TBX21基因多态性与类风湿关节炎相关性的研究
摘要
目的:研究转录因子TBX21基因在rs4794067, rs2240017 ,rs17250932, rs2074190和rs12721470位点的单核苷酸多态性( SNPs),探讨其与中国汉族人群类风湿性关节炎(RA)易感性之间的关系。
方法:采用单碱基延伸法( SBE)检测288例RA患者和288名正常健康者TBX21基因的5个SNPs:rs4794067, rs2240017 ,rs17250932, rs2074190和rs12721470的基因型。
结果:5个SNP位点的基因型均符合Hardy-Weinberg平衡(P>0.05)。rs12721470位点的基因型频率和等位基因频率在RA组和对照组间的差别具有统计学意义。rs4794067位点的基因型频率在RA组和对照组间无统计学差异,而等位基因频率在RA组和对照组间的差异则具有统计学意义((P<0.05)。rs17250932,rs2240017和rs12721470基因型及等位基因频率在RA组和对照组间无统计学意义(P>0.05)。
结论:TBX21基因单核酸多态性rs12721470与中国汉人群类风湿关节炎是显著相关联的。
Objective :To investigate the relationship between the single nucleotide polymorphisms ( SNPs) of TBX21 gene with rheumatoid arthritis (RA) in Chinese Han population.
Methods : The SNPs of TBX21 gene ( rs4794067, rs2240017 ,rs17250932, rs2074190 and rs12721470) in 288 patients with RA and 288 healthy controls were determined, and relationship between TBX21gene SNPs and patients with RA SNPs genotyping were performed by a method of Single Base Extension ( SBE).
Results : All the genotype frequencies of these SNPs were in Hardy- Weinberg equilibrium (HWE) (P>0.05). The genotype and allele frequencies of the rs12721470 polymorphism in the RA patients were significantly different from those of the healthy control group. The genotype frequencies of rs4794067 were not significant between patients with RA and healthy controls , but allele frequencies of the rs12721470 polymorphism were significantly(P<0.05). There were not significant differences in genotypes and allele frequency distribution of rs17250932,rs2240017and rs12721470 between patients with RA and healthy controls ( P > 0. 05).
Conclusion :TBX21 polymorphisms analyzed in the present study are the susceptible genes for rheumatoid arthritis (RA) in Chinese Han ethnicity.
方法:采用单碱基延伸法( SBE)检测288例RA患者和288名正常健康者TBX21基因的5个SNPs:rs4794067, rs2240017 ,rs17250932, rs2074190和rs12721470的基因型。
结果:5个SNP位点的基因型均符合Hardy-Weinberg平衡(P>0.05)。rs12721470位点的基因型频率和等位基因频率在RA组和对照组间的差别具有统计学意义。rs4794067位点的基因型频率在RA组和对照组间无统计学差异,而等位基因频率在RA组和对照组间的差异则具有统计学意义((P<0.05)。rs17250932,rs2240017和rs12721470基因型及等位基因频率在RA组和对照组间无统计学意义(P>0.05)。
结论:TBX21基因单核酸多态性rs12721470与中国汉人群类风湿关节炎是显著相关联的。
Objective :To investigate the relationship between the single nucleotide polymorphisms ( SNPs) of TBX21 gene with rheumatoid arthritis (RA) in Chinese Han population.
Methods : The SNPs of TBX21 gene ( rs4794067, rs2240017 ,rs17250932, rs2074190 and rs12721470) in 288 patients with RA and 288 healthy controls were determined, and relationship between TBX21gene SNPs and patients with RA SNPs genotyping were performed by a method of Single Base Extension ( SBE).
Results : All the genotype frequencies of these SNPs were in Hardy- Weinberg equilibrium (HWE) (P>0.05). The genotype and allele frequencies of the rs12721470 polymorphism in the RA patients were significantly different from those of the healthy control group. The genotype frequencies of rs4794067 were not significant between patients with RA and healthy controls , but allele frequencies of the rs12721470 polymorphism were significantly(P<0.05). There were not significant differences in genotypes and allele frequency distribution of rs17250932,rs2240017and rs12721470 between patients with RA and healthy controls ( P > 0. 05).
Conclusion :TBX21 polymorphisms analyzed in the present study are the susceptible genes for rheumatoid arthritis (RA) in Chinese Han ethnicity.
