Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis.
Rheumatoid arthritis (RA) is an inflammatory disease with a complex genetic component. An association between RA and the human leukocyte antigen (HLA) complex has long been observed in many different populations, and most studies have focused on a direct role for the HLA-DRB1 "shared epitope" in disease susceptibility. We have performed an extensive haplotype analysis, using 54 markers distributed across the entire HLA complex, in a set of 469 multicase families with RA. The results show that, in addition to associations with the DRB1 alleles, at least two additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral A1-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. These data emphasize the importance of defining haplotypes when trying to understand the HLA associations with disease, and they clearly demonstrate that such associations with RA are complex and cannot be completely explained by the DRB1 locus.
Center for Genomics and Human Genetics, North Shore-Long Island Jewish Research Institute, Manhasset, NY, 11030, USA.
Damini
D
Jawaheer
Wentian
W
Li
Robert R
RR
Graham
Wei
W
Chen
Aarti
A
Damle
Xiangli
X
Xiao
Joanita
J
Monteiro
Houman
H
Khalili
Annette
A
Lee
Robert
R
Lundsten
Ann
A
Begovich
Teodorica
T
Bugawan
Henry
H
Erlich
James T
JT
Elder
Lindsey A
LA
Criswell
Michael F
MF
Seldin
Christopher I
CI
Amos
Timothy W
TW
Behrens
Peter K
PK
Gregersen
D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D019277:Entropy; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006680:HLA Antigens / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D010375:Pedigree; D012984:Software
D006680:HLA Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains