amino acid 247 of beta(2)GPI and clinical disease supports a genetic cause for APS among children and adolescents. Neither novel exon 7 beta(2)GPI mutations or the previously described C306G polymorphism was identified in this pediatric cohort.