中国汉族人群免疫球蛋白受体同系物家簇基因单核苷酸多态性与强直性脊柱炎的关联研究
|
摘要
强直性脊柱炎(Ankylosing Spondylitis,AS)是一种血清学阴性,主要侵犯中轴骶骼关节的慢性炎症性自身免疫性疾病,其临床发病率较高,多见于青壮年男性,且有较高的家族聚集性。该病目前病因尚不明确,其发病被认为与多种因素有关,是一种十分复杂的疾病,又称为多因子疾病(multifactorial disease)。虽然针对AS的病因和发病机制,已经提出过很多学说,包括分子模拟学说、致关节炎多肽学说、HLA-B27分子非折叠蛋白理论假说等,但到目前为止,AS发生的确切原因尚不清楚。国内外大量研究表明,遗传因素是强直性脊柱炎发病的主导因素,通过全基因组扫描发现,多个区域与AS易感性有关[1,2]。其中以HLA-B27为代表的HLA区基因与AS的关联性最强,HLA-B27与AS的遗传易感性研究已经经历了30多年,在不同国家和地区都得到了证实,但确切的发病机理还不是十分清楚,而且整个HLA区域只能解释AS遗传易感性的40-50%,因此,非HLA区基因与AS易感性关联研究将是下一步研究的重点和热点。
本研究旨在通过较大规模的强直性脊柱炎的遗传流行病学调查,借助人类基因组计划的研究成果,明确中国汉族人群易感区域易感基因(免疫球蛋白受体同系物基因)的单核苷酸多态性及单倍型与AS的遗传关联性,构建中国人群该易感家簇基因中与AS有关联意义的单核苷酸多态性(Single nucleotide polymorphism,SNP)和单倍型,并初步探讨基因和环境的交互作用。本研究采用经典病例对照设计方案,以问卷调查的方式,共收集169例HLA-B27阳性患者(107男性和62女性)和184个HLA-B27阳性健康对照(112个男性和72个女性)的一般流行病学资料和DNA血样,选择免疫球蛋白受体同系物家族基因中的FCRL1(1个功能SNP)、FCRL3(3个功能SNP)、FCRL4(1个功能SNP)、以及FCRL5(4个功能SNP)四个基因中的9个功能SNP(即改变氨基酸序列的非同义突变),通过PCR扩增后,用连接酶检测反应的方法筛查这些功能SNP位点的基因型及其在中国人群中的频率;并构建中国汉族人群中与AS有关联的SNPs和单倍型。用EPIdata 3.0软件建立数据库,数据经检错、整理后分别应用社会科学统计软件包(SPSS10.01)和经典的病例对照在线分析软件Shesis(http://analysis.bio-x.cn/myAnalysis.php)进行统计学分析。应用非条件多元Logistic回归方法分析AS可能存在的基因和环境交互作用。
169个患者来自安徽医科大学第一附属医院的门诊和住院病人,平均年龄为26.38±6.32岁(其中最小为14岁,最大为78岁)。通过对FCRL中的五个基因中的9个SNP位点进行筛查,结果未发现FCRL1、FCRL3和FCRL4中的SNPs与AS有遗传关联性,而FCRL5基因中的2个SNPs(rs12036228和rs6427384)与AS存在遗传上的关联性,进一步分析提示rs12036228位点上C等位基因的出现增加AS发病的风险性,而rs6427384位点上T等位基因的出现增加AS发病的风险性,在对上述2个SNP位点进行单倍型分析后发现:携带有C-C单倍型的个体对AS发病具有保护性作用,而携带有C-T单倍型的个体则对AS的发病具有更高风险性。同时我们对中国汉族人群的HLA-B27及其亚型的结果进行筛查,研究结果提示在中国汉族人群中存在四种亚型(B * 2703,B * 2704, B * 2705和B * 2706),其中病例组中以B*2704和B*2705两个亚型较常见,分别占53.8%和34.9%,对照组中同样是B*2704和B*2705两个亚型较常见,病例组这两个亚型的比例高于对照组,但结果无统计学意义(χ2=7.014,P=0.056);另外对影响总体背痛程度因素进行单因素分析,没有发现对总体背痛程度有统计学意义的因素,故没有进一步进行多元分析。通对BASFI影响因素进行多因素分析结果提示性别、病程、学历、饮酒史可能是BASFI影响因素;同时我们将可能与AS发病有关的环境因素和可能易感SNP位点及交互项进行非条件logistic回归的拟合分析,结果显示:在调整其他自变量的情况下,最后进入模型的两个变量是有感染史和家庭居住环境,但没有发现FCRL5基因与上述环境因素之间存在交互作用。
综上所述,我们认为在中国汉族人群中免疫球蛋白受体同系物家族基因(位于1q23-24区域)可能与强直性脊柱炎的遗传易感性有关,特别是FCRL5基因;同时还受到环境因素的作用,但本次研究未发现基因和环境因素对AS存在交互作用。至于不同HLA-B27亚型的AS在该区域的遗传易感性是否有差别将有待于进一步研究和证实。
Ankylosing spondylitis (Ankylosing Spondylitis, AS) is a seronegative, chronic inflammatory autoimmune disease, which mainly affects the axial skeleton of the young men with a higher clinical incidence and family aggregation. The exact cause of the disease is currently unknown, it is generally accepted that AS is a very complex disease, also known as a multi-factorial diseases. Although many previous studies aimed at the etiology and pathogenesis of AS has been put forward many theories, including molecular simulation theory, theory of peptide-induced arthritis, HLA-B27 molecules of non-folded protein hypothesis, etc.But so far, the exact cause of AS remains unclear. However, a large number of domestic and overseas studies have shown that genetic factors take an important part in the pathogenesis of AS, a genome-wide scan have revealed multiple regions associated with AS susceptibility [1,2]. Among them, HLA region, represented by HLA-B27 gene, have robust association with AS, studies on HLA-B27 and the genetic susceptibility to AS has gone through more than 30 years, which have been confirmed in different countries and regions, but the exact pathogenesis of AS is still not very clear, and the entire HLA region can explain only a fraction (40 -50%) of AS genetic susceptibility, therefore, the non-HLA genes may also be associated with the susceptibility to AS.
