Toll样9受体单核苷酸多态性与尖锐湿疣感染相关性的初步研究
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摘要
尖锐湿疣是由人乳头瘤病毒感染引起的一种性感染疾病,发病率高,已居性感染疾病的第二位。该病传染性强,复发率高,对人类身心危害较大。近年来研究发现,免疫失衡在尖锐湿疣的发生、发展及转归等方面发挥重要作用。Toll样受体是一类天然识别受体,在天然免疫和适应性免疫中发挥着重要的桥梁作用。Toll样受体9(Toll like receptor 9,SNP)是其中的一种,主要识别未甲基化的CpG基序,从而在抗病毒免疫和自身免疫方面发挥重要的作用。本课题着重研究了尖锐湿疣患者外周血TLR9的单核苷酸多态性(Singlenucleotide polymorphism,SNP),分析Toll样受体9的SNP与尖锐湿疣发病的相关性。
研究目的
探讨Toll样受体9的单核苷酸多态性与尖锐湿疣发病的相关性。
研究方法
抽取63例确诊的尖锐湿疣患者和23例健康对照组的外周静脉血,采用TLR9基因直接测序的方法分析TLR9受体的单核苷酸多态性。
结果
1.TLR9基因自翻译起始点第+1174、1635、1269、1724位均存在单核苷酸多态性位点,分别称为SNP1、SNP2、SNP3和SNP4,其中SNP3、SNP4为新发现位点,SNP1、SNP2为NCBI数据库中公布的位点,登录号分别为：rs352139、rs352140。SNP1、SNP2在人群中均可表现为三种基因型：AA纯合、AG杂合和GG纯合,这两个位点的三种基因型在尖锐湿疣患者和健康对照组间比较差异均无统计学意义(P>0.05)。SNP3、SNP4均只在1例尖锐湿疣患者中发现,均表现为AG杂合,其余个体该两位点均为GG纯合。
2.尖锐湿疣患者与健康对照组的SNP1位点的等位基因A的频率分别为0.690、0.609,等位基因G的频率0.309、0.391,两组间比较差异均无统计学意义(P>0.05)。SNP2位点的等位基因A的频率分别为0.302、0.369,等位基因G的频率0.698、0.630,两组间比较差异无统计学意义(P>0.05)。
3.SNP1、SNP2两个多态性位点存在4种单倍体型,分别为AA、AG、GA、GG。每种单倍体型在尖锐湿疣患者组和健康对照组间比较差异均无统计学意义(P>0.05)。
4.尖锐湿疣患者初发组与复发组的CD3+分别为：63.24%±10.09%、67.11%±9.28%,两组间比较差异均无统计学意义(P>0.05)；CD4+分别为：32.13%±8.65%、30.89%±5.81%,两组间比较差异均无统计学意义(P>0.05)；CD8+分别为：29.04%±9.29%、33.00%±8.06%,两组间比较差异均无统计学意义(P>0.05)；Th／Ts分别为：1.25±0.53、1.00±0.33,两组间差异具有统计学意义(P<0.05)。
5.SNP1位点AA、AG、GG三种基因型的Th／Ts分别为：1.08±0.48、0.92±0.35、1.09±0.47,三种基因型间比较差异无统计学意义(P>0.05)；SNP2位点AA、AG、GG三种基因型的Th／Ts分别为：1.08±0.42、0.92±0.37、1.08±0.48,三种基因型间比较差异无统计学意义(P>0.05)。
结论
1.TLR9基因在广东汉族人群中存在4个单核苷酸多态性位点,分别为SNP1、SNP2、SNP3、SNP4。
2.SNP1、SNP2两位点均与尖锐湿疣的发病易感性可能无相关性。
3.初发与复发的尖锐湿疣患者间存在T淋巴细胞亚群免疫失衡。
4.SNP1、SNP2两位点与尖锐湿疣患者的T淋巴细胞亚群间可能无相关性。
Condyloma Acuminate is a kind of Sexually Transmitted Disease (STD). In recent years, the incidence of catching this disease appears to have an upward trend, and pathogenesis of Condyloma Acuminatum is not yet thoroughly clear. There is, so far, no effective anti-viral treatment for Condyloma Acuminate, and no satisfactory solution to the recurrence. Different individuals have different responses to HPV infection, suggesting that immunity, particularly, the host cell immunity, has a certain impact in the occurrence of Condyloma Acuminate. It has been widely recognized that the change of cellular immune function closely relates to the occurrence of Condyloma Acuminate. That the body can not build an effective immune response is the main reason for HPV persistent infection; so to explore the immune mechanisms of Condyloma Acuminate has important oretical and clinical significance.