引文
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[3] Firestein GS. Evolving concepts of rheumatoid arthritis[J]. Nature ,2003,423:356–61.
[4] Merete Pedersen, S?ren Jacobsen, Mette Klarlund. Environmental risk factors differ between rheumatoid arthritis with and without auto-antibodies against cyclic citrullinated peptides[J]. Arthritis Res Ther, 2006, 8(4): R133.
[5] Ted R, Mikuls, Laura B. Cigarette smoking, disease severity, and autoantibody expression in African Americans with recent-onset rheumatoid arthritis Ann Rheum Dis[J]. 2008 November,67(11): 1529–1534.
[6]Silman AJ, MacGregor AJ, Thomson W et al. Twin concordance rates for rheumatoid arthritis: results from a nationwide study[J]. Br J Rheumatol ,1993,32:903–7.
[7]Seldin MF, Amos CI, Ward R, Gregersen PK. The genetics revolution and the assault on rheumatoid arthritis[J]. Arthritis Rheum ,1999,42:1071–9.
[8] Loots GG,Locksley RM,Blankespoor CM,et al.Identification of a coordinate regulator of interleukins4,13,and5bycross-speciesequencecomparisons[J].Science,2000,288(5463):136–140。
[9] Newton JL, Harney SM, Wordsworth BP, Brown MA. A review of the MHC genetics of rheumatoid arthritis[J]. Genes Immun ,2004,5:151–7.
[10]Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis: An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis[J].Arthritis Rheum ,1987,30:1205–13.
[11] Sabatos CA,Chakravarti S,Cha E,et al.Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance[J].Nat. Immunol,2003,4(11):1102–1110.
[12]Simmons WJ,Koneru M,Mohindru M,et al.Tim-3C,T-betC tumor-specific Th1 cells colocalize with and inhibit development and growth of murine neoplasms[J].Immunol,2005,174:1405–1415.
[13] Hill RJ, Zozulya S, Lu YL, Ward K, Gishizky M, Jallal B. The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation[J]. Exp Hematol ,2002,30:237–44.
[14] Lee HS, Remmers EF, Le JM, Kastner DL, Bae SC, Gregersen PK. Association of STAT4 with rheumatoid arthritis in the Korean population[J]. Mol Med ,2007,13:455–60.
[15] Remmers EF, Plenge RM, Lee AT et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus[J]. N Engl J Med ,2007,357:977–86
[16] Plenge RM, Cotsapas C, Davies L et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis[J]. Nat Genet,2007,39:1477–82.
[17] Plenge RM, Seielstad M, Padyukov L et al. TRAF1-C5 as a risk locus for rheumatoid arthritis– a genomewide study[J]. N Eng Med ,2007,357:1199–209.
[18] Go?b V, DieudéP, Vittecoq O, et al.Association between the TNFRII 196R allele and diagnosis of rheumatoid arthritis[J]. Arthritis Res Ther.,2005,7(5):R1056-62.
[19] Jaworski J, Maslinski W, Pazdur J et al Decreased expression of integrins by hematopoietic cells in patients with rheumatoid arthritis and anemia: relationship with bone marrow cytokine levels[J]. J Investig Allergol Clin Immunol.,2008,18(1):17-21.
[20] Angel Gonzalez, Murat Icen, Hilal Maradit Kremers.Mortality Trends in Rheumatoid Arthritis: The role of Rheumatoid Factor [J].Rheumatol,2008,35(6): 1009–1014.
[21] Timothy R.Mosmann, Holly Cherwinski, et al.Two types of murine helper T cellclone Definition according to profiles of lymphokine activities and secreted proteins[J].Immunol,1986,136(7):2348-2357.
[22] O’Garra A,Arai N.The molecular basis of T helper 1 and T helper 2 cell differentiation[J].Trends Cell Biol,2000,10(12):542-550.
[23] Abbas AK,Murphy KM,Sher A.Functional diversity of helper T lymphocytes[J]. Nature,1996,383(6603):787–793.
[24] Liblau RS,Singer SM,McDevitt HO,et al.Th1 and Th2 CD4+T cells in The pathogenesis of organ-specific autoimmune diseases[J].Immunol Today,1995,16(1):34–38.