The purpose of this study was to explore the association of single nucleotide polymorphisms (SNPs) and haplotypes of Fc receptor-like genes with susceptibility to AS in a Chinese Han population, and to explore the interaction of genes and the environmental factors.
Questionnaire investigation was performed to obtain information in this case-control study. we collected 169 cases of HLA-B27 positive AS patients (107 males and 62 females) from the department of rheumatology, the first affiliated hospital of Anhui Medical University, including outpatient and inpatient. 184 HLA-B27 positive healthy controls (112 male and 72 female) are also recruited from the same region. Their general epidemiological data and DNA samples were collected. in this study, we have chosen an important candidate family gene (immunoglobulin receptor homologue family gene) for AS . 9 non-synonymous mutation functional SNPs, from FCRL1 (1 SNP), FCRL3 (3 SNPs), FCRL4 (1 SNP) and FCRL5 (4 SNPs) respectively, are genotyped by PCR ligase detection reaction method to obtain their genotype frequency and haplotype in population. The database was established by EPIdata 3.0 software. The Social Science Statistical Package (SPSS10.01) and the classic case-control on-line analysis Software Shesis (http://analysis.bio-x.cn/myAnalysis.php) are used for statistical analysis.
In total,169 patients are recruited, with an average age of 26.38±6.32 years, ranging form 14 to 78 years. through multiple SNP loci screening, except for FCRL5, FCRL1, FCRL3 and FCRL4 gene was not associated with AS genetic susceptibility.2 SNPs(rs12036228 and rs6427384) from FCRL5 gene is associated with AS. C allele in rs12036228 occurred more frequently in case group than in control group,and T allele in rs6427384 more frequently in case group. haplotype C-T, On the basis of the two SNPs above, occurres more frequently in case group than in control group,but haplotype C-C more frequently in control. Meanwhile, we analyzed the HLA-B27 gene subtypes and find that there are four subtypes (B * 2703,B * 2704, B * 2705 and B * 2706) in the Chinese Han population, in which B * 2704 and B * 2705 frequence in case group are more common than the others, accounting for 53.8% and 34.9% and the two subtypes is also more common in control group. The difference of HLA-B27 gene subtype frequence is not statistically significant between case group and control group ( 2=7.014, P = 0.056). In the study we find that environmental risk factors is not associated with the general back pain level in patients with AS. the results of multivariate analysis shows that Such factors as gender, disease duration, education, drinking history may be associated with the BASDFI of patients with AS. Meanwhile, the environmental factors and two SNPs associated with AS above is analyzed by non-conditional logistic regression analysis on the basis of other independent variables adjusted. the results showed that the two variables(infection history and family living environment) go into the model, but no interactions of FCRL5 gene with environmental factors was found associated with AS.
In summary, our results suggested that FCRL family genes (located on 1q21-23 region), in particular FCRL5 gene, may be related to the genetic susceptibility to AS in the Chinese Han population. In addition, environmental factors also paly an important role in the onset of AS. However, no interactions of FCRL genes with environmental factors was found. Nevertheless, the sample size is relatively small, further studies in different populations are still needed.
