Specific combinations of HLA-DR2 and DR3 class II haplotypes contribute graded risk for disease susceptibility and autoantibodies in human SLE.
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.
Graham
Robert R
RR
Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Ortmann
Ward
W
Rodine
Peter
P
Espe
Karl
K
Langefeld
Carl
C
Lange
Ethan
E
Williams
Adrienne
A
Beck
Stephanie
S
Kyogoku
Chieko
C
Moser
Kathy
K
Gaffney
Patrick
P
Gregersen
Peter K
PK
Criswell
Lindsey A
LA
Harley
John B
JB
Behrens
Timothy W
TW
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
D001323:Autoantibodies; D015802:HLA-DR2 Antigen; D015803:HLA-DR3 Antigen