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中华妇幼临床医学杂志(电子版) ›› 2014, Vol. 10 ›› Issue (04) : 451 -456. doi: 10.3877/cma.j.issn.1673-5250.2014.04.010

所属专题： 文献；

论著

趋化因子CXCL12和肿瘤坏死因子-α基因多态性与宫颈上皮内瘤变和宫颈癌易感性之间的相关性研究
尹格平1,*,*(), 武爱芳1, 梁静1, 支圆圆1, 朱彤宇1, 李娟1   
  1. 1. 250031　济南军区总医院妇产科
  • 收稿日期:2013-10-09 修回日期:2014-01-10 出版日期:2014-08-01
  • 通信作者: 尹格平

Chemokine CXCL12 and TNF-a Polymorphisms and Susceptibility to Cervical Intraepithelial Neoplasia and Cervical Cancer

Geping Yin1(), Aifang Wu1, Jing Liang1, Yuanyuan Zhi1, Tongyu Zhu1, Juan Li1   

  1. 1. Department of Obstetrics and Gynecology, Jinan Military General Hospital, Jinan 250031, Shandong Province, China
  • Received:2013-10-09 Revised:2014-01-10 Published:2014-08-01
  • Corresponding author: Geping Yin
  • About author:
    (Corresponding author: Yin Geping, Email: )
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引用本文：

尹格平, 武爱芳, 梁静, 支圆圆, 朱彤宇, 李娟. 趋化因子CXCL12和肿瘤坏死因子-α基因多态性与宫颈上皮内瘤变和宫颈癌易感性之间的相关性研究[J/OL]. 中华妇幼临床医学杂志(电子版), 2014, 10(04): 451-456.

Geping Yin, Aifang Wu, Jing Liang, Yuanyuan Zhi, Tongyu Zhu, Juan Li. Chemokine CXCL12 and TNF-a Polymorphisms and Susceptibility to Cervical Intraepithelial Neoplasia and Cervical Cancer[J/OL]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2014, 10(04): 451-456.

目的

探讨趋化因子CXCL12/rs266085和肿瘤坏死因子(TNF)-α/rs1799724的2个基因位点的基因型(GT)和等位基因频率(AF)分布与宫颈上皮内瘤变(CIN) I~Ⅲ型及宫颈癌发病易感性之间的相关性。

方法

选择2011年1月至2012年10月在5家医院进行宫颈癌筛查的790例中国大陆汉族人群外周血液样本为研究对象。按照宫颈组织诊断性病理学检查结果等将790例受试者分为：CIN I组(n = 78)、CIN Ⅱ组(n= 92)、CIN Ⅲ组(n= 137，包括宫颈原位癌77例)和宫颈癌(浸润癌)组(n = 132)及健康对照组(n = 351)。采用TaqMan探针法对外周血液淋巴细胞DNA进行实时荧光定量PCR技术检测要求的位点(本研究遵循的程序符合济南军区总医院等收集病例的5家医疗单位人体试验委员会制定的伦理学标准，得到该委员会批准，分组征得受试对象知情同意，并与之签署临床研究知情同意书)。本研究数据资料采用SPSS 17.0统计学软件包进行统计学分析。

结果

研究结果为：①AF对比显示，TNF-α/rs1799724和趋化因子CXCL12/rs266085与宫颈癌之间有相关性：宫颈癌组和对照组中rs1799724位点的胞嘧啶(C)-AF(分别为73.9%和92.0%)比较，差异有统计学意义[OR = 0.245，95%CI (0.166～0.361)，P = 0.000]；宫颈癌组中胸腺嘧啶(T)-AF显著高于对照组，并且差异有统计学意义[OR = 4.082，95%CI(2.771~6.012),P = 0.000]。宫颈癌组和对照组中rs266085位点的C-AF分别为40.9%和49.7% [OR = 0.700，95%CI(0.526～0.933),P = 0.015],宫颈癌组中T-AF显著高于对照组[OR= 1.428，95% CI(1.072～1.902),P = 0.015]。②rs1799724位点的GT和AF在对照组与CINI组和CIN Ⅱ组之间比较，差异无统计学意义(P>0.05)，而对照组与CIN Ⅲ组和宫颈癌组比较，差异有统计学意义(P<0.05)。rs266085位点在对照组与I～Ⅲ型CIN组的GT和AF比较，差异均无统计学意义(P>0.05)。③两位点(rs1799724和rs266085)在I~Ⅲ型CIN组之间GT和AF对比，差异均无统计学意义(P>0.05)。④宫颈癌组与I~Ⅲ型CIN组之间rs1799724和rs266085位点GT对比提示：与CIN I组之间比较，差异有统计学意义(P< 0.05),与CIN Ⅲ组之间比较，差异无统计学意义(P>0.05)；rs1799724 AF对比提示：宫颈癌组与CIN I组和CINⅡ组之间比较，差异有统计学意义(P<0.05)，与CIN Ⅲ组比较，差异无统计学意义(P>0.05)；rs266085位点AF对比提示：宫颈癌组与CIN I~Ⅲ组之间比较，差异有统计学意义(P < 0.05)。

