title: Contribution of functional KIR3DL1 to ankylosing spondylitis.
abstract: Increasing evidence points to a role for killer immunoglobulin-like receptors (KIRs) in the development of autoimmune diseases. In particular, a positive association of KIR3DS1 (activating receptor) and a negative association of KIR3DL1 (inhibitory receptor) alleles with ankylosing spondylitis (AS) have been reported by several groups. However, none of the studies analyzed these associations in the context of functionality of polymorphic KIR3DL1. To better understand how the KIR3DL1/3DS1 genes determine susceptibility to AS, we analyzed the frequencies of alleles and genotypes encoding functional (KIR3DL1*F) and non-functional (KIR3DL1*004) receptors. We genotyped 83 AS patients and 107 human leukocyte antigen (HLA)-B27-positive healthy controls from the Russian Caucasian population using a two-stage sequence-specific primer PCR, which distinguishes KIR3DS1, KIR3DL1*F and KIR3DL1*004 alleles. For the patients carrying two functional KIR3DL1 alleles, those alleles were additionally genotyped to identify KIR3DL1*005 and KIR3DL1*007 alleles, which are functional but are expressed at low levels. KIR3DL1 was negatively associated with AS at the expense of KIR3DL1*F but not of KIR3DL1*004. This finding indicates that the inhibitory KIR3DL1 receptor protects against the development of AS and is not simply a passive counterpart of the segregating KIR3DS1 allele encoding the activating receptor. However, analysis of genotype frequencies indicates that the presence of KIR3DS1 is a more important factor for AS susceptibility than the absence of KIR3DL1*F. The activation of either natural killer (NK) or T cells via the KIR3DS1 receptor can be one of the critical events in AS development, while the presence of the functional KIR3DL1 receptor has a protective effect. Nevertheless, even individuals with a genotype that carried two inhibitory KIR3DL1 alleles expressed at high levels could develop AS.
authors.affiliation: Shemiakin-Ovchinnikov Institute of Bioorganic Chemistry, RAS, Moscow, Russia.
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Zvyagin
authors.forename: Ilgar Z
authors.initials: IZ
authors.lastname: Mamedov
authors.forename: Olga V
authors.initials: OV
authors.lastname: Britanova
authors.forename: Dmitriy B
authors.initials: DB
authors.lastname: Staroverov
authors.forename: Evgeni L
authors.initials: EL
authors.lastname: Nasonov
authors.forename: Anna G
authors.initials: AG
authors.lastname: Bochkova
authors.forename: Anna V
authors.initials: AV
authors.lastname: Chkalina
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Kotlobay
authors.forename: Dmitriy O
authors.initials: DO
authors.lastname: Korostin
authors.forename: Denis V
authors.initials: DV
authors.lastname: Rebrikov
authors.forename: Sergey
authors.initials: S
authors.lastname: Lukyanov
authors.forename: Yuri B
authors.initials: YB
authors.lastname: Lebedev
authors.forename: Dmitriy M
authors.initials: DM
authors.lastname: Chudakov
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D005787:Gene Frequency / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D054341:Receptors, KIR3DL1 / Q000235:genetics*; D054349:Receptors, KIR3DS1 / Q000235:genetics; D012426:Russia; D013030:Spain; D013167:Spondylitis, Ankylosing / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C515083:KIR3DL1 protein, human; D054341:Receptors, KIR3DL1; D054349:Receptors, KIR3DS1
references.citation: Rheumatology (Oxford). 2002 Aug;41(8):857-68
references.pmid: 12154202
references.citation: PLoS Genet. 2008 Nov;4(11):e1000254
references.pmid: 19008943
references.citation: J Immunol. 2004 Dec 15;173(12):7223-9
references.pmid: 15585844
references.citation: N Engl J Med. 1973 Apr 5;288(14):704-6
references.pmid: 4688372
references.citation: AIDS Res Hum Retroviruses. 2007 Mar;23(3):451-5
references.pmid: 17411378
references.citation: Arthritis Rheum. 1984 Apr;27(4):361-8
references.pmid: 6231933
references.citation: Immunity. 1997 Dec;7(6):753-63
