title: 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.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.forename: Ward
authors.initials: W
authors.lastname: Ortmann
authors.forename: Peter
authors.initials: P
authors.lastname: Rodine
authors.forename: Karl
authors.initials: K
authors.lastname: Espe
authors.forename: Carl
authors.initials: C
authors.lastname: Langefeld
authors.forename: Ethan
authors.initials: E
authors.lastname: Lange
authors.forename: Adrienne
authors.initials: A
authors.lastname: Williams
authors.forename: Stephanie
authors.initials: S
authors.lastname: Beck
authors.forename: Chieko
authors.initials: C
authors.lastname: Kyogoku
authors.forename: Kathy
authors.initials: K
authors.lastname: Moser
authors.forename: Patrick
authors.initials: P
authors.lastname: Gaffney
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
mesh_terms: D001323:Autoantibodies / Q000096:biosynthesis*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D015802:HLA-DR2 Antigen / Q000235:genetics*; D015803:HLA-DR3 Antigen / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D008297:Male; D018570:Risk Assessment
chemical_list: D001323:Autoantibodies; D015802:HLA-DR2 Antigen; D015803:HLA-DR3 Antigen