结论

趋化因子CXCL12/rs266085和TNF-α/rs1799724位点的风险基因型是TT和TC，上述位点异常同时合并人乳头状瘤病毒(HPV)感染者，是子宫颈癌的高危人群。

关键词: 基因多态性, 趋化因子CXCL12, 肿瘤坏死因子alpha, 子宫颈新生物, 子宫颈上皮内瘤变, 疾病遗传易感性
Objective

To investigate the associations between chemokine CXCL12/rs266085 and Tumor Necrosis Factor-alpha(TNF-α)/rs1799724 single nucleotide polymorphisms(SNP) loci of the gene types(GT) and allele frequency (AF) and I-Ⅲ stages of cervical intraepithelial neoplasia(CIN) and cervical cancer risk in the mainland Chinese women.

Methods

Fluorescent quantitative reverse transcription polymerase chain reaction(FQ-PCR) was used to measure the SNP of the chemokine CXCL12/rs266085 and TNF-α/rs1799724 in peripheral blood of 790 cases of which screening for cervical cancer in 5 hospitals. In accordance with the cervical tissue diagnostic pathology results, the study objects from January 2011 to October 2012 were divided into 5 groups : included 78 cases in CIN I group, 92 cases in CIN Ⅱ group, 137 cases in CIN Ⅲ group (including 77 cases of carcinoma in situ), 132 cases in cervical cancer (invasive carcinoma of cervix) group and 351 cases in normal women for control group. The study protocol was approved by the Ethical Review Board of Investigation in Human Beings of Jinan Military General Hospital, etc. Informed consent was obtained from each participating patient. All data were analyzed by SPSS 17.0 statistic software.

Results

The results is ① There had an association of TNF-α/rs1799724 polymorphism with cervical cancer. The cytosine (C)-AF was less prevalent compared to control group {73.9 % vs. 92.0 %,[OR = 0.245, 95%CI(0.166-0.361),P = 0.000]}, while the thymine (T)-AF was more prevalent compared to control group[OR = 4.082, 95%CI(2.771-6.012), P = 0.000]. Chemokine CXCL12/rs266085 polymorphism also showed an association with cervical cancer. The C-allele was less prevalent compared to control group{40.9 % vs. 49.7%,[OR =0.700, 95%CI(0.526-0.933),P = 0.015]} while the T-allele was more prevalent compared to control group[OR=1.428,95%CI(1.072-1.902),P=0.015]. ②There had no significant difference in the rs1799724 site of GT and AF between the control group with CIN I and CIN Ⅱgroups(P>0.05), but had significant difference compare to the CIN Ⅲ and cervix cancer groups (P < 0.05). There had no significant differences between the control group with each CIN group of GT and AF in the rs266085 site (P> 0.05).③ The GF and AF of rs1799724 and rs266085 sites had no significant difference among every CIN group(P>0.05).④There had significant difference in GT of the rs1799724 and rs266085 sites between cervical cancer and the CIN I group (P < 0.05),but had no significant difference compared to CIN Ⅲ group(P>0.05) ; AF of the rs1799724 contrast showed there had significant differences in cervical cancer group compared to CIN I and CIN Ⅱ groups (P < 0.05), but had no significant difference compared to CIN Ⅲ group(P>0.05) ;The AF of rs266085 sites contrast showed there had significant difference between cervical cancer group and every CIN group(P<0.05).

