白细胞介素-18基因启动子多态性与鼻咽癌遗传易感性的研究

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潘国刚, 罗斌, 滕元姬, 梁丽娜. 白细胞介素-18基因启动子多态性与鼻咽癌遗传易感性的研究. 检验医学, 2013, 28(6): 457-461
PAN Guogang, LUO Bin, TENG Yuanji, LIANG Lina. Research on interleukin-18 gene promoter polymorphisms and genetic susceptibility of nasopharyngeal carcinoma. Labratory Medicine, 2013, 28(6): 457-461 复制到剪切板

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白细胞介素-18基因启动子多态性与鼻咽癌遗传易感性的研究

潘国刚, 罗斌, 滕元姬, 梁丽娜

右江民族医学院附属医院检验科,广西百色 533000

作者简介:潘国刚,男,1973年生,学士,主管技师,主要从事分子生物学研究。

基金:广西自然科学基金资助项目(2011GXNSFA018198)

摘要

目的探讨白细胞介素-18 (IL-18) 基因单核苷酸多态性及其单倍型与鼻咽癌(NPC)易感性之间的关系。方法以190例NPC患者和200名健康对照者为研究对象,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)的方法对IL-18基因-137G/C (rs 187238 G/C)、-607C/A (rs 1946518 C/A)单核苷酸多态性进行基因分型,并分析IL-18基因的连锁不平衡及单倍型频率。结果 IL-18基因-607C/A多态性在NPC组和正常人群中的分布差异无统计学意义(P>0.05),而IL-18基因-137G/C多态性在2组人群中的分布差异有统计学意义(P<0.05),等位基因频率的相对风险分析发现,C等位基因携带者患NPC的风险是G等位基因的1.730倍 (OR=1.730,95%CI:1.227~2.439)。联合基因型分析发现,IL-18基因-137G/C、-607C/A单核苷酸多态性存在着强烈的连锁不平衡, -137C/-607A单倍型频率在NPC组中明显高于对照组(P<0.05),-137C/-607A 单倍型携带者显著增加了NPC的发病风险(OR=1.699,95%CI:1.174~2.457)。结论 IL-18基因-137G/C多态性和-137C/-607A单倍型与NPC的发病可能具有相关性,其中-137C等位基因可能是NPC的遗传易感基因。

关键词: 白细胞介素-18; 鼻咽癌; 基因; 多态性

中图分类号:Q503 文献标志码:A 文章编号:1673-8640(2013)06-0457-05

Research on interleukin-18 gene promoter polymorphisms and genetic susceptibility of nasopharyngeal carcinoma

PAN Guogang, LUO Bin, TENG Yuanji, LIANG Lina

Department of Clinical Laboratory,Affiliated Hospital of Youjiang Medical University for Nationalities,Guangxi Baise 533000, China

Abstract

Objective To investigate the relationship of the single nucleotide polymorphisms and haplotypes of interleukin-18 (IL-18) gene promoter with genetic susceptibility of nasopharyngeal carcinoma (NPC).Methods The single nucleotide polymorphisms of IL-18 gene promoter -137G/C (rs 187238 G/C) and -607C/A (rs 1946518 C/A) in 190 patients with NPC and 200 healthy controls were determined by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP). The frequency of haplotypes and linkage disequilibrium of IL-18 gene in different groups were analyzed.Results The distributions of IL-18 gene -607C/A polymorphism had no statistical significance between NPC and control groups(P>0.05),but the distributions of IL-18 gene -137G/C polymorphism were significantly different between them (P<0.05). The relative risk suffered from NPC group found that of C allele was 1.730 times of the G allele [odds ratio(OR)=1.730,95%confidence interval(CI): 1.227-2.439)]. Being consistent with the results of the genotyping analysis,IL-18 gene -137G/C and -607C/A single nucleotide polymorphisms showed strong linkage disequilibrium,and the frequency of the -137C/-607A haplotype in NPC group was significantly higher than that in control group (P<0.05). The -137C/-607A haplotype was associated with a significantly increased risk of NPC (OR=1.699,95%CI:1.174-2.457).Conclusions IL-18 gene -137G/C polymorphism and its -137C/-607A haplotype are associated with NPC,and -137C allele is an important genetic susceptibility gene for NPC.

