Objective: To investigate the familial basis of antiphospholipid antibodies by studying putative risk factors at the C4 and MHC class II loci.
Methods: Autoimmune diseases, anticardiolipin (aCL) and other autoantibodies were studied in 38 first and 2nd degree family members of 3 index cases selected for primary antiphospholipid syndrome (APS) and 33 controls. C4 protein phenotyping and restriction fragment length polymorphism analysis of C4 and MHC class II loci were performed.
Results: Nineteen family members (46%) had autoimmune diseases or autoantibodies; aCL were present in 10 family members, 4 of whom had primary APS. Each family had 2 or more subjects with aCL. Among 22 independent haplotypes in family members, there was a high frequency of C4A and C4B deficiency alleles (0.41 vs 0.18 in 66 controls, p = 0.03) and a strong trend toward an increase in MHC DQB1 putative risk factors that share the TRAELDT structural domain. This DQB1 structural domain was present in 4/5 different haplotypes that contained a C4B deficiency genotype; however, neither of 2 different haplotypes with a C4A deletion (one being a common ancestral haplotype) contained this DQB1 putative risk factor. Among the 10 family members who had aCL, 10/20 haplotypes contained a C4 deficiency genotype; moreover, the DQB1 putative risk factor was present in all 16 MHC haplotypes that did not contain a C4A deletion.
Conclusion: In these families, expression of an autoimmunity trait as aCL antibody appears to be associated with the coexistence of C4 deficiency alleles with DQB1 alleles that contain the TRAELDT structural domain.