STAT4基因rs7574865位点多态性与武陵山地区类风湿性关节炎具有相关性
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摘要
目的探讨信号转导子与转录激活子4(STAT4) rs7574865和miRNA146a rs2910164基因单核苷酸多态性(SNP)与武陵山地区类风湿性关节炎(RA)的相关性。方法选择287例RA患者和同期305例体检的健康人群为对照组,采用多重PCR结合高通量测序技术(Hi-SNP)测定RA患者和同期对照人群rs7574865和rs2910164位点基因型,用χ2检验比较分析两组人群中基因型和等位基因型频率分布,并分析这两个位点多态性与RA发病风险的相关性以及与患者类风湿因子(RF)和抗环瓜氨酸肽(ACCP)抗体水平的相关性。结果 rs7574865位点的基因型频率在两组间存在统计学差异,TT基因型和T等位基因均是RA的易感因素(OR=2. 42,95%CI:1. 37～4. 28; OR=1. 43,95%CI:1. 12～1. 82),同时显性模型和隐性模型也显示与RA的发病易感相关。rs2910164位点单核苷酸多态性与RA易感性无关,并且rs7574865和rs2910164位点多态性与RF和ACCP抗体水平均无显著相关性。结论 STAT4 rs7574865位点单核苷酸多态与武陵山地区RA的发病相关,与患者RF和ACCP抗体水平无关;而miRNA146a rs2910164多态性与RA无显著相关性。
Objective To investigate the association of single nucleotide polymorphisms( SNPs) of signal transducerand activator of transcription 4( STAT4) rs7574865 and miRNA146 a rs2910164 with rheumatoid arthritis( RA) in Wulingmountain area. Methods 287 RA patients and 305 age-matched healthy controls were included. The rs7574865 andrs2910164 SNPs of RA patients and control subjects were measured by multiplex PCR combined with high throughputsequencing( HI-SNP). The distributions of genotype and allele frequencies in the two groups were analyzed by theChi-squared test,and also the relationship between these two SNPs and the risk of RA,rheumatoid factor( RF) and anti-cycliccitrullinated peptide( ACCP) antibody were investigated. Results Data showed that the genotype distribution of rs7574865 were significantly different between the cases and controls. The TT genotype and the T allele from rs7574865 were allassociated with the risk of RA( OR = 2. 42,95% CI: 1. 37-4. 28; OR = 1. 43,95% CI: 1. 12-1. 82),and dominant andrecessive models showed similar results. While,we found miRNA146 a rs2910164 has no role in susceptibility to RA,andthere was no statistically significant association between the SNPs of rs7574865 and rs2910164 and the level of RF or ACCPantibody. Conclusion STAT4 rs7574865 polymorphism is associated with RA,but not with RF or ACCP antibody levels inWuling mountain area. In contrast,miRNA146 a rs2910164 polymorphism is not correlated with RA.
Objective To investigate the association of single nucleotide polymorphisms( SNPs) of signal transducerand activator of transcription 4( STAT4) rs7574865 and miRNA146 a rs2910164 with rheumatoid arthritis( RA) in Wulingmountain area. Methods 287 RA patients and 305 age-matched healthy controls were included. The rs7574865 andrs2910164 SNPs of RA patients and control subjects were measured by multiplex PCR combined with high throughputsequencing( HI-SNP). The distributions of genotype and allele frequencies in the two groups were analyzed by theChi-squared test,and also the relationship between these two SNPs and the risk of RA,rheumatoid factor( RF) and anti-cycliccitrullinated peptide( ACCP) antibody were investigated. Results Data showed that the genotype distribution of rs7574865 were significantly different between the cases and controls. The TT genotype and the T allele from rs7574865 were allassociated with the risk of RA( OR = 2. 42,95% CI: 1. 37-4. 28; OR = 1. 43,95% CI: 1. 12-1. 82),and dominant andrecessive models showed similar results. While,we found miRNA146 a rs2910164 has no role in susceptibility to RA,andthere was no statistically significant association between the SNPs of rs7574865 and rs2910164 and the level of RF or ACCPantibody. Conclusion STAT4 rs7574865 polymorphism is associated with RA,but not with RF or ACCP antibody levels inWuling mountain area. In contrast,miRNA146 a rs2910164 polymorphism is not correlated with RA.
