Human Molecular Genetics Advance Access published online on July 13, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi247
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1 Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan 812-8582; Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 113-0033
* To whom correspondence should be addressed. Leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1/LIR1/ILT2), is an inhibitory receptor broadly expressed on leukocytes, and recognizes HLA-class I and human cytomegalovirus UL18. LILRB1 is encoded within the leukocyte receptor complex on 19q13.4, previously implicated to be a susceptibility region to systemic lupus erythematosus (SLE). In this study, we screened for polymorphisms of LILRB1 and examined their association with SLE and rheumatoid arthritis (RA). In the 5' portion of LILRB1, three haplotypes containing four nonsynonymous substitutions within the ligand binding domains and two single nucleotide polymorphisms within the promoter region were identified and designated as PE01-03. In the 3' portion, two haplotypes (CY01, 02) containing a nonsynonymous substitution of the cytoplasmic region were identified. CY01 and 02 did not co-segregate with PE01-03. Significant association with susceptibility to SLE or RA was not observed; however, among the subjects not carrying RA-associated HLA-DRB1 shared epitope (SE), LILRB1.PE01/01 diplotype was significantly associated with RA (odds ratio 2.05, P = 0.019, Pc = 0.038). Gross difference was not observed in the crystal structures, thermostabilities and binding affinities to HLA-class I ligands among LILRB1.PE01-03 haplotype products; however, surface expression of LILRB1 was significantly decreased in lymphocytes and monocytes from the carriers of PE01 haplotype. These findings demonstrated that LILRB1 is highly polymorphic, and is associated with susceptibility to RA in HLA-DRB1 SE negative subjects, possibly by insufficient inhibitory signaling in leukocytes. In addition, these observations suggested that the polymorphisms of LILR family members may be substantially involved in the diversity of human immune responses.
Received June 21, 2005
Accepted July 5, 2005
Article
Extensive polymorphisms of LILRB1 (ILT2, LIR1) and their association with HLA-DRB1 shared epitope negative rheumatoid arthritis
2 Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 113-0033
3 Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan 812-8582
4 Department of Medicine II, Hokkaido University, Sapporo, Japan 060-8638
5 Matsuta Clinic, Tokyo, Japan 155-0032
6 Department of Rheumatology and Internal Medicine, Juntendo University, Tokyo, Japan 113-8421
7 Tumor Suppression & Functional Genomics Project, National Cancer Center Research Institute, Tokyo, Japan 104-0045
8 Division of Viral Immunology, Center for AIDS Research, Kumamoto University, Kumamoto, Japan 860-8556
9 Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan 105-8521
10 Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 113-0033
Naoyuki Tsuchiya, E-mail: tsuchiya-tky{at}umin.ac.jp
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