[25]Szabo SJ,Sullivan BM,Peng SL,et al.Molecular mechanisms regulating Th1 immuneresponses.Annu[J]. Rev Immunol,2003,21:713–758.
[26] Sher,A,Coffman,R.L.Regulation of immunity to parasites by T cells and T cell-derived cytokines[J].Annu Rev Immunol,1992,10:385–409.
[27]Pawlik A,Ostanek L,Brzosko I,et al.The expansion of CD4+CD28-T cells in patients wiTh rheumatoid arthritis[J].Arthritis Res Ther, 2003,5(4): R210-213.
[28]Hewaat D,De Keyser F,DeWeverN,et a1. A comparative phenotypical analysis of rheumatoid nodules and rhetmmtoid synovium with special reference to adhesion mo1ecules and activation markers[J].Ann Rheum Dis,1998,57,480一486.
[29]陈红波,涂胜豪,胡永红.单核苷酸多态性在类风湿关节炎中的研究进展[J].中华风湿病学杂志,2004,8(3):171-173.
[30] Collins FS, Partinos A, Jordan E, et al. New goals for the US Human Genome Project:1998-2003[J]. Science ,1998,282(5389):682-689.
[31] Marshall E. NIH plans peer-review overhaul[J]. Science,1997,276(5314):888-889.
[32] Alina Deshpande, Yolanda Valdez, et al. Multiplexed SNP Genotyping Using Primer Single‐Base Extension (SBE) and Microsphere Arrays[J], Curr Protoc Cytom.,2005 , 13:13-4.
[33] Szabo SJ,Kim ST, Costa GL,et al. A novel transcription factor, T-bet, directs Th1 lineage commitment[J]. Cell , 2000,100: 655-669.
[34]. Mullen AC,High FA, Hutchins A, et al.Role of T-bet in commitment of T(H)1 cells before IL-12-dependent selection[J]. Science ,292: 1907-1910, 2001.
[35] Finotto S,Neurath MF,Glickman JN, Qin S,et al Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet[J]. Science, 295: 336-338, 2002.
[36]Akahoshi M, Obara K, HirotaT, Matsuda, et al.Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma[J]. Hum Genet,2005,117: 16-26.
[37] Shakhov AN,Rybtsov S,Tumanov AV,et al.SMUCKLER/TIM4 is a distinct member of TIM family expressed by stromal cells of secondary lymphoid tissues and associated with lymphotoxin signaling[J].Immunol,2004,34(2):494–503.
[38] Wang J, Fathman J W, Lugo-Villarino G, et al. Transcription factor T-bet regulatesinflammatory arthritis through its function in dendritic cells. J. Clin. Invest. 116: 414-421, 2006.
[39] Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties[J]. Annu Rev Immunol ,1989,7:145-73.
[40] Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes[J] . Nature ,1996,383:787-93.
[41]Murphy KM, Reiner SL.The lineage decisions of helper T cells[J]. Nature Rev Immunol ,2002,2:933-44.
[42] Szabo SJ, Sullivan BM, Stemmann C, et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-γ? production in CD4+ and CD8+ T cells[J]. Science, 2002, 295:338-42.
[43] Yin Z, Chen C, Szabo SJ, et al. T-Bet expression and failure of GATA-3 cross-regulation lead to default production of IFN-γbyγδT cells[J]. J Immunol, 2002, 168:1566-71.
[44] Kuchroo VK, Das MP, Brown JA, et al. B7-1 and B7-2 costimulatory molecules differentially activate the TH1/TH2 developmental pathways: application to autoimmune disease therapy[J]. Cell ,1995,80:707-16.
[45] Klimiuk PA,Goronzy JJ,Weyand CM. IL-16 as an anti-inflammatory cytokine in rheumatoid synovitis[J]. J Immunol. 1999, 162:4293.
[46]Suzuki M, Konya C, Goronzy JJ, Weyand CM. Inhibitory CD8+ T cells in autoimmune disease[J].Hum Immunol. 2008 ,69:781-9.
[47]Soo-Cheon Chae, Seung-Cheol Shim,Hun-Taeg Chung .Association of TBX21 polymorphisms in a Korean population with rheumatoid arthritis[J]. Exp Mol Med, 2009 , 41: 1,33-41.