引文
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[6]Liang Y L,Wu H,Shen X,et al. Association of STAT4 rs7574865polymorphism with autoimmune diseases:a meta-analysis[J]. MolBiol Rep,2012,39(9):8873-8882.
[7]Taganov K D,Boldin M P,Chang K J,et al. NF-kappaB-dependentinduction of microRNA miR-146,an inhibitor targeted to signalingproteins of innate immune responses[J]. Proc Natl Acad Sci U S A,2006,103(33):12481-12486.
[8] Li C,Fu W,Zhang Y,et al. Meta-analysis of microRNA-146ars2910164 G> C polymorphism association with autoimmune diseasessusceptibility,an update based on 24 studies[J/OL]. PLo S One,2015,10(4):e0121918. DOI:10. 1371/journal. pone. 0121918.e Collection 2015.
[9]王姣,齐晓明,张小珍,等. ARL15、HLA-DMA基因多态性与中国西北地区汉族人群类风湿性关节炎易感性相关[J].细胞与分子免疫学杂志,2017,33(12):1684-1685.
[10]Rodríguez-Elías A K,Maldonado-Murillo K,López-Mendoza L F,et al.Genetics and genomics in rheumatoid arthritis(RA):An update[J]. Gac Med Mex,2016,152(2):218-227.
[11]Barton A,Worthington J. Genetic susceptibility to rheumatoid arthritis:an emerging picture[J]. Arthritis Rheum, 2010, 61(10):1441-1446.
[12]郑立明,周红. STAT4 rs7574865位点单核苷酸多态性与江苏部分地区汉族人群原发性胆汁性肝硬化相关[J].细胞与分子免疫学杂志,2017,33(4):521-525.
[13]Schwarting A,Tesch G,Kinoshita K,et al. IL-12 drives IFN-gamma-dependent autoimmune kidney disease in MRL-Fas(lpr)mice[J].J Immunol,1999,163(12):6884-6891.
[14] Gu E,Lu J,Xing D,et al. Rs7574865 polymorphism in signaltransducers and activators of transcription 4 gene and rheumatoidarthritis:an updated meta-analysis of 28 case-control comparisons[J]. Int J Rheum Dis,2015,18(1):3-16.
[15]Liang Y L,Wu H,Li P Q,et al. Signal transducer and activator oftranscription 4 gene polymorphisms associated with rheumatoidarthritis in Northwestern Chinese Han population[J]. Life Sci,2011,89(5/6):171-175.
[16]杨美娟,张东,张敏,等. STAT4、PSORS1C1基因多态性与兰州汉族RA易感性关系研究[J].免疫学杂志,2018(7):618-624.
[17]庞红梅,舒荣,崔刘福,等.信号转导和转录激活因子4基因多态性与类风湿关节炎发病的相关性[J].苏州大学学报(医学版),2010,30(3):548-550.
[18]梁爱凤,费樱,程萍,等. STAT4基因多态性与类风湿性关节炎相关性研究[J].贵州医科大学学报,2012,37(4):372-375.
[19]徐振兴,陈进春,邱明山,等. 5种单核苷酸多态性与厦门地区汉族人群类风湿关节炎易感性的关系[J].广东医学,2016,37(7):1003-1006.
[20]魏萌,谢庆云,王涛,等.信号传导和转录活化因子-4的单核苷酸多态性与中国汉族人类风湿关节炎的相关性研究[J].中华风湿病学杂志,2016(2):83-87.
[21] El-Lebedy D,Raslan H,Ibrahim A,et al. Association of STAT4rs7574865 and PTPN22 rs2476601 polymorphisms with rheumatoidarthritis and non-systemically reacting antibodies in Egyptian patients[J]. Clin Rheumatol,2017,36(9):1981-1987.
