Specific combinations of HLA-DR2 and DR3 class II haplotypes contribute graded risk for disease susceptibility and autoantibodies in human SLE
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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A substantial genetic contribution to SLE risk is conferred by MHC gene(s) on chromosome 6p21.
“A substantial genetic contribution to systemic lupus erythematosus (SLE) risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6p21.”
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The International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN), Harley, J. B., Alarcón-Riquelme, M. E., Criswell, L. A., Jacob, C. O., Kimberly, R. P., Moser, K. L., Tsao, B. P., Vyse, T. J., & Langefeld, C. D. (2008) · Nature Genetics · doi:10.1038/ng.81 · Cited by 1,309 · see citing works
Self-citationBarcellos, L. F., May, S. L., Ramsay, P. P., Quach, H. L., Lane, J. A., Nititham, J., Noble, J. A., Taylor, K. E., Quach, D. L., Chung, S. A., et al. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000696 · Cited by 131 · see citing works
“Work by Graham and colleagues [8,9] examining ,50 microsatellite markers across the MHC region highlighted the importance of HLA class II haplotypes involving the HLA-DRB1 and –DQB1 loci, particularly those corresponding to serologic types HLA-DR2 and DR3 (DRB1*1501-DQB1*0602 and DRB1*0301-DQB1*0201, respectively).”
BackgroundSelf-citation
- Authors
- Graham, R. R., Ortmann, W., Rodine, P., Espe, K., Langefeld, C., Lange, E., Williams, A., Beck, S., Kyogoku, C., Moser, K., Gaffney, P., Gregersen, P. K., Criswell, L. A., Harley, J. B., & Behrens, T. W.
- Affiliations
- Harvard University (US)
- University of Minnesota (US)
- Wake Forest University Health Sciences (US)
- Northwell Health (US)
- University of California, San Francisco (US)
- Oklahoma Medical Research Foundation (US)
- Corresponding author
- Behrens, Timothy W
- ORCID
- Venue
- European Journal of Human Genetics
- Published
- 2007-04-04
- Volume
- 15
- Issue
- 8
- Pages
- 823-830
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- OpenAlex
- W1972437174
- Cited by
- 174
- References
- 0
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 11 · 2023: 3 · 2022: 7 · 2021: 11 · 2020: 10 · 2019: 6 · 2018: 10 · 2017: 6 · 2016: 7 · 2015: 9 · 2014: 9 · 2013: 15 · 2012: 13
- FWCI
- 8.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Oklahoma Medical Research Foundation
- Lupus Research Alliance
- National Institutes of Health (5p60ar048094-05, 5r01ai032584-03, n01ar012253-007, 1g20rr024013-01a1, 5m01rr000079-42, AR048940, AI24717)
- University of California, San Francisco
- National Institute of Allergy and Infectious Diseases (AI32584, AI-24717)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR048940, R01AR042460, AR048094, P60AR053308, AR-12253, AR 42460, P50AR048940)
- National Center for Research Resources (5M01-RR00079, RR024013)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- systemic lupus erythematosus, HLA-DR2, HLA-DR3, HLA class II haplotypes, disease susceptibility, autoantibodies, anti-Sm antibodies, compound heterozygosity, family-based association, genetic risk
- MeSH terms
- Autoantibodies, Female, Haplotypes, Humans, Lupus Erythematosus, Systemic, Male, Cohort Studies, HLA-DR2 Antigen, HLA-DR3 Antigen, Case-Control Studies, Risk Assessment, Genetic Predisposition to Disease
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