Abstract
The human leukocyte antigen (HLA) Class II antigen presentation alleles DR and DQ are associated with susceptibility to systemic lupus erythematosus (SLE) and the production of lupus-related autoantibodies. Here, we explore the effect of different combinations of Class II risk haplotypes in a large, multi-center collection of 780 SLE families. Haplotypes bearing the DRB1*1501/DQB1*0602 (DR2) and DRB1*0301/DQB1*0201 (DR3) alleles were present in nearly two-thirds of SLE cases and were significantly associated with disease susceptibility in both family-based and case-control study designs. DR3-containing haplotypes conferred higher risk for disease than DR2, and individual homozygous for DR3 or compound heterozygous for DR3 and DR2 showed the highest risk profile. DR2 haplotypes were also found to be associated with antibodies to the nuclear antigen Sm, and, as previously observed, DR3 genotypes were associated with Ro and La autoantibodies. Interestingly, SLE cases and unaffected family members who were DR2/DR3 compound heterozygotes showed particularly strong risk of developing antibodies to Ro, and were enriched for La and Sm. These data provide convincing evidence that particular combinations of HLA Class II DR2 and DR3 haplotypes are key determinants of autoantibody production and disease susceptibility in human SLE.
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Acknowledgements
We gratefully acknowledge the many patients, families and physicians who have cooperated for the purposes of genetic studies in SLE. This work was supported by grants, contracts and fellowships from the National Institute of Arthritis, Musculoskeletal and Skin Diseases, the National Institute of Allergy and Infectious Disease, the Minnesota Lupus Foundation, the Mary Kirkland Center for Lupus Research, and the Alliance for Lupus Research. These studies were performed in part at the General Clinical Research Center, Moffitt Hospital, University of California, San Francisco, with funds provided by the National Center for Research Resources (5 M01 RR00079, US Public Health Service) and at the Oklahoma Medical Research Foundation with grants awarded to JBH (NIH grants: AR12253, AI24717, AR42460, AR048094, RR024013, AI32584, and AR048940).
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Graham, R., Ortmann, W., Rodine, P. et al. Specific combinations of HLA-DR2 and DR3 class II haplotypes contribute graded risk for disease susceptibility and autoantibodies in human SLE. Eur J Hum Genet 15, 823–830 (2007). https://doi.org/10.1038/sj.ejhg.5201827
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DOI: https://doi.org/10.1038/sj.ejhg.5201827
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