[22]Durán-Avelar M J,Vibanco-Pérez N,Hernández-Pacheco R R,et al.STAT4 rs7574865 G/T polymorphism is associated with rheumatoidarthritis and disease activity,but not with anti-CCP antibody levels ina Mexican population[J]. Clin Rheumatol, 2016, 35(12):2909-2914.
[23]Bae S C,Lee Y H. miR-146a levels in rheumatoid arthritis and theircorrelation with disease activity:a meta-analysis[J]. Int J RheumDis,2018,21(7):1335-1342.
[24]Elshal A S,Aly N M,Galil S M,et al. Association of microRNAsgenes polymorphisms with rheumatoid arthritis in Egyptian femalepatients[J]. Joint Bone Spine,2013,80(6):626-631.
[25] Shaker O G,El Boghdady N A,El Sayed A E. Association ofmiRNA-146a,miRNA-499,IRAK1 and PADI4 polymorphisms withrheumatoid arthritis in Egyptian population[J]. Cell PhysiolBiochem,2018,46(6):2239-2249.
[26]Ciccacci C,Conigliaro P,Perricone C,et al. Polymorphisms inSTAT-4, IL-10, PSORS1C1, PTPN2 and miR146A genes areassociated differently with prognostic factors in Italian patientsaffected by rheumatoid arthritis[J]. Clin Exp Immunol,2016,186(2):157-163.
[27]Li K,Tie H,Hu N,et al. Association of two polymorphismsrs2910164 in miRNA-146a and rs3746444 in miRNA-499 withrheumatoid arthritis:A meta-analysis[J]. Hum Immunol,2014,75(7):602-608.
[2]Karlson E W,van Schaardenburg D,van der Helm-van Mil A H.Strategies to predict rheumatoid arthritis development in at-riskpopulations[J]. Rheumatology(Oxford),2016,55(1):6-15.
[3]Watford W T,Hissong B D,Bream J H,et al. Signaling by IL-12and IL-23 and the immunoregulatory roles of STAT4[J]. ImmunolRev,2004,202:139-156.
[4]Mathur A N,Chang H C,Zisoulis D G,et al. Stat3 and Stat4 directdevelopment of IL-17-secreting Th cells[J]. J Immunol,2007,178(8):4901-4907.
[5]Beltrán Ramírez O,Mendoza Rincón J F,Barbosa Cobos R E,et al.STAT4 confers risk for rheumatoid arthritis and systemic lupuserythematosus in Mexican patients[J]. Immunol Lett,2016,175:40-43.
[6]Liang Y L,Wu H,Shen X,et al. Association of STAT4 rs7574865polymorphism with autoimmune diseases:a meta-analysis[J]. MolBiol Rep,2012,39(9):8873-8882.
[7]Taganov K D,Boldin M P,Chang K J,et al. NF-kappaB-dependentinduction of microRNA miR-146,an inhibitor targeted to signalingproteins of innate immune responses[J]. Proc Natl Acad Sci U S A,2006,103(33):12481-12486.
[8] Li C,Fu W,Zhang Y,et al. Meta-analysis of microRNA-146ars2910164 G> C polymorphism association with autoimmune diseasessusceptibility,an update based on 24 studies[J/OL]. PLo S One,2015,10(4):e0121918. DOI:10. 1371/journal. pone. 0121918.e Collection 2015.
[9]王姣,齐晓明,张小珍,等. ARL15、HLA-DMA基因多态性与中国西北地区汉族人群类风湿性关节炎易感性相关[J].细胞与分子免疫学杂志,2017,33(12):1684-1685.
[10]Rodríguez-Elías A K,Maldonado-Murillo K,López-Mendoza L F,et al.Genetics and genomics in rheumatoid arthritis(RA):An update[J]. Gac Med Mex,2016,152(2):218-227.
[11]Barton A,Worthington J. Genetic susceptibility to rheumatoid arthritis:an emerging picture[J]. Arthritis Rheum, 2010, 61(10):1441-1446.
