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Abstract

Antibodies against phospholipids (PL) and PL-binding proteins have been causally implicated in antiphospholipid syndrome (APS). Mutations in the fifth domain of the β₂-glycoprotein I (β₂GPI) protein, a putative PL-binding site, may play a critical role in APS pathogenesis. The purpose of this study was to identify associations between β₂GPI 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 β₂GPI 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 β₂GPI gene, and their association with aPL-associated clinical manifestations.

Our results demonstrate an association between substitution of Val for Leu at AA247 (L247V) of β₂GPI 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 β₂GPI and clinical disease supports a genetic cause for APS among children and adolescents. Neither novel exon 7 β₂GPI mutations or the previously described C306G polymorphism was identified in this pediatric cohort.

Keywords

antiphospholipid syndrome β2-glycoprotein I children genetic SLE

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Association between β2-glycoprotein I gene polymorphisms and pediatric SLE and antiphospholipid antibodies

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