Molecular analysis of major histocompatibility complex alleles associated with the lupus anticoagulant.

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Abstract

Autoantibodies to phospholipids (APA) occur frequently in systemic lupus erythematosus (SLE) and other autoimmune disorders and predispose to intravascular thromboses. Major histocompatibility complex (MHC) class II alleles (HLA-DR and DQ) were determined by restriction fragment length polymorphisms (RFLP) in 20 patients with APA (lupus anticoagulant). HLA-DQw7 (DQB1*0301), linked to HLA-DR5 and -DR4 haplotypes, occurred in 70% and was significantly increased compared to 139 race-matched normal controls (P = 0.002, P corrected [pc] = 0.05, odds ratio [OR] = 5.1). Moreover, the frequency of HLA-DQw7 was significantly higher in SLE patients with APA as compared with patients without APA but with other autoantibodies, including anti-Ro and La (P = 0.0001, pc = 0.002, OR = 10.7), anti-Ro alone (P = 0.001, pc = 0.02, OR = 11.2), anti-dsDNA (P = 0.001, pc = 0.02, OR = 7.1), and possibly anti-Sm (P = 0.04, pc = NS, OR = 6.8) and anti-nRNP (U1-RNP) (P = 0.01, pc = NS, OR = 7.8). The DQB1*0301 allele of DQw7 showed the strongest association, while the frequencies of the DQA1*0301 (45%) and DQA1*0501 (50%) alleles did not differ from the controls. Among the HLA-DQB1*0301 (DQw7) negative patients, all possessed HLA-DQw8 (DQB1*0302) and/or HLA-DQw6 (DQB1*0602 or DQB1*0603) alleles. The HLA-DQB1*0301 chain shares an identical seven amino acid sequence with DQB1*0302, *0602, and *0603 chains in the third hypervariable region of the HLA-DQ molecule. This candidate "epitope" may play a role in mediating an autoimmune response to APA.

Authors

F C Arnett, M L Olsen, K L Anderson, J D Reveille