Keyword: Interleukin-18; Nasopharyngeal carcinoma; Gene; Polymorphism

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引言

鼻咽癌 (nasopharyngeal carcinoma,NPC)是一种多基因、多因素综合作用而导致的一种常见疾病,然其病因和发病机制尚未完全阐明,但遗传基因在鼻咽癌发病过程中可能起着重要的作用,随着人类基因组计划的迅速发展,NPC相关基因的定位和识别已成为研究的热点。白细胞介素-18 (interleukin-18,IL-18) 是一种多效性细胞因子,主要由激活的单核巨噬细胞产生,可诱导γ-干扰素 (interferon-γ,IFN-γ) 产生,参与了多种疾病病理过程,在感染、免疫调节、肿瘤发生中的作用受到广泛关注^{[ 1, 2]}。近年对IL-18基因多态性与疾病的关系有较多研究报道。但是,IL-18 在肿瘤发生和进程中的分子机制还尚未完全阐明。IL-18基因位于11号染色体长臂上(11q22.2-q22.3),由6个外显子和5个内含子组成,分子生物学研究表明IL-18基因存在着单核苷酸多态性(single nucleotide polymorphisms,SNPs)。这种基因多态性与人类多种肿瘤、霍奇金病及自身免疫性疾病的关系^{[ 3, 4, 5]}已成为国内、外学者研究的热点。目前,有关IL-18基因多态性与NPC关系的研究国内较少文献报道。为此,我们采用聚合酶链反应-限制性片段长度多态性(polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)的方法,研究IL-18 基因多态性及单倍型与NPC的关系,为认识NPC的发病机制提供一定的理论依据。

材料和方法

一、研究对象

全部NPC来自于右江民族医学院附属医院住院的患者,全部研究对象均经病理证实,共190例,其中男135例,女55例,年龄(48±8)岁;选择年龄、性别相匹配的200名无血缘关系的同期正常健康体检者为对照组,其中男140名,女60名,年龄(47±8)岁。全部研究对象均为广西籍人。该研究获得右江民族医学院附属医院伦理委员会批准,且以上标本采集均由本人知情同意。

二、研究方法

1.基因组DNA提取采集静脉血3mL,用乙二胺四乙酸二钾(EDTA-K₂)抗凝;采用改良碘化钠法提取白细胞基因组DNA,-70℃保存备用。

2.PCR扩增参照Genbank公布的序列(NT033899.7)设计2对引物,由上海英俊有限公司合成。(引物序列的起止位置为:-655位点至-519位点)用于特异性扩增IL-18基因包含-607位点的一段DNA引物序列,上游引物为:5'- CCCTCTCCCCAAGCTTACTT-3';下游引物为:5'- TTCAGTGGAACAGGAGTCCA-3';(引物序列的起止位置为:-366位点至-111位点)用于特异性扩增IL-18基因包含-137位点的一段DNA引物序列,上游引物为:5'-TTGTAACATTGTAGGAATTACC-3';下游引物为:5'-ATGTAATATCACTATTTTCATGAGA -3',IL-18的PCR扩增反应体系均为25 μL,其中含10×PCR 缓冲液2.5 μL,2.5 mmol/L dNTPs 2.0 μL,上、下游引物各20 pmoL,模板DNA 2.0 μL,TaqDNA聚合酶1.25 U,不足体积用灭菌双蒸水补足至25 μL。置热循环仪(Bio-Rad)中94 ℃预变性5 min;再按下列程序循环35次,即94 ℃变性30 s,60 ℃退火45 s,72 ℃延伸55 s;末次循环后,72 ℃延伸5 min。