本研究旨在通过较大规模的强直性脊柱炎的遗传流行病学调查,借助人类基因组计划的研究成果,明确中国汉族人群易感区域易感基因(免疫球蛋白受体同系物基因)的单核苷酸多态性及单倍型与AS的遗传关联性,构建中国人群该易感家簇基因中与AS有关联意义的单核苷酸多态性(Single nucleotide polymorphism,SNP)和单倍型,并初步探讨基因和环境的交互作用。本研究采用经典病例对照设计方案,以问卷调查的方式,共收集169例HLA-B27阳性患者(107男性和62女性)和184个HLA-B27阳性健康对照(112个男性和72个女性)的一般流行病学资料和DNA血样,选择免疫球蛋白受体同系物家族基因中的FCRL1(1个功能SNP)、FCRL3(3个功能SNP)、FCRL4(1个功能SNP)、以及FCRL5(4个功能SNP)四个基因中的9个功能SNP(即改变氨基酸序列的非同义突变),通过PCR扩增后,用连接酶检测反应的方法筛查这些功能SNP位点的基因型及其在中国人群中的频率;并构建中国汉族人群中与AS有关联的SNPs和单倍型。用EPIdata 3.0软件建立数据库,数据经检错、整理后分别应用社会科学统计软件包(SPSS10.01)和经典的病例对照在线分析软件Shesis(http://analysis.bio-x.cn/myAnalysis.php)进行统计学分析。应用非条件多元Logistic回归方法分析AS可能存在的基因和环境交互作用。
169个患者来自安徽医科大学第一附属医院的门诊和住院病人,平均年龄为26.38±6.32岁(其中最小为14岁,最大为78岁)。通过对FCRL中的五个基因中的9个SNP位点进行筛查,结果未发现FCRL1、FCRL3和FCRL4中的SNPs与AS有遗传关联性,而FCRL5基因中的2个SNPs(rs12036228和rs6427384)与AS存在遗传上的关联性,进一步分析提示rs12036228位点上C等位基因的出现增加AS发病的风险性,而rs6427384位点上T等位基因的出现增加AS发病的风险性,在对上述2个SNP位点进行单倍型分析后发现:携带有C-C单倍型的个体对AS发病具有保护性作用,而携带有C-T单倍型的个体则对AS的发病具有更高风险性。同时我们对中国汉族人群的HLA-B27及其亚型的结果进行筛查,研究结果提示在中国汉族人群中存在四种亚型(B * 2703,B * 2704, B * 2705和B * 2706),其中病例组中以B*2704和B*2705两个亚型较常见,分别占53.8%和34.9%,对照组中同样是B*2704和B*2705两个亚型较常见,病例组这两个亚型的比例高于对照组,但结果无统计学意义(χ2=7.014,P=0.056);另外对影响总体背痛程度因素进行单因素分析,没有发现对总体背痛程度有统计学意义的因素,故没有进一步进行多元分析。通对BASFI影响因素进行多因素分析结果提示性别、病程、学历、饮酒史可能是BASFI影响因素;同时我们将可能与AS发病有关的环境因素和可能易感SNP位点及交互项进行非条件logistic回归的拟合分析,结果显示:在调整其他自变量的情况下,最后进入模型的两个变量是有感染史和家庭居住环境,但没有发现FCRL5基因与上述环境因素之间存在交互作用。
综上所述,我们认为在中国汉族人群中免疫球蛋白受体同系物家族基因(位于1q23-24区域)可能与强直性脊柱炎的遗传易感性有关,特别是FCRL5基因;同时还受到环境因素的作用,但本次研究未发现基因和环境因素对AS存在交互作用。至于不同HLA-B27亚型的AS在该区域的遗传易感性是否有差别将有待于进一步研究和证实。
Ankylosing spondylitis (Ankylosing Spondylitis, AS) is a seronegative, chronic inflammatory autoimmune disease, which mainly affects the axial skeleton of the young men with a higher clinical incidence and family aggregation. The exact cause of the disease is currently unknown, it is generally accepted that AS is a very complex disease, also known as a multi-factorial diseases. Although many previous studies aimed at the etiology and pathogenesis of AS has been put forward many theories, including molecular simulation theory, theory of peptide-induced arthritis, HLA-B27 molecules of non-folded protein hypothesis, etc.But so far, the exact cause of AS remains unclear. However, a large number of domestic and overseas studies have shown that genetic factors take an important part in the pathogenesis of AS, a genome-wide scan have revealed multiple regions associated with AS susceptibility [1,2]. Among them, HLA region, represented by HLA-B27 gene, have robust association with AS, studies on HLA-B27 and the genetic susceptibility to AS has gone through more than 30 years, which have been confirmed in different countries and regions, but the exact pathogenesis of AS is still not very clear, and the entire HLA region can explain only a fraction (40 -50%) of AS genetic susceptibility, therefore, the non-HLA genes may also be associated with the susceptibility to AS.
The purpose of this study was to explore the association of single nucleotide polymorphisms (SNPs) and haplotypes of Fc receptor-like genes with susceptibility to AS in a Chinese Han population, and to explore the interaction of genes and the environmental factors.
Questionnaire investigation was performed to obtain information in this case-control study. we collected 169 cases of HLA-B27 positive AS patients (107 males and 62 females) from the department of rheumatology, the first affiliated hospital of Anhui Medical University, including outpatient and inpatient. 184 HLA-B27 positive healthy controls (112 male and 72 female) are also recruited from the same region. Their general epidemiological data and DNA samples were collected. in this study, we have chosen an important candidate family gene (immunoglobulin receptor homologue family gene) for AS . 9 non-synonymous mutation functional SNPs, from FCRL1 (1 SNP), FCRL3 (3 SNPs), FCRL4 (1 SNP) and FCRL5 (4 SNPs) respectively, are genotyped by PCR ligase detection reaction method to obtain their genotype frequency and haplotype in population. The database was established by EPIdata 3.0 software. The Social Science Statistical Package (SPSS10.01) and the classic case-control on-line analysis Software Shesis (http://analysis.bio-x.cn/myAnalysis.php) are used for statistical analysis.
In total,169 patients are recruited, with an average age of 26.38±6.32 years, ranging form 14 to 78 years. through multiple SNP loci screening, except for FCRL5, FCRL1, FCRL3 and FCRL4 gene was not associated with AS genetic susceptibility.2 SNPs(rs12036228 and rs6427384) from FCRL5 gene is associated with AS. C allele in rs12036228 occurred more frequently in case group than in control group,and T allele in rs6427384 more frequently in case group. haplotype C-T, On the basis of the two SNPs above, occurres more frequently in case group than in control group,but haplotype C-C more frequently in control. Meanwhile, we analyzed the HLA-B27 gene subtypes and find that there are four subtypes (B * 2703,B * 2704, B * 2705 and B * 2706) in the Chinese Han population, in which B * 2704 and B * 2705 frequence in case group are more common than the others, accounting for 53.8% and 34.9% and the two subtypes is also more common in control group. The difference of HLA-B27 gene subtype frequence is not statistically significant between case group and control group ( 2=7.014, P = 0.056). In the study we find that environmental risk factors is not associated with the general back pain level in patients with AS. the results of multivariate analysis shows that Such factors as gender, disease duration, education, drinking history may be associated with the BASDFI of patients with AS. Meanwhile, the environmental factors and two SNPs associated with AS above is analyzed by non-conditional logistic regression analysis on the basis of other independent variables adjusted. the results showed that the two variables(infection history and family living environment) go into the model, but no interactions of FCRL5 gene with environmental factors was found associated with AS.