Toll-like receptor (TLR) is the first recognition receptor of the inherent immunity, which is a defending response caused by direct perception of microbial pathogen. This kind of receptor plays an important part in inherent immunity defense, and can also adjust adaptive immunity, which makes it a bridge of connecting inherent immunity and adaptive immunity. TLR9 mainly identifies bacteria and virus genome DNA and synthetic CpG ODNs, and it has an important role in the pathogenesis of anti-infection, anti-tumor, mediated cell apoptosis and autoimmune disease.
Objective
This study aims at investigating whether polymorphism in the TLR9 gene differentially affect the incidence and the clinical course of Condyloma Acuminatum.
Methods
Following informed consent from all patients and healthy volunteers,2ml of peripheral blood was collected from each of 63 Guangdong Condyloma Acuminatum patients and 23 unrelated healthy Guangdong individuals admitted to The Fourth Affiliated Hospital of Jinan University. The patients were divided into groups in terms of the primary and recurrent Condyloma Acuminatum patients. With DNA samples from all subjects prepared, all single nucleotide polymorphisms of TLR9 was tested through polymerase chain reaction and direct sequencing.
Results
There are 4 SNPs in TLR9:SNP1、SNP2、SNP3 and SNP4. SNP1 was located in intron 1 region, SNP2、SNP3 and SNP4 located in exon2. The registration number of SNP1 is rs352139 in NCBI database, and that of SNP2 is rs352140. SNP2 is non-synonymous cSNP. Based on a SNP map that had been constructed, we also constructed a haplotype map of TLR9. The frequency of alleles and genotypes in chinses was revealed as well. But there were no significantly increase in patients compared with controls on SNP1 and SNP2. There are statistical differences between the two groups of the primary and recurrent Condyloma Acuminatum patients on Th/Ts. Two sites of three genotypes were not statistically significant compared with Th/Ts. SNP3 and SNP4 were observed only in the patients, therefore, we don't have analyzed these two sites.
Conclusions
TLR9 genes exist as four single nucleotide polymorphisms (SNPs), respectively, SNP2, SNP1, SNP3, SNP4, in Guangdong Han ethnic population. Compared with the control group, no significant increase of single nucleotide polymorphisms in TLR9 can be seen in the patient group. But the data of TLR9 polymorphism in Guangdong Han Ethnic Group will significantly contribute to the improvement of research on disease association and basic immunology.