3.扩增产物的限制性酶切取PCR扩增产物3 μL,分别用2 U 限制性内切酶 Mse I和 BfuC I(英国Biolabs公司)酶切IL-18基因-607和-137位点,37℃孵育3h,反应终止后,消化片段在8 %的聚丙烯酰胺凝胶上电泳,EB染色,染色后通过凝胶成像系统判断结果。

三、统计学方法

用SPSS11.5软件包进行分析。基因型和等位基因频率采用基因直接计数法计算,研究对象与Hardy-Weinberg平衡的符合程度及各组间基因型及等位基因频率比较采用 χ²检验,并以比值比(odds ratio, OR)及其95%可信区间(confidence interval , CI)表示相对风险度。以 P<0.05表示差异有统计学意义。

结果

一、IL-18基因型检测结果

IL-18 基因-137 G/C多态性,PCR扩增产物片段大小为256 bp,根据限制性内切酶 BfuC I酶切片段的情况,检测到基因型有3种,CC型(256 bp 1条带),GC型(256 bp,229 bp和27 bp 3条带),GG型(229 bp和27 bp 2条带),见图 1;IL-18基因-607 C/A多态性,PCR扩增产物片段大小为137 bp,根据限制性内切酶Mse I酶切片段的情况,检测到基因型有3种,AA型(91 bp,46 bp 2条带),CA型(137 bp,91 bp和46 bp 3条带),CC型(137 bp 1条带),见图2。为验证基因型结果,PCR产物直接测序结果与Genbank 参照序列(NT033899.7)相一致,见图 3~4。

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	图1 IL-18基因-137 G/C多态性8 %的聚丙烯酰胺凝胶电泳图注:1,3: GC基因型; 2,4: GG基因型; 5,6: CC基因型;M: 标准相对分子质量

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	图2 IL-18基因-607 C/A多态性8 %的聚丙烯酰胺凝胶电泳图注:1,6: CC基因型; 2,3,5: AA基因型; 4: CA基因型;M: 标准相对分子质量

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	图3 IL-18基因-137 G/C测序图注:(a)、(b)、(c)分别表示GG、GC 和 CC基因型;箭头所示为基因突变位点

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	图4 IL-18基因-607C/A测序图注:(a)、(b)、(c)分别表示CC、CA 和 AA基因型;箭头所示为基因突变位点

二、NPC与对照组IL-18基因多态性的比较

IL-18基因型在2组人群中分布频率,经Hardy-Weinberg遗传平衡定律检验,2组均达到遗传平衡,具有群体代表性。经 χ²检验及相关分析,IL-18 -137位点等位基因频率在2组人群中的分布差异有统计学意义( χ²=9.895, P<0.05);等位基因频率的相对风险分析发现,C等位基因携带者患NPC的风险是G等位基因的1.730倍( OR=1.730,95% CI:1.227~2.439);IL-18 基因-607 C/A多态性在2组人群中的分布差异无统计学意义( P>0.05),见表1。

表1 NPC组与对照组IL-18基因多态性分布频率的比较

三、NPC组与对照组IL-18基因的连锁不平衡及单倍型分析

应用单倍型SHEsis 分析软件对IL-18基因-137 G/C和-607 C/A这2个位点的单核苷酸多态性进行连锁不平衡分析,结果显示IL-18基因-137 G/C与-607 C/A单核苷酸多态性存在强烈的连锁不平衡(|D'|= 0.951)。联合基因型分析发现,3种单倍型分布频率在NPC组与对照组间分布差异有统计学意义( χ²=9.530, P=0.009),-137C/-607A单倍型携带者显著增加了NPC的发病风险( OR=1.699,95% CI:1.174~2.457),见表 2。