[12]郑立明,周红. STAT4 rs7574865位点单核苷酸多态性与江苏部分地区汉族人群原发性胆汁性肝硬化相关[J].细胞与分子免疫学杂志,2017,33(4):521-525.
[13]Schwarting A,Tesch G,Kinoshita K,et al. IL-12 drives IFN-gamma-dependent autoimmune kidney disease in MRL-Fas(lpr)mice[J].J Immunol,1999,163(12):6884-6891.
[14] Gu E,Lu J,Xing D,et al. Rs7574865 polymorphism in signaltransducers and activators of transcription 4 gene and rheumatoidarthritis:an updated meta-analysis of 28 case-control comparisons[J]. Int J Rheum Dis,2015,18(1):3-16.
[15]Liang Y L,Wu H,Li P Q,et al. Signal transducer and activator oftranscription 4 gene polymorphisms associated with rheumatoidarthritis in Northwestern Chinese Han population[J]. Life Sci,2011,89(5/6):171-175.
[16]杨美娟,张东,张敏,等. STAT4、PSORS1C1基因多态性与兰州汉族RA易感性关系研究[J].免疫学杂志,2018(7):618-624.
[17]庞红梅,舒荣,崔刘福,等.信号转导和转录激活因子4基因多态性与类风湿关节炎发病的相关性[J].苏州大学学报(医学版),2010,30(3):548-550.
[18]梁爱凤,费樱,程萍,等. STAT4基因多态性与类风湿性关节炎相关性研究[J].贵州医科大学学报,2012,37(4):372-375.
[19]徐振兴,陈进春,邱明山,等. 5种单核苷酸多态性与厦门地区汉族人群类风湿关节炎易感性的关系[J].广东医学,2016,37(7):1003-1006.
[20]魏萌,谢庆云,王涛,等.信号传导和转录活化因子-4的单核苷酸多态性与中国汉族人类风湿关节炎的相关性研究[J].中华风湿病学杂志,2016(2):83-87.
[21] El-Lebedy D,Raslan H,Ibrahim A,et al. Association of STAT4rs7574865 and PTPN22 rs2476601 polymorphisms with rheumatoidarthritis and non-systemically reacting antibodies in Egyptian patients[J]. Clin Rheumatol,2017,36(9):1981-1987.
[22]Durán-Avelar M J,Vibanco-Pérez N,Hernández-Pacheco R R,et al.STAT4 rs7574865 G/T polymorphism is associated with rheumatoidarthritis and disease activity,but not with anti-CCP antibody levels ina Mexican population[J]. Clin Rheumatol, 2016, 35(12):2909-2914.
[23]Bae S C,Lee Y H. miR-146a levels in rheumatoid arthritis and theircorrelation with disease activity:a meta-analysis[J]. Int J RheumDis,2018,21(7):1335-1342.
[24]Elshal A S,Aly N M,Galil S M,et al. Association of microRNAsgenes polymorphisms with rheumatoid arthritis in Egyptian femalepatients[J]. Joint Bone Spine,2013,80(6):626-631.
[25] Shaker O G,El Boghdady N A,El Sayed A E. Association ofmiRNA-146a,miRNA-499,IRAK1 and PADI4 polymorphisms withrheumatoid arthritis in Egyptian population[J]. Cell PhysiolBiochem,2018,46(6):2239-2249.
[26]Ciccacci C,Conigliaro P,Perricone C,et al. Polymorphisms inSTAT-4, IL-10, PSORS1C1, PTPN2 and miR146A genes areassociated differently with prognostic factors in Italian patientsaffected by rheumatoid arthritis[J]. Clin Exp Immunol,2016,186(2):157-163.
[27]Li K,Tie H,Hu N,et al. Association of two polymorphismsrs2910164 in miRNA-146a and rs3746444 in miRNA-499 withrheumatoid arthritis:A meta-analysis[J]. Hum Immunol,2014,75(7):602-608.