研究目的
探讨Toll样受体9的单核苷酸多态性与尖锐湿疣发病的相关性。
研究方法
抽取63例确诊的尖锐湿疣患者和23例健康对照组的外周静脉血,采用TLR9基因直接测序的方法分析TLR9受体的单核苷酸多态性。
结果
1.TLR9基因自翻译起始点第+1174、1635、1269、1724位均存在单核苷酸多态性位点,分别称为SNP1、SNP2、SNP3和SNP4,其中SNP3、SNP4为新发现位点,SNP1、SNP2为NCBI数据库中公布的位点,登录号分别为：rs352139、rs352140。SNP1、SNP2在人群中均可表现为三种基因型：AA纯合、AG杂合和GG纯合,这两个位点的三种基因型在尖锐湿疣患者和健康对照组间比较差异均无统计学意义(P>0.05)。SNP3、SNP4均只在1例尖锐湿疣患者中发现,均表现为AG杂合,其余个体该两位点均为GG纯合。
2.尖锐湿疣患者与健康对照组的SNP1位点的等位基因A的频率分别为0.690、0.609,等位基因G的频率0.309、0.391,两组间比较差异均无统计学意义(P>0.05)。SNP2位点的等位基因A的频率分别为0.302、0.369,等位基因G的频率0.698、0.630,两组间比较差异无统计学意义(P>0.05)。
3.SNP1、SNP2两个多态性位点存在4种单倍体型,分别为AA、AG、GA、GG。每种单倍体型在尖锐湿疣患者组和健康对照组间比较差异均无统计学意义(P>0.05)。
4.尖锐湿疣患者初发组与复发组的CD3+分别为：63.24%±10.09%、67.11%±9.28%,两组间比较差异均无统计学意义(P>0.05)；CD4+分别为：32.13%±8.65%、30.89%±5.81%,两组间比较差异均无统计学意义(P>0.05)；CD8+分别为：29.04%±9.29%、33.00%±8.06%,两组间比较差异均无统计学意义(P>0.05)；Th／Ts分别为：1.25±0.53、1.00±0.33,两组间差异具有统计学意义(P<0.05)。
5.SNP1位点AA、AG、GG三种基因型的Th／Ts分别为：1.08±0.48、0.92±0.35、1.09±0.47,三种基因型间比较差异无统计学意义(P>0.05)；SNP2位点AA、AG、GG三种基因型的Th／Ts分别为：1.08±0.42、0.92±0.37、1.08±0.48,三种基因型间比较差异无统计学意义(P>0.05)。
结论
1.TLR9基因在广东汉族人群中存在4个单核苷酸多态性位点,分别为SNP1、SNP2、SNP3、SNP4。
2.SNP1、SNP2两位点均与尖锐湿疣的发病易感性可能无相关性。
3.初发与复发的尖锐湿疣患者间存在T淋巴细胞亚群免疫失衡。
4.SNP1、SNP2两位点与尖锐湿疣患者的T淋巴细胞亚群间可能无相关性。
Condyloma Acuminate is a kind of Sexually Transmitted Disease (STD). In recent years, the incidence of catching this disease appears to have an upward trend, and pathogenesis of Condyloma Acuminatum is not yet thoroughly clear. There is, so far, no effective anti-viral treatment for Condyloma Acuminate, and no satisfactory solution to the recurrence. Different individuals have different responses to HPV infection, suggesting that immunity, particularly, the host cell immunity, has a certain impact in the occurrence of Condyloma Acuminate. It has been widely recognized that the change of cellular immune function closely relates to the occurrence of Condyloma Acuminate. That the body can not build an effective immune response is the main reason for HPV persistent infection; so to explore the immune mechanisms of Condyloma Acuminate has important oretical and clinical significance.
Toll-like receptor (TLR) is the first recognition receptor of the inherent immunity, which is a defending response caused by direct perception of microbial pathogen. This kind of receptor plays an important part in inherent immunity defense, and can also adjust adaptive immunity, which makes it a bridge of connecting inherent immunity and adaptive immunity. TLR9 mainly identifies bacteria and virus genome DNA and synthetic CpG ODNs, and it has an important role in the pathogenesis of anti-infection, anti-tumor, mediated cell apoptosis and autoimmune disease.
Objective
This study aims at investigating whether polymorphism in the TLR9 gene differentially affect the incidence and the clinical course of Condyloma Acuminatum.
Methods
Following informed consent from all patients and healthy volunteers,2ml of peripheral blood was collected from each of 63 Guangdong Condyloma Acuminatum patients and 23 unrelated healthy Guangdong individuals admitted to The Fourth Affiliated Hospital of Jinan University. The patients were divided into groups in terms of the primary and recurrent Condyloma Acuminatum patients. With DNA samples from all subjects prepared, all single nucleotide polymorphisms of TLR9 was tested through polymerase chain reaction and direct sequencing.