表2 NPC组与对照组IL-18基因单倍型分布频率的比较

四、NPC多因素Logistic回归分析

将全体研究对象作为整体进行分析,以性别、年龄、吸烟、饮酒、IL-18基因-137 G/C和-607 C/A多态性作为自变量,建立NPC的Logistic回归模型,见表3。经混杂因素调整后可见,IL-18基因-137 G/C多态性是NPC的独立危险因素。其他相关的危险因素有吸烟、饮酒,与公认的NPC危险因素相符。

表3 NPC危险因素的Logistic回归分析结果

讨论

NPC是由环境因素和遗传基因相互作用而导致的一种头颈部恶性肿瘤。然其病因和发病机制尚未完全阐明,但细胞因子在其中的作用越来越受到重视。IL-18 是一种具有多种生物学功能的细胞因子,IL-18 除能强烈地诱导免疫细胞释放γ-干扰素(IFN-γ)、α-干扰素(TNF-α)等细胞因子外,其亦具有增强FasL 表达和自然杀伤细胞(NK)细胞毒作用等多种生物学效能。IL-18在免疫调节、抗肿瘤及抗感染等方面有着潜在的应用前景,并与多种肿瘤的发病可能密切相关。近年来,许多临床研究表明IL-18基因转染到树突状细胞和乳腺癌细胞中均具有特异性和非特异性的抗肿瘤作用,认为IL-18 在肿瘤的发病和活动性中可能起着重要的作用^{[ 6, 7]}。IL-18基因位于11号染色体长臂上,由6个外显子和5个内含子组成。研究表明,IL-18 基因具有遗传多态性,这种基因多态性影响IL-18的基因转录和表达,进而影响到IL-18的生物学功能,从而影响到肿瘤的发生、发展。因而,我们推测IL-18基因多态性可能与肿瘤的易患性有关。

关于IL-18 基因多态性与肿瘤的关系,文献报道较少。Farjadfar等^{[ 8]} 检测肺癌IL-18 基因多态性,结果发现IL-18 基因-607 C/A 多态性与肺癌的发病具有相关性,其中-607 A等位基因频率在肺癌患者中显著高于对照组,-607 A等位基因携带者明显降低血清IL-18的表达,因而提出-607 A等位基因携带者机体抗肿瘤减弱,从而导致肺癌易感。Nong等^{[ 9]}通过对NPC IL-18 基因多态性的研究发现,IL-18 基因-137 G/C多态性与NPC的发病具有相关性,其中-137 C等位基因可能是NPC的遗传易感基因;联合基因型进一步发现,-137 C/-607 A单倍型携带者明显增加了NPC的发病风险。但西班牙学者Sáenz-López等^{[ 10]}研究发现IL-18 基因-137 G/C和-607 C/A 两位点多态性与肾细胞癌都具有相关性。由于基因多态性存在地域间的差异,IL-18 基因多态性与NPC之间是否真正存在相关性,目前尚无定论。为进一步明确IL-18 基因多态性是否与NPC的发生相关,我们采用病例-对照的研究方法对IL-18基因多态性进行分析,结果发现NPC患者IL-18基因-137 G/C多态性分布与正常人比较差异具有统计学意义,其中C等位基因携带者频率在NPC组明显高于对照组( P<0.05)。本研究为排除年龄、生活习惯等混杂因素对统计结果的干扰,采用Logistic回归分析后发现,IL-18基因-137 G/C多态性与NPC明显相关,是NPC的一个独立危险因素。联合基因型进一步分析发现,IL-18基因-137 G/C与-607 C/A单核苷酸多态性存在强烈的连锁不平衡(|D'|= 0.951),3种单倍型分布频率在NPC组与对照组间分布差异有统计学意义( χ²=9.530, P=0.009),-137 C/-607 A单倍型携带者明显增加了NPC的发病风险( OR=1.699,95% CI:1.174~2.457)。结果提示,IL-18基因-137 G/C多态性和-137 C/-607 A单倍型与NPC的发病可能具有相关性,其中-137 C等位基因可能是NPC的遗传易感基因。本研究结果与Nong等^{[ 3]}报道相一致。

综上所述,NPC是一种多因素参与的常见病,除环境因素影响之外,遗传因素在其中也起着更为重要的作用,通过本研究可以发现,IL-18基因-137 G/C多态性和-137 C/-607 A单倍型与NPC的发病可能具有相关性,其中-137 C等位基因可能是NPC的遗传易感基因。但IL-18基因多态性是通过何种机制对NPC产生影响以及在NPC发病中的确切分子机制尚待进一步研究。

The authors have declared that no competing interests exist.

