Familial anticardiolipin antibodies and C4 deficiency genotypes that coexist with MHC DQB1 risk factors

To investigate the familial basis of antiphospholipid antibodies by studying putative risk factors at the C4 and MHC class II loci.

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.

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.

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.