In summary, our results suggested that FCRL family genes (located on 1q21-23 region), in particular FCRL5 gene, may be related to the genetic susceptibility to AS in the Chinese Han population. In addition, environmental factors also paly an important role in the onset of AS. However, no interactions of FCRL genes with environmental factors was found. Nevertheless, the sample size is relatively small, further studies in different populations are still needed.
引文
1.顾鸣敏,袁文涛,杨珏琴,等。全基因组扫描寻找强直性脊柱炎的易感基因位点。遗传学报,2004,31(3):217～220
2. Laval SH, Timms A, Edwards S, et al. Whole-Genome Screening in Ankylosing Spondylitis:Evidence of Non-MHC Genetic-Susceptibility Loci. Am. J. Hum. Genet.2001, 68:918–926
3. Brown MA, Laval SH, Brophy S, Calin A: Recurrence risk modeling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis 2000, 59:883–886.
4. Brown MA, Kennedy LG, MacGregor AJ, et al.: Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum 1997, 40:1823–1828.
5. John D. The Genetic Basis of Spondyloarthritis. Current Rheumatology Reports 2004, 6:117–125.
6.Salmon JE, Pricop L. Human receptors for immunoglobulin G. Arthritsi Rheum 2001;44: 739-50
7. Mechetina LV, Najakshin AM, Volkova OY,et al.FCRL, a novel member of the leukocyte Fc receptor family possesses unique structural features. European Journal of Immunology, 2002,32:87–96.
8. Facchetti F,Cella M, Festa S, et al.An unusual Fc receptor-related protein expressed in human centroblasts.Proceedings of the National Academy of Sciences of the United States of America, 2002,99:3776–3781.
9. Davis RS, Li H, Chen CC, et al.Definition of an Fc receptor-related gene (FcRX) expressed in human and mouse B cells. International Immunology,2002,14: 1075–1083.
10. Kochi Y, Yamada R, Suzuki A,et al.A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet,2005,37:478
11. Ikari K, Momohara S, Nakamura T, et al.Supportive evidence for a geneticassociation of the FCRL3 promoter polymorphism with rheumatoid arthritis. Ann Rheum Dis,2006,65:671
12. Hu X, Chang M, Saiki RK,et al: The functional -169T/C single-nucleotide polymorphism in FCRL3 is not associated with rheumatoid arthritis in white North Americans.Arthritis Rheum 54:1022, 2006.
13.Mart?nez A, Sanchez E, Valdivia A,et al.Epistatic interaction between FCRL3 and NFκB1 genes in Spanish patients with rheumatoid arthritis. Ann Rheum Dis 65:1188, 2006.
14. Leirisalo-Repo M.Reactive arthritis. Scand J Rheumatol.2005,34:251–259
15. Martinez A, Pacheco-Tena C, Vazquez-Mellado J, et al.Relationship between disease activity and infection inpatients with spondyloarthropathies. Ann Rheum Dis ,2004,63:1338–1340
16. Boonen A, de Vet H, van der Heijde D, van der Linden S (2001) Work status and its determinants among patients with ankylosing spondylitis. A systematic literature review. J Rheumatol 28:1056–1062
17. Sims AM, Wordsworth BP, Brown MA.Genetic susceptibility to ankylosing spondylitis. Curr Mol Med ,2004,4:13–20
18. Vazquez MN, Lopez de Castro JA.Similar cell surface expression of beta2-microglobulin-free heavy chains by HLA-B27 subtypes differentially associated with ankylosing spondylitis. Arthritis Rheum,2005,52:3290–3299
19.Kono H, Kyogoku C, Suzuki T, et al.FcgammaRⅡB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum Mol Genet. 2005;14(19):2881-92.
20.Hong CH, Lee JS, Lee HS, Bae SC, Yoo DH.The association between fcgammaRⅡIB polymorphisms and systemic lupus erythematosus in Korea. Lupus. 2005;14(5):346-50.
21.Blank MC, Stefanescu RN, Masuda E, et al.Decreased transcription of the humanFCGR2B gene mediated by the -343 G/C promoter polymorphism and association with systemic lupus erythematosus. Hum Genet. 2005;117(2-3):220-7.
22. Dimitry A. Chistiakov,Alexander P. Chistiakov. Is FCRL3 a New General Autoimmunity Gene? Human Immunology ,2007,68:375–383 .
23. Prokunina L, Alarcon-Riquelme M. The genetic basis of systemic lupus erythematosus: konwledge of today and thoughts tomorrow. Hum Mol Genet 2004; 13,R143-R148
24. Burton PR, Clayton DG, Cardon LR , et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007 Nov;39(11):1329-37
25. Thabet MM, Wesoly J. FCRL3 promoter 169 CC homozygosity is associated with susceptibility to rheumatoid arthritis in Dutch Caucasians. Ann Rheum Dis. 2007 Jun;66(6):803-6
26. Davis RS, et al. Fc receptor homologs: newest members of a remarkably diverse Fc receptor gene family. Immunol Rev 2002;190:123–136
27. Bowcock AM, Cookson WO. The genetics of psoriasis, psoriatic arthritis and atopic dermatitis. Hum Mol Genet. 2004 Apr 1;13 Spec No 1:R43-55.