[2] McIntire JJ, Umetsu SE, Akbari O,et al..Identification of Tapr an airway hyperreactivity regulatory locus)and the linked Tim gene family[J].Nat Immunol,2001,2(12):1109-1116.
[3] Firestein GS. Evolving concepts of rheumatoid arthritis[J]. Nature ,2003,423:356–61.
[4] Merete Pedersen, S?ren Jacobsen, Mette Klarlund. Environmental risk factors differ between rheumatoid arthritis with and without auto-antibodies against cyclic citrullinated peptides[J]. Arthritis Res Ther, 2006, 8(4): R133.
[5] Ted R, Mikuls, Laura B. Cigarette smoking, disease severity, and autoantibody expression in African Americans with recent-onset rheumatoid arthritis Ann Rheum Dis[J]. 2008 November,67(11): 1529–1534.
[6]Silman AJ, MacGregor AJ, Thomson W et al. Twin concordance rates for rheumatoid arthritis: results from a nationwide study[J]. Br J Rheumatol ,1993,32:903–7.
[7]Seldin MF, Amos CI, Ward R, Gregersen PK. The genetics revolution and the assault on rheumatoid arthritis[J]. Arthritis Rheum ,1999,42:1071–9.
[8] Loots GG,Locksley RM,Blankespoor CM,et al.Identification of a coordinate regulator of interleukins4,13,and5bycross-speciesequencecomparisons[J].Science,2000,288(5463):136–140。
[9] Newton JL, Harney SM, Wordsworth BP, Brown MA. A review of the MHC genetics of rheumatoid arthritis[J]. Genes Immun ,2004,5:151–7.
[10]Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis: An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis[J].Arthritis Rheum ,1987,30:1205–13.
[11] Sabatos CA,Chakravarti S,Cha E,et al.Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance[J].Nat. Immunol,2003,4(11):1102–1110.
[12]Simmons WJ,Koneru M,Mohindru M,et al.Tim-3C,T-betC tumor-specific Th1 cells colocalize with and inhibit development and growth of murine neoplasms[J].Immunol,2005,174:1405–1415.
[13] Hill RJ, Zozulya S, Lu YL, Ward K, Gishizky M, Jallal B. The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation[J]. Exp Hematol ,2002,30:237–44.
[14] Lee HS, Remmers EF, Le JM, Kastner DL, Bae SC, Gregersen PK. Association of STAT4 with rheumatoid arthritis in the Korean population[J]. Mol Med ,2007,13:455–60.
[15] Remmers EF, Plenge RM, Lee AT et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus[J]. N Engl J Med ,2007,357:977–86
[16] Plenge RM, Cotsapas C, Davies L et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis[J]. Nat Genet,2007,39:1477–82.
[17] Plenge RM, Seielstad M, Padyukov L et al. TRAF1-C5 as a risk locus for rheumatoid arthritis– a genomewide study[J]. N Eng Med ,2007,357:1199–209.
[18] Go?b V, DieudéP, Vittecoq O, et al.Association between the TNFRII 196R allele and diagnosis of rheumatoid arthritis[J]. Arthritis Res Ther.,2005,7(5):R1056-62.
[19] Jaworski J, Maslinski W, Pazdur J et al Decreased expression of integrins by hematopoietic cells in patients with rheumatoid arthritis and anemia: relationship with bone marrow cytokine levels[J]. J Investig Allergol Clin Immunol.,2008,18(1):17-21.
[20] Angel Gonzalez, Murat Icen, Hilal Maradit Kremers.Mortality Trends in Rheumatoid Arthritis: The role of Rheumatoid Factor [J].Rheumatol,2008,35(6): 1009–1014.
[21] Timothy R.Mosmann, Holly Cherwinski, et al.Two types of murine helper T cellclone Definition according to profiles of lymphokine activities and secreted proteins[J].Immunol,1986,136(7):2348-2357.
[22] O’Garra A,Arai N.The molecular basis of T helper 1 and T helper 2 cell differentiation[J].Trends Cell Biol,2000,10(12):542-550.
[23] Abbas AK,Murphy KM,Sher A.Functional diversity of helper T lymphocytes[J]. Nature,1996,383(6603):787–793.
[24] Liblau RS,Singer SM,McDevitt HO,et al.Th1 and Th2 CD4+T cells in The pathogenesis of organ-specific autoimmune diseases[J].Immunol Today,1995,16(1):34–38.