参考文献

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2012

12.812

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2011

0.0

2011

2.147

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. 2011, 28(4):1107-1115 DOI:10.1007/s12032-010-9569-1

Review and pooled analysis of studies on -607(C/A) and -137(G/C) polymorphisms in IL-18 and cancer risk

1.Department of Urology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China 2.Department of Ophthalmology, Affiliated Wuxi People’s Hospital of Nanjing Medical University, 299 Qingyang Road, 214023 Wuxi, China 3.Department of Orthopaedics, First Affiliated Hospital of Shantou University Medical College, 22 Xinling Road, Shantou, 515041 China

Interleukin-18 (IL-18) is a pleiotropic, pro-inflammatory cytokine with dual effects on tumor development and progression. The -607(C/A) and -137(G/C) polymorphisms in IL-18 gene region have been implicated in cancer risk; however, data from published studies with individually low statistical power are conflicting. To clarify the role of IL-18 -607(C/A) and -137(G/C) genotype in global cancer, we examined all the available published studies through a pooled analysis approach. Overall, IL-18 -607A allele was associated with increased total cancer risk when compared with -607C allele (OR = 1.14, 95% CI = 1.01–1.28, P = 0.010), as well as in the heterozygote comparison (OR = 1.10, 95% CI = 1.04–1.15, P = 0.256) and the dominant model (OR = 1.07, 95% CI = 1.03–1.11, P = 0.124). Furthermore, IL-18 -137(G/C) polymorphism was associated with increased nasopharyngeal carcinoma risk. In the stratified analysis for -607(C/A) polymorphism, a significantly increased cancer risk in Asian population was found, as well as subgroup in source of control. Similar results were found in the stratified analysis for -137(G/C) polymorphism. Our pooled analysis supported that IL-18 is a good candidate for large-scale epidemiological case–control studies that may be a low-penetrance susceptibility biomarker for cancer.

... 本研究结果与Nong等^[3]报道相一致 ...

2011

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. 2011, 50(1):36-46

Hodgkin disease risk: Role of genetic polymorphisms and gene–gene interactions in inflammation pathway genes

Claudia M. Monroy 1 ,Andrea C. Cortes 1 ,Mirtha S. Lopez 1 ,Anthony M. D'Amelio Jr. 1 ,Carol J. Etzel 1 ,Anas Younes 2 ,Sara S. Strom 1 andRanda A. El-Zein 1,*

1Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 2Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, Texas *Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, P.O. Box 301439, Houston, TX 77030-1439.

Inflammation is a critical component of cancer development. The clinical and pathological features of Hodgkin disease (HD) reflect an abnormal immunity that results from cytokines secreted by Reed–Sternberg cells and the surrounding tumor. Numerous studies have reported the association between genetic polymorphisms in cytokine genes and the susceptibility to different hematologic cancers. However, the effects of such SNPs on modulating HD risk have not yet been investigated. We hypothesized that gene–gene interactions between candidate genes in the anti- and pro-inflammatory pathways carrying suspicious polymorphisms may contribute to susceptibility to HD. To test this hypothesis, we conducted a study on 200 HD cases and 220 controls to assess associations between HD risk and 38 functional SNPs in inflammatory genes. We evaluated potential gene–gene interactions using a multi-analytic strategy combining logistic regression, multi-factor dimensionality reduction, and classification and regression tree (CART) approaches. We observed that, in combination, allelic variants in the COX2, IL18, ILR4, and IL10 genes modify the risk for developing HD. Moreover, the cumulative genetic risk score (CGRS) revealed a significant trend where the risk for developing HD increases as the number of adverse alleles in the cytokine genes increase. These findings support the notion that epigenetic-interactions between these cytokines may influence pathogenesis of HD modulating the proliferation of regulatory T cells. In this way, the innate and adaptative immune responses may be altered and defy their usual functions in the host anti-tumor response. Our study is the first to report the association between polymorphisms in inflammation genes and HD susceptibility risk. Mol. Carcinog. © 2010 Wiley-Liss, Inc.