28. Cantor RM, Yuan J, Napier S, et al. Support for linkage at 1q23, 2q33, 16q12-13, and 17q21-23 and novel evidence at 3p24, 10q23-24, 13q32, and 18q22-23. Arthritis Rheum. 2004:50:3203
29. Kochi Y, Yamada R, Suzuki A, et al. A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet 2005:37:478.
30. Ikari K, Momohara S, Nakamura T, et al. Supportive evidence for a genetic association of the FCRL3 promoter polymorphism with rheumatoid arthritis. Ann Rheum Dis 2006: 65:671
31. Newman WG, Zhang Q, Liu X, et al. Rheumatoid arthritis association with the FCRL3 -169Cpolymorphism is restricted to PTPN22 1858T-homozygous individuals in a Canadian population. Arthritis Rheum. 2006:54:3820.
32. Sanchez E, Callejas JL, Sabio JM,et al. Polymorphisms of the FCRL3 gene in a Spanish population of systemic lupus erythematosus patients. Rheumatology (Oxford) 2006:45:1044
33. Simmonds MJ, Heward JM, Carr-Smith J, et al. Contribution of single nucleotide polymorphisms within FCRL3 and MAP3K7IP2 to the pathogenesis of Graves’disease. J Clin Endocrinol Metab2006: 91:1056
34. Grubi? Z, Zunec R, Stingl K,et al. Haplotipic associations of the two most common HLA-B*27 alleles in the Croatian population. Reumatizam. 2008;55(1):5-9
35.Wei JCC, Tsai WC, Lin HS,et al. HLA-B60 and B61 are strongly associated with ankylosing spondylitis in HLA-B27-negative Taiwan Chinese patients. Rheumatology 2004;43:839–842
36.Kim TJ, Kim TH, Lee HJ,et al. Interleukin 1 polymorphisms in patients with ankylosing spondylitis in Korea. Rheumatol. 2008;35(8):1603-1608
37.Tara Snelgrove, Sooyeol Lim, Celia Greenwood,et al. Association of Toll-like Receptor 4 Variants andAnkylosing Spondylitis: A Case-Control Study. The Journal of Rheumatology 2007; 34:368-370
38.Roberto DP, Miguel Angel BG, Beatriz S,et al. Activating KIR genes are associated with ankylosing spondylitis in Asian populations. Human Immunology 2008:69, 437–442
39. Yen JH, Tsai WC, Chen CJ,et al. Cytochrome P450 1A1 and manganese superoxide dismutase genes polymorphisms in ankylosing spondylitis. Immunology 2003,88:113-116
1. Hatzivassiliou G, Miller I, Takizawa J, Palanisamy N, Rao PH, Iida S, Tagawa S, Taniwaki M, Russo J, Neri A, Cattoretti G, Clynes R, Mendelsohn C, Chaganti RS, Dalla-Favera R. IRTA1 and IRTA2, novel immunoglobulin superfamily receptors expressed in B cells and involved in chromosome 1q21 abnormalities in B cell malignancy. Immunity. 2001;14(3):277-89.
2. Davis RS, Dennis G Jr, Odom MR, Gibson AW, Kimberly RP, Burrows PD, Cooper MD. Fc receptor homologs: newest members of a remarkably diverse Fc receptor gene family. Immunol Rev. 2002;190:123-36.
3. Davis RS, Wang YH, Kubagawa H, Cooper MD. Identification of a family of Fc receptor homologs with preferential B cell expression. Proc Natl Acad Sci U S A. 2001;98(17):9772-7.
4. Nakayama Y, Weissman SM, Bothwell AL. BXMAS1 identifies a cluster of homologous genes differentially expressed in B cells. Biochem Biophys Res Commun. 2001;285(3):830-7.
5. Ershova SA, Naiakshin AM, Mechetina LV, Peklo MM, Shevelev AIa, Vlasik TN, Chikaev NA, Taranin AV. [Expression patterns of the human and mouse IFGP family genes] Mol Biol (Mosk). 2005;39(5):776-85.[Article in Russian]
6. Leu CM, Davis RS, Gartland LA, Fine WD, Cooper MD. FcRH1: an activation coreceptor on human B cells. Blood.;105(3):1121-6.
7. Xu MJ, Zhao R, Zhao ZJ. Molecular cloning and characterization of SPAP1, an inhibitory receptor. Biochem Biophys Res Commun. 2001;280(3):768-75.
8. Xu MJ, Zhao R, Cao H, Zhao ZJ. SPAP2, an Ig family receptor containing both ITIMs and ITAMs. Biochem Biophys Res Commun. 2002;293(3):1037-46.
9. Wilson TJ, Colonna M. A new Fc receptor homolog, FREB2, found in germinal center B cells. Genes Immun. 2005;6(4):341-6.
10. Mechetina LV, Najakshin AM, Volkova OY, Guselnikov SV, Faizulin RZ, Alabyev BY, Chikaev NA, Vinogradova MS, Taranin AV. FCRL, a novel member of the leukocyte Fc receptor family possesses unique structural features. Eur J Immunol. 2002;32(1):87-96.