[25]Szabo SJ,Sullivan BM,Peng SL,et al.Molecular mechanisms regulating Th1 immuneresponses.Annu[J]. Rev Immunol,2003,21:713–758.
[26] Sher,A,Coffman,R.L.Regulation of immunity to parasites by T cells and T cell-derived cytokines[J].Annu Rev Immunol,1992,10:385–409.
[27]Pawlik A,Ostanek L,Brzosko I,et al.The expansion of CD4+CD28-T cells in patients wiTh rheumatoid arthritis[J].Arthritis Res Ther, 2003,5(4): R210-213.
[28]Hewaat D,De Keyser F,DeWeverN,et a1. A comparative phenotypical analysis of rheumatoid nodules and rhetmmtoid synovium with special reference to adhesion mo1ecules and activation markers[J].Ann Rheum Dis,1998,57,480一486.
[29]陈红波,涂胜豪,胡永红.单核苷酸多态性在类风湿关节炎中的研究进展[J].中华风湿病学杂志,2004,8(3):171-173.
[30] Collins FS, Partinos A, Jordan E, et al. New goals for the US Human Genome Project:1998-2003[J]. Science ,1998,282(5389):682-689.
[31] Marshall E. NIH plans peer-review overhaul[J]. Science,1997,276(5314):888-889.
[32] Alina Deshpande, Yolanda Valdez, et al. Multiplexed SNP Genotyping Using Primer Single‐Base Extension (SBE) and Microsphere Arrays[J], Curr Protoc Cytom.,2005 , 13:13-4.
[33] Szabo SJ,Kim ST, Costa GL,et al. A novel transcription factor, T-bet, directs Th1 lineage commitment[J]. Cell , 2000,100: 655-669.
[34]. Mullen AC,High FA, Hutchins A, et al.Role of T-bet in commitment of T(H)1 cells before IL-12-dependent selection[J]. Science ,292: 1907-1910, 2001.
[35] Finotto S,Neurath MF,Glickman JN, Qin S,et al Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet[J]. Science, 295: 336-338, 2002.
[36]Akahoshi M, Obara K, HirotaT, Matsuda, et al.Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma[J]. Hum Genet,2005,117: 16-26.
[37] Shakhov AN,Rybtsov S,Tumanov AV,et al.SMUCKLER/TIM4 is a distinct member of TIM family expressed by stromal cells of secondary lymphoid tissues and associated with lymphotoxin signaling[J].Immunol,2004,34(2):494–503.
[38] Wang J, Fathman J W, Lugo-Villarino G, et al. Transcription factor T-bet regulatesinflammatory arthritis through its function in dendritic cells. J. Clin. Invest. 116: 414-421, 2006.
[39] Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties[J]. Annu Rev Immunol ,1989,7:145-73.
[40] Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes[J] . Nature ,1996,383:787-93.
[41]Murphy KM, Reiner SL.The lineage decisions of helper T cells[J]. Nature Rev Immunol ,2002,2:933-44.
[42] Szabo SJ, Sullivan BM, Stemmann C, et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-γ? production in CD4+ and CD8+ T cells[J]. Science, 2002, 295:338-42.
[43] Yin Z, Chen C, Szabo SJ, et al. T-Bet expression and failure of GATA-3 cross-regulation lead to default production of IFN-γbyγδT cells[J]. J Immunol, 2002, 168:1566-71.
[44] Kuchroo VK, Das MP, Brown JA, et al. B7-1 and B7-2 costimulatory molecules differentially activate the TH1/TH2 developmental pathways: application to autoimmune disease therapy[J]. Cell ,1995,80:707-16.
[45] Klimiuk PA,Goronzy JJ,Weyand CM. IL-16 as an anti-inflammatory cytokine in rheumatoid synovitis[J]. J Immunol. 1999, 162:4293.
[46]Suzuki M, Konya C, Goronzy JJ, Weyand CM. Inhibitory CD8+ T cells in autoimmune disease[J].Hum Immunol. 2008 ,69:781-9.
[47]Soo-Cheon Chae, Seung-Cheol Shim,Hun-Taeg Chung .Association of TBX21 polymorphisms in a Korean population with rheumatoid arthritis[J]. Exp Mol Med, 2009 , 41: 1,33-41.