1. ¹Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
2. ²Department of Rheumatology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA
3. ³Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA
4. ⁴Robert S Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, North Shore Long Island Jewish Health System, Manhasset, NY, USA
5. ⁵Department of Medicine, Division of Rheumatology, Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, CA, USA
6. ⁶Department of Medicine, Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

Correspondence: Dr TW Behrens, Immunology, Tissue Growth & Repair, Genentech, Inc, Exploratory Clinical Development, 1 DNA Way, S San Francisco, CA 94080, USA. Tel: 650 467 4319/243 8269; Fax: 650 225 8221; E-mail: behrens.tim@gene.com

⁷Current address: Genentech, Inc., South San Francisco, CA, USA

Received 4 April 2006; Revised 12 January 2007; Accepted 27 February 2007; Published online 4 April 2007.

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.