Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Major Histocompatibility Complex Associations with Thrombosis and Antiphospholipid Antibody Production in Systemic Lupus Erythematosus.
Kaiser4, Rachel, Chung4, Sharon A., Taylor5, Kimberly E., May2, Suzanne L., Ramsay2, Patricia P., Quach2, Hong L., Quach2, Diana L.
Thrombosis occurs at a younger age and at an increased frequency in systemic lupus erythematosus (SLE) compared to the general population. Known risk factors such as antiphospholipid antibodies (aPL) incompletely explain outcomes in this complex phenotype. The major histocompatibility complex (MHC) has the strongest association with SLE but associations with subphenotypes are less well-established due in part to linkage disequilibrium in the region. Prior studies in Caucasians suggest that HLA-DRB1 allele frequencies differ between SLE patients with and without aPL, and that DR4 and DR7 may be associated with anticardiolipin autoantibodies (aCL). We investigated the association of HLA-DRB1 and other MHC loci (independent of HLA-DRB1) with thrombosis and aPL production in SLE.
We genotyped 909 SLE cases of European descent for 2360 single nucleotide polymorphisms (SNPs) across 4.9 Mb of the MHC using the Illumina Combined MHC panel. These cases were also genotyped for HLA-DRB1 and 384 ancestry informative markers. Thrombotic events (deep venous thrombosis, myocardial infarction, stroke, pulmonary embolism, retinal vein thrombosis, recurrent miscarriage) and aPL status (aCL IgG and IgM, lupus anticoagulant (LAC)) were obtained from medical record review. Associations with HLA-DRB1 alleles were identified using a relative predispositional effects (RPE) method. SNPs associated with aPL and thrombosis were identified using forward selection with conditional logistic regression based on haplotypes implemented in WHAP.
We genotyped 1974 SNPs and 640 SLE cases after stringent quality control criteria were applied and subjects with <90% northern European ancestry were removed. Five percent of the subjects were LAC positive, 33% were aCL positive, 35% were positive for at least one of these aPLs, and 24% experienced at least one thrombosis. HLA-DRB1*0701 was associated with thrombosis in a global C2 test and in a multivariate model adjusting for age, gender, smoking history, disease duration, nephritis history, aPL, Northern European ancestry and medications (including immunodmodulators and hydroxychloroquine) (OR 2.06, 95%C.I. 1.093.90, p=0.027). No DRB1 associations were found with aPL (global c2 p>0.05). Conditional logistic regression identified associations independent of HLA-DRB1 in or near the BAT3-MDC1-HCP5 region with thrombosis (OR=2.53, haplotype specific p=1.35×10-10) and in or near the BTNL2-HLA-E-HLA-B region with aPL (OR 4.50, haplotype specific p=6.80×10-5).
HLA-DRB1*0701 is associated with thrombosis in SLE but no HLA-DRB1 associations were found with aPL, possibly due to a lack of power to detect an association. We also identified several MHC associations with thrombosis and aPL independent of the HLA-DRB1 locus. Interestingly, these associations were in Class I and III in addition to the previously associated Class II loci. Furthermore, these associations were different for the outcomes of thrombosis and aPL. Thrombosis risk in SLE may be explained in part by MHC genetic variation.
To cite this abstract, please use the following information:
Kaiser, Rachel, Chung, Sharon A., Taylor, Kimberly E., May, Suzanne L., Ramsay, Patricia P., Quach, Hong L., et al; Major Histocompatibility Complex Associations with Thrombosis and Antiphospholipid Antibody Production in Systemic Lupus Erythematosus. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1602