11. Miller I, Hatzivassiliou G, Cattoretti G, Mendelsohn C, Dalla-Favera R. IRTAs: a new family of immunoglobulinlike receptors differentially expressed in B cells. Blood. 2002;99(8):2662-9.
12. Falini B, Tiacci E, Pucciarini A, Bigerna B, Kurth J, Hatzivassiliou G, Droetto S, Galletti BV, Gambacorta M, Orazi A, Pasqualucci L, Miller I, Kuppers R, Dalla-Favera R, Cattoretti G. Expression of the IRTA1 receptor identifies intraepithelial and subepithelial marginal zone B cells of the mucosa-associated lymphoid tissue (MALT). Blood. 2003;102(10):3684-92.
13. Brown MA, Laval SH, Brophy S, Calin A: Recurrence risk modeling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis 2000,59:883–886.
14. Brown MA, Kennedy LG, MacGregor AJ, et al.: Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum 1997, 40:1823–1828.
15. John D. The Genetic Basis of Spondyloarthritis. Current Rheumatology Reports 2004, 6:117–125.
16. Laval SH, Timms A, Edwards S, et al. Whole-Genome Screening in Ankylosing Spondylitis:Evidence of Non-MHC Genetic-Susceptibility Loci. Am. J. Hum. Genet.2001, 68:918–926
17. Kochi Y, Yamada R, Suzuki A,et al.A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet,2005,37:478
18. Ikari K, Momohara S, Nakamura T, et al.Supportive evidence for a genetic association of the FCRL3 promoter polymorphism with rheumatoid arthritis. Ann Rheum Dis,2006,65:671
19. Hu X, Chang M, Saiki RK,et al: The functional -169T/C single-nucleotide polymorphism in FCRL3 is not associated with rheumatoid arthritis in white North Americans.Arthritis Rheum 54:1022, 2006.
20. Mart?nez A, Sanchez E, Valdivia A,et al.Epistatic interaction between FCRL3 and NFκB1 genes in Spanish patients with rheumatoid arthritis. Ann Rheum Dis 65:1188, 2006.
21. You Y, Wang Z, Deng G, Hao F. Lack of association between Fc receptor-like 3 gene polymorphisms and systemic lupus erythematosus in Chinese population. J Dermatol Sci. 2008;52(2):118-22.
22. Mao C, Pan H, Chen Q, Wang X, Ye D, Qiu L.Association between Fc receptor-like 3 C169T polymorphism and risk of systemic lupus erythematosus: a meta-analysis. Mol Biol Rep. 2009 Jun 30. [Epub ahead of print]
23. Xia G, Pan F, Liao F, Tang X, Ge R, Mei Y, Pan H, Xu S, Xu J. No significantassociation between Fc receptor-like 3 gene polymorphisms and human leukocyte antigen-B27 positive ankylosing spondylitis in Han Chinese population. Mol Biol Rep. 2009 Aug 6. [Epub ahead of print]
24. Tang X, Pan F, Xia G, Liao F, Ge R, Mei Y, Ye D, Xu S, Xu J. A single-nucleotide polymorphism marker within the FCRL5 gene and HLA-B27 positive Han Chinese ankylosing spondylitis patients. Tissue Antigens. 2009;74(4):314-6.
2. Laval SH, Timms A, Edwards S, et al. Whole-Genome Screening in Ankylosing Spondylitis:Evidence of Non-MHC Genetic-Susceptibility Loci. Am. J. Hum. Genet.2001, 68:918–926
3. Brown MA, Laval SH, Brophy S, Calin A: Recurrence risk modeling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis 2000, 59:883–886.
4. Brown MA, Kennedy LG, MacGregor AJ, et al.: Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum 1997, 40:1823–1828.
5. John D. The Genetic Basis of Spondyloarthritis. Current Rheumatology Reports 2004, 6:117–125.
6.Salmon JE, Pricop L. Human receptors for immunoglobulin G. Arthritsi Rheum 2001;44: 739-50
7. Mechetina LV, Najakshin AM, Volkova OY,et al.FCRL, a novel member of the leukocyte Fc receptor family possesses unique structural features. European Journal of Immunology, 2002,32:87–96.
8. Facchetti F,Cella M, Festa S, et al.An unusual Fc receptor-related protein expressed in human centroblasts.Proceedings of the National Academy of Sciences of the United States of America, 2002,99:3776–3781.
9. Davis RS, Li H, Chen CC, et al.Definition of an Fc receptor-related gene (FcRX) expressed in human and mouse B cells. International Immunology,2002,14: 1075–1083.
10. Kochi Y, Yamada R, Suzuki A,et al.A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet,2005,37:478
11. Ikari K, Momohara S, Nakamura T, et al.Supportive evidence for a geneticassociation of the FCRL3 promoter polymorphism with rheumatoid arthritis. Ann Rheum Dis,2006,65:671
12. Hu X, Chang M, Saiki RK,et al: The functional -169T/C single-nucleotide polymorphism in FCRL3 is not associated with rheumatoid arthritis in white North Americans.Arthritis Rheum 54:1022, 2006.
13.Mart?nez A, Sanchez E, Valdivia A,et al.Epistatic interaction between FCRL3 and NFκB1 genes in Spanish patients with rheumatoid arthritis. Ann Rheum Dis 65:1188, 2006.