2006

2.783

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2004

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2004

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. 2004, 5(4):472-476 DOI:10.1631/jzus.2004.0472

Study on interleukin-18 gene transfer into human breast cancer cells to prevent tumorigenicity

1.Zhejiang University Cancer Institute, Second Affiliated Hospital, School of Medicine 310009 Hangzhou China 2.Shandong Tumor Hospital 250117 Jinan China

To study the effect of interleukin-18 gene transfection on the tumorigenesis of breast cancer cell line Bacp37, human breast cancer cell line Bcap37 were transfected with Lipofectamine and selected by G418. The biological expression of rhlL-18 was tested by RT-PCR and ELISA method; nude mice were injected with Bcap37 cell with or without the hlL-18 gene. The hIL-18 cDNA was successfully integrated into Bcap37 cell; 126.3±4.5 pg hIL-18 secreted by one million transduced cells in 24 hours. Nude mice injected with IL-18 gene engineered Bcap37 cell had no tumor growth. These findings indicated that human breast cancer cells were successfully modified by the gene of IL-18 cytokine; the IL-18 gene engineered Bcap37 cells secreted hIL-18 and lost their tumorigenicity. The Bcap37 cells transduced with IL-18 gene may be used as breast cancer vaccine.

2009

2.867

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... Farjadfar等^[8] 检测肺癌IL-18 基因多态性,结果发现IL-18 基因-607 C/A 多态性与肺癌的发病具有相关性,其中-607 A等位基因频率在肺癌患者中显著高于对照组,-607 A等位基因携带者明显降低血清IL-18的表达,因而提出-607 A等位基因携带者机体抗肿瘤减弱,从而导致肺癌易感 ...

2009

2.344

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... Nong等^[9]通过对NPC IL-18 基因多态性的研究发现,IL-18 基因-137 G/C多态性与NPC的发病具有相关性,其中-137 C等位基因可能是NPC的遗传易感基因 ...

2010

2.298

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. 2010, 71(3):309-313 DOI:10.1016/j.humimm.2009.11.010

Impact of interleukin-18 polymorphisms-607 and -137 on clinical characteristics of renal cell carcinoma patients

Abstract

Current evidence suggests that chronic inflammation is associated with tumor development and progression. Interleukin-18 (IL-18) plays a central role in inflammation and the immune response, contributing to the pathogenesis and pathophysiology of infectious and inflammatory diseases. The objective of this study was to determine whether the presence of IL-18 polymorphisms -137 G/C (rs187238) and -607 A/C (rs1946518) was associated with size, grade, TNM stage, and survival in patients with renal cell carcinoma (RCC). The study cohort included 158 patients with RCC. Control group consisted of 506 samples from Spanish population. The studied IL-18 gene polymorphisms did not influence susceptibility to RCC in the analyzed group of patients (IL-18-607, p = 0.318; IL-18-137 p = 0.740) but may contribute to disease onset and aggressiveness. IL-18-607 CC genotype was significantly associated with higher tumor size (p = 0.001), grade (p = 0.030), T (p = 0.001), M (p = 0.012), and stage (p = 0.002). IL-18-103 GG genotype was correlated with higher tumor size (p = 0.036), grade (p = 0.017), T (p = 0.026), and stage (p = 0.011). The Cox proportional hazard model showed that nuclear grade and stage grouping were independent prognostic factors but IL-18 polymorphism was not. Polymorphism variants in the IL-18 gