Human Molecular Genetics Advance Access originally published online on July 13, 2005
Human Molecular Genetics 2005 14(16):2469-2480; doi:10.1093/hmg/ddi247
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Extensive polymorphisms of LILRB1 (ILT2, LIR1) and their association with HLA-DRB1 shared epitope negative rheumatoid arthritis
1Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan, 2Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, 3Department of Medicine II, Hokkaido University, Sapporo 060-8638, Japan, 4Matsuta Clinic, Tokyo 155-0032, Japan, 5Department of Rheumatology and Internal Medicine, Juntendo University, Tokyo 113-8421, Japan, 6Tumor Suppression and Functional Genomics Project, National Cancer Center Research Institute, Tokyo 104-0045, Japan, 7Division of Viral Immunology, Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan and 8Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, Tokyo 105-8521, Japan
* To whom correspondence should be addressed. Tel: +81 358413693; Fax: +81 358028619; Email: tsuchiya-tky{at}umin.ac.jp
Received June 21, 2005; Accepted July 5, 2005
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 non-synonymous 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 non-synonymous 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 and 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.
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