references.pmid: 9430221
references.citation: Hum Immunol. 2008 Jul;69(7):437-42
references.pmid: 18638658
references.citation: Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1453-7
references.pmid: 8643653
references.citation: Ann Rheum Dis. 2009 Apr;68(4):595-8
references.pmid: 19019897
references.citation: Annu Rev Immunol. 2002;20:217-51
references.pmid: 11861603
references.citation: Semin Immunol. 2008 Dec;20(6):343-52
references.pmid: 18635379
references.citation: Nat Genet. 2002 Aug;31(4):429-34
references.pmid: 12134147
references.citation: Best Pract Res Clin Rheumatol. 2006 Jun;20(3):571-91
references.pmid: 16777583
references.citation: Zhonghua Yi Xue Za Zhi. 2009 Jan 13;89(2):91-5
references.pmid: 19489269
references.citation: Hum Immunol. 2006 Jul;67(7):521-6
references.pmid: 16829306
references.citation: Ann Rheum Dis. 2010 Apr;69(4):733-6
references.pmid: 19433412
references.citation: J Exp Med. 2006 Mar 20;203(3):633-45
references.pmid: 16533882
references.citation: Mol Immunol. 2005 Feb;42(4):459-62
references.pmid: 15607799
references.citation: Nat Genet. 2007 Nov;39(11):1329-37
references.pmid: 17952073
references.citation: Hum Mol Genet. 2009 Nov 1;18(21):4204-12
references.pmid: 19692350
references.citation: Nature. 1998 Feb 12;391(6668):703-7
references.pmid: 9490415
references.citation: J Exp Med. 1995 Mar 1;181(3):1133-44
references.pmid: 7532677
references.citation: Curr Opin Rheumatol. 2009 Jul;21(4):318-23
references.pmid: 19496308
references.citation: Ann Neurol. 2009 Jun;65(6):658-66
references.pmid: 19630074
references.citation: J Immunol. 2003 Dec 15;171(12):6640-9
references.pmid: 14662867
references.citation: Lancet. 1973 Apr 28;1(7809):904-7
references.pmid: 4123836
references.citation: Eur J Immunol. 2005 Jan;35(1):16-24
references.pmid: 15580659
references.citation: Genome Res. 2005 Jan;15(1):25-35
references.pmid: 15632087
references.citation: Arthritis Rheum. 2005 Nov;52(11):3586-95
references.pmid: 16255049
references.citation: J Clin Immunol. 2008 Jul;28(4):343-9
references.pmid: 18297378
references.citation: J Immunol. 2008 Mar 1;180(5):2767-71
references.pmid: 18292496
references.citation: J Exp Med. 2007 Nov 26;204(12):3027-36
references.pmid: 18025129
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10285-8
references.pmid: 9294202
references.citation: Eur J Immunol. 2007 Mar;37(3):780-7
references.pmid: 17301953
references.citation: Rheumatology (Oxford). 2008 Feb;47(2):132-7
references.pmid: 18037607
references.citation: J Immunol. 2009 Jan 1;182(1):92-101
references.pmid: 19109139
references.citation: Int J Immunogenet. 2008 Feb;35(1):1-8
references.pmid: 18093180
references.citation: Curr Opin Rheumatol. 2006 Jul;18(4):332-41
references.pmid: 16763451
references.citation: J Exp Med. 1994 Aug 1;180(2):537-43
references.pmid: 8046332
references.citation: Rheumatology (Oxford). 2007 May;46(5):763-71
references.pmid: 17259653
references.citation: Adv Exp Med Biol. 2009;649:286-99
references.pmid: 19731638
references.citation: J Immunol. 2007 Aug 1;179(3):1625-33
references.pmid: 17641029
references.citation: J Immunol. 2001 Mar 1;166(5):2992-3001
references.pmid: 11207248
references.citation: Nat Rev Immunol. 2005 Mar;5(3):201-14
references.pmid: 15719024
references.citation: Arthritis Res Ther. 2006;8(4):R101
references.pmid: 16805919
references.citation: Arthritis Rheum. 2009 May;60(5):1317-23
references.pmid: 19404951
references.citation: Eur J Immunol. 2005 Jul;35(7):2191-9
references.pmid: 15940669
references.citation: J Immunol. 2004 Oct 1;173(7):4273-6
references.pmid: 15383555
references.citation: Curr Mol Med. 2004 Feb;4(1):13-20
references.pmid: 15011955
references.citation: J Invest Dermatol. 2005 Oct;125(4):721-30
references.pmid: 16185272
references.citation: Nat Genet. 2007 Jun;39(6):733-40
references.pmid: 17496894
references.citation: Methods Mol Biol. 2008;415:49-64
references.pmid: 18370147
references.citation: J Clin Pathol. 1973 May;26(5):387
references.pmid: 4714966