14. Leirisalo-Repo M.Reactive arthritis. Scand J Rheumatol.2005,34:251–259
15. Martinez A, Pacheco-Tena C, Vazquez-Mellado J, et al.Relationship between disease activity and infection inpatients with spondyloarthropathies. Ann Rheum Dis ,2004,63:1338–1340
16. Boonen A, de Vet H, van der Heijde D, van der Linden S (2001) Work status and its determinants among patients with ankylosing spondylitis. A systematic literature review. J Rheumatol 28:1056–1062
17. Sims AM, Wordsworth BP, Brown MA.Genetic susceptibility to ankylosing spondylitis. Curr Mol Med ,2004,4:13–20
18. Vazquez MN, Lopez de Castro JA.Similar cell surface expression of beta2-microglobulin-free heavy chains by HLA-B27 subtypes differentially associated with ankylosing spondylitis. Arthritis Rheum,2005,52:3290–3299
19.Kono H, Kyogoku C, Suzuki T, et al.FcgammaRⅡB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum Mol Genet. 2005;14(19):2881-92.
20.Hong CH, Lee JS, Lee HS, Bae SC, Yoo DH.The association between fcgammaRⅡIB polymorphisms and systemic lupus erythematosus in Korea. Lupus. 2005;14(5):346-50.
21.Blank MC, Stefanescu RN, Masuda E, et al.Decreased transcription of the humanFCGR2B gene mediated by the -343 G/C promoter polymorphism and association with systemic lupus erythematosus. Hum Genet. 2005;117(2-3):220-7.
22. Dimitry A. Chistiakov,Alexander P. Chistiakov. Is FCRL3 a New General Autoimmunity Gene? Human Immunology ,2007,68:375–383 .
23. Prokunina L, Alarcon-Riquelme M. The genetic basis of systemic lupus erythematosus: konwledge of today and thoughts tomorrow. Hum Mol Genet 2004; 13,R143-R148
24. Burton PR, Clayton DG, Cardon LR , et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007 Nov;39(11):1329-37
25. Thabet MM, Wesoly J. FCRL3 promoter 169 CC homozygosity is associated with susceptibility to rheumatoid arthritis in Dutch Caucasians. Ann Rheum Dis. 2007 Jun;66(6):803-6
26. Davis RS, et al. Fc receptor homologs: newest members of a remarkably diverse Fc receptor gene family. Immunol Rev 2002;190:123–136
27. Bowcock AM, Cookson WO. The genetics of psoriasis, psoriatic arthritis and atopic dermatitis. Hum Mol Genet. 2004 Apr 1;13 Spec No 1:R43-55.
28. Cantor RM, Yuan J, Napier S, et al. Support for linkage at 1q23, 2q33, 16q12-13, and 17q21-23 and novel evidence at 3p24, 10q23-24, 13q32, and 18q22-23. Arthritis Rheum. 2004:50:3203
29. Kochi Y, Yamada R, Suzuki A, et al. A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet 2005:37:478.
30. Ikari K, Momohara S, Nakamura T, et al. Supportive evidence for a genetic association of the FCRL3 promoter polymorphism with rheumatoid arthritis. Ann Rheum Dis 2006: 65:671
31. Newman WG, Zhang Q, Liu X, et al. Rheumatoid arthritis association with the FCRL3 -169Cpolymorphism is restricted to PTPN22 1858T-homozygous individuals in a Canadian population. Arthritis Rheum. 2006:54:3820.
32. Sanchez E, Callejas JL, Sabio JM,et al. Polymorphisms of the FCRL3 gene in a Spanish population of systemic lupus erythematosus patients. Rheumatology (Oxford) 2006:45:1044
33. Simmonds MJ, Heward JM, Carr-Smith J, et al. Contribution of single nucleotide polymorphisms within FCRL3 and MAP3K7IP2 to the pathogenesis of Graves’disease. J Clin Endocrinol Metab2006: 91:1056
34. Grubi? Z, Zunec R, Stingl K,et al. Haplotipic associations of the two most common HLA-B*27 alleles in the Croatian population. Reumatizam. 2008;55(1):5-9
35.Wei JCC, Tsai WC, Lin HS,et al. HLA-B60 and B61 are strongly associated with ankylosing spondylitis in HLA-B27-negative Taiwan Chinese patients. Rheumatology 2004;43:839–842
36.Kim TJ, Kim TH, Lee HJ,et al. Interleukin 1 polymorphisms in patients with ankylosing spondylitis in Korea. Rheumatol. 2008;35(8):1603-1608
37.Tara Snelgrove, Sooyeol Lim, Celia Greenwood,et al. Association of Toll-like Receptor 4 Variants andAnkylosing Spondylitis: A Case-Control Study. The Journal of Rheumatology 2007; 34:368-370
38.Roberto DP, Miguel Angel BG, Beatriz S,et al. Activating KIR genes are associated with ankylosing spondylitis in Asian populations. Human Immunology 2008:69, 437–442
39. Yen JH, Tsai WC, Chen CJ,et al. Cytochrome P450 1A1 and manganese superoxide dismutase genes polymorphisms in ankylosing spondylitis. Immunology 2003,88:113-116
1. Hatzivassiliou G, Miller I, Takizawa J, Palanisamy N, Rao PH, Iida S, Tagawa S, Taniwaki M, Russo J, Neri A, Cattoretti G, Clynes R, Mendelsohn C, Chaganti RS, Dalla-Favera R. IRTA1 and IRTA2, novel immunoglobulin superfamily receptors expressed in B cells and involved in chromosome 1q21 abnormalities in B cell malignancy. Immunity. 2001;14(3):277-89.