Conclusions

Our study showed that the chemokine CXCL12/ rs266085 and TNF-α/rs1799724 sites' risk genotype is TT and TC, the abnormal of them with human papilloma virus (HPV) infection is a high-risk population of cervical cancer.

Key words: Polymorphism, genetic, Chemokine CXCL12, Tumor necrosis factor-alpha, Uterine cervical neoplasms, Cervical intraepithelial neoplasia, Genetic predisposition to disease
表1 各组人口学特征和HR-HPV感染情况比较(±s)
Table 1 Comparison of general demographic characteristics and HR-HPV infection among different groups(±s)
组别 n 年龄(岁） 初婚年龄(岁） 孕次（次） 产次(次） 职业人员比例[n(％)] 吸烟率[n(%)] HR-HPV感染率[n (％)]
CIN I组 78 38.5±12.0 23.5±3.5 5.7±1.9 1.7±1.5 48(61.5) 16(20.5) 32(41.0)
CIN Ⅱ组 92 39.0±14.5 25.5±3.5 6.3±2.7 1.9±1.3 50(54.3) 18(19.6) 37(40.2)
CIN组 137 44.0±11.5 24.7±2.5 4.6±2.3 1.8±1.1 66(50.1) 31(19.3) 90(65.7)
宫颈癌组 132 47.5±17.5 24.0±3.0 5.9±3.1 2.7±1.3 56(42.4) 28(28.0) 126(95.5)
对照组 351 48.0±18.5 24.6±3.7 5.1±2.8 2.3±1.7 162(46.2) 61(17.4) 929 (8.3)
χ2/F 　 75.303 1.636 1.677 1.564 9.294 1.220 356.749
P 　 0.961 0.177 0.080 0.133 0.054 0.875 0.000
表2 宫颈癌组与对照组CXCL12、TNF-α的2个SNP位点中胞嘧啶及胸腺嘧啶的AF比较(％)
Table 2 Comparison of C and T's AF of CXCL12 and TNF-α's two SNP loci between the uterine cervix cancer group and control group(%)
组别 n rs1799724 rs266085
C T C T
宫颈癌组 132 73.9 26.1 40.9 59.1
对照组 351 92.0 8.0 49.7 50.3
OR 　 0.245 4.082 0.700 1.428
95%CI 　 0.166～0.361 2.771～6.012 0.526～0.933 1.072～1.902
P 　 0.000 0.000 0.015 0.015
表3 各组TNF-α/rs1799724位点的GT频率及AF比较[n(%)]
Table 3 Comparison of GT frequency and AF on TNF-α/rs1799724 among different groups[n(%)]
组别 n GT AF
TT TC CC T C
CIN I组 78 3 (3.8) 9(11.5) 66(84.6) 15 (9.6) 141(90.4)
CIN Ⅱ组 92 5 (5.4) 12(13.0) 75(81.5) 22(12.0) 162(88.0)
CIN Ⅲ组 137 14(10.2) 30(21.9) 93(67.9) 58(21.2) 216(78.8)
宫颈癌组 132 18(13.6) 33(25.0) 81(61.4) 69(26.1) 195(73.9)
对照组 351 6 (1.7) 44(12.5) 301(85.8) 56 (8.0) 646(92.0)
χ2 　 30.935 16.199 44.380 68.572
P 　 0.000 0.003 0.000 0.000
表4 各组趋化因子CXCL12/rs266085位点的GT频率及AF比较[n(%)]
Table 4 Comparison of GT frequency and AF on chemokine CXCL12/rs266085 among different groups[n(%)]
组别 n GT AF
TT TC CC T C
CIN I组 78 16(20.5) 47(60.3) 15(19.2) 79(50.6) 77(49.4)
CIN Ⅱ组 92 18(19.6) 49(53.3) 25(27.1) 85(46.2) 99(53.8)
CIN Ⅲ组 137 42(30.7) 59(43.1) 36(26.2) 143(52.2) 131(47.8)
宫颈癌组 132 51(38.6) 54(40.9) 27(20.5) 156(59.1) 108(40.9)
对照组 351 68(19.4) 217(61.8) 66(18.8) 353(50.3) 349(49.7)
χ2 　 23.803 25.591 5.431 8.718
P 　 0.000 0.000 0.264 0.069
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