Results
There are 4 SNPs in TLR9:SNP1、SNP2、SNP3 and SNP4. SNP1 was located in intron 1 region, SNP2、SNP3 and SNP4 located in exon2. The registration number of SNP1 is rs352139 in NCBI database, and that of SNP2 is rs352140. SNP2 is non-synonymous cSNP. Based on a SNP map that had been constructed, we also constructed a haplotype map of TLR9. The frequency of alleles and genotypes in chinses was revealed as well. But there were no significantly increase in patients compared with controls on SNP1 and SNP2. There are statistical differences between the two groups of the primary and recurrent Condyloma Acuminatum patients on Th/Ts. Two sites of three genotypes were not statistically significant compared with Th/Ts. SNP3 and SNP4 were observed only in the patients, therefore, we don't have analyzed these two sites.
Conclusions
TLR9 genes exist as four single nucleotide polymorphisms (SNPs), respectively, SNP2, SNP1, SNP3, SNP4, in Guangdong Han ethnic population. Compared with the control group, no significant increase of single nucleotide polymorphisms in TLR9 can be seen in the patient group. But the data of TLR9 polymorphism in Guangdong Han Ethnic Group will significantly contribute to the improvement of research on disease association and basic immunology.
引文
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52竹立,邹良建.汉族人群Toll样受体5、9基因单核苷酸多态性与风湿性心脏病的相关性研究.第二军医大学硕士学位论文,上海：第二军医大学,2009.
53 Soriano-Sarabia N, Vallejo A, Ramirez-Lorca R, Rodriguez Mdel M, Salinas A, Pulido I, Saez ME, Leal M Influence of the Toll-like receptor 9 1635A/G poly-morphism on the CD4 count, HIV viral load, and clinical progression. J Acquir Immune Defic Syndr,2008, 49(2):128-135.
54 Bochud PY, Hersberger M, Taffe P, Bochud M, Stein CM, Rodrigues SD, Calandra T, Francioli P, Telenti A, Speck RF, Aderem A. Swiss HIV Cohort Study Polymorphisms in Toll-like receptor 9 influence the clinical course of HIV-1 infection. AIDS,2007,21 (4): 441-446.
55 尹光文,李冬芹,何秋波,于建斌,贺付成,刘新郑.复发尖锐湿疣患者外周血T淋巴细胞亚群测定.郑州大学学报(医学版),2005,40(2)：374-375.
56 车雅敏,王家璧,刘跃华,左亚刚,方凯.尖锐湿疣患者外周血及皮损T淋巴细胞亚群的检测.临床皮肤科杂志,2005,34(1)：23-25.
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50徐昌娟,叶冬青.安徽籍汉族人群Toll样受体9基因多态性及环境因素与系统性红斑狼疮的关联性研究.安徽医科大学硕士学位论文,安徽：安徽医科大学,2009.
51张合喜,邹立君,王友洁.用PCR-SSCP方法检测TLR9基因多态性.新乡医学院学报,2006,23(3)：217-219.
52竹立,邹良建.汉族人群Toll样受体5、9基因单核苷酸多态性与风湿性心脏病的相关性研究.第二军医大学硕士学位论文,上海：第二军医大学,2009.
53 Soriano-Sarabia N, Vallejo A, Ramirez-Lorca R, Rodriguez Mdel M, Salinas A, Pulido I, Saez ME, Leal M Influence of the Toll-like receptor 9 1635A/G poly-morphism on the CD4 count, HIV viral load, and clinical progression. J Acquir Immune Defic Syndr,2008, 49(2):128-135.
54 Bochud PY, Hersberger M, Taffe P, Bochud M, Stein CM, Rodrigues SD, Calandra T, Francioli P, Telenti A, Speck RF, Aderem A. Swiss HIV Cohort Study Polymorphisms in Toll-like receptor 9 influence the clinical course of HIV-1 infection. AIDS,2007,21 (4): 441-446.
55 尹光文,李冬芹,何秋波,于建斌,贺付成,刘新郑.复发尖锐湿疣患者外周血T淋巴细胞亚群测定.郑州大学学报(医学版),2005,40(2)：374-375.
56 车雅敏,王家璧,刘跃华,左亚刚,方凯.尖锐湿疣患者外周血及皮损T淋巴细胞亚群的检测.临床皮肤科杂志,2005,34(1)：23-25.
57 Medzhitov R, Janeway C. Innated Immunity. The New Englnad Journal of Medicine,2000, 343(5):338-344.
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