2. Davis RS, Dennis G Jr, Odom MR, Gibson AW, Kimberly RP, Burrows PD, Cooper MD. Fc receptor homologs: newest members of a remarkably diverse Fc receptor gene family. Immunol Rev. 2002;190:123-36.
3. Davis RS, Wang YH, Kubagawa H, Cooper MD. Identification of a family of Fc receptor homologs with preferential B cell expression. Proc Natl Acad Sci U S A. 2001;98(17):9772-7.
4. Nakayama Y, Weissman SM, Bothwell AL. BXMAS1 identifies a cluster of homologous genes differentially expressed in B cells. Biochem Biophys Res Commun. 2001;285(3):830-7.
5. Ershova SA, Naiakshin AM, Mechetina LV, Peklo MM, Shevelev AIa, Vlasik TN, Chikaev NA, Taranin AV. [Expression patterns of the human and mouse IFGP family genes] Mol Biol (Mosk). 2005;39(5):776-85.[Article in Russian]
6. Leu CM, Davis RS, Gartland LA, Fine WD, Cooper MD. FcRH1: an activation coreceptor on human B cells. Blood.;105(3):1121-6.
7. Xu MJ, Zhao R, Zhao ZJ. Molecular cloning and characterization of SPAP1, an inhibitory receptor. Biochem Biophys Res Commun. 2001;280(3):768-75.
8. Xu MJ, Zhao R, Cao H, Zhao ZJ. SPAP2, an Ig family receptor containing both ITIMs and ITAMs. Biochem Biophys Res Commun. 2002;293(3):1037-46.
9. Wilson TJ, Colonna M. A new Fc receptor homolog, FREB2, found in germinal center B cells. Genes Immun. 2005;6(4):341-6.
10. Mechetina LV, Najakshin AM, Volkova OY, Guselnikov SV, Faizulin RZ, Alabyev BY, Chikaev NA, Vinogradova MS, Taranin AV. FCRL, a novel member of the leukocyte Fc receptor family possesses unique structural features. Eur J Immunol. 2002;32(1):87-96.
11. Miller I, Hatzivassiliou G, Cattoretti G, Mendelsohn C, Dalla-Favera R. IRTAs: a new family of immunoglobulinlike receptors differentially expressed in B cells. Blood. 2002;99(8):2662-9.
12. Falini B, Tiacci E, Pucciarini A, Bigerna B, Kurth J, Hatzivassiliou G, Droetto S, Galletti BV, Gambacorta M, Orazi A, Pasqualucci L, Miller I, Kuppers R, Dalla-Favera R, Cattoretti G. Expression of the IRTA1 receptor identifies intraepithelial and subepithelial marginal zone B cells of the mucosa-associated lymphoid tissue (MALT). Blood. 2003;102(10):3684-92.
13. Brown MA, Laval SH, Brophy S, Calin A: Recurrence risk modeling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis 2000,59:883–886.
14. Brown MA, Kennedy LG, MacGregor AJ, et al.: Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum 1997, 40:1823–1828.
15. John D. The Genetic Basis of Spondyloarthritis. Current Rheumatology Reports 2004, 6:117–125.
16. Laval SH, Timms A, Edwards S, et al. Whole-Genome Screening in Ankylosing Spondylitis:Evidence of Non-MHC Genetic-Susceptibility Loci. Am. J. Hum. Genet.2001, 68:918–926
17. Kochi Y, Yamada R, Suzuki A,et al.A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet,2005,37:478
18. Ikari K, Momohara S, Nakamura T, et al.Supportive evidence for a genetic association of the FCRL3 promoter polymorphism with rheumatoid arthritis. Ann Rheum Dis,2006,65:671
19. Hu X, Chang M, Saiki RK,et al: The functional -169T/C single-nucleotide polymorphism in FCRL3 is not associated with rheumatoid arthritis in white North Americans.Arthritis Rheum 54:1022, 2006.
20. Mart?nez A, Sanchez E, Valdivia A,et al.Epistatic interaction between FCRL3 and NFκB1 genes in Spanish patients with rheumatoid arthritis. Ann Rheum Dis 65:1188, 2006.
21. You Y, Wang Z, Deng G, Hao F. Lack of association between Fc receptor-like 3 gene polymorphisms and systemic lupus erythematosus in Chinese population. J Dermatol Sci. 2008;52(2):118-22.
22. Mao C, Pan H, Chen Q, Wang X, Ye D, Qiu L.Association between Fc receptor-like 3 C169T polymorphism and risk of systemic lupus erythematosus: a meta-analysis. Mol Biol Rep. 2009 Jun 30. [Epub ahead of print]
23. Xia G, Pan F, Liao F, Tang X, Ge R, Mei Y, Pan H, Xu S, Xu J. No significantassociation between Fc receptor-like 3 gene polymorphisms and human leukocyte antigen-B27 positive ankylosing spondylitis in Han Chinese population. Mol Biol Rep. 2009 Aug 6. [Epub ahead of print]
24. Tang X, Pan F, Xia G, Liao F, Ge R, Mei Y, Ye D, Xu S, Xu J. A single-nucleotide polymorphism marker within the FCRL5 gene and HLA-B27 positive Han Chinese ankylosing spondylitis patients. Tissue Antigens. 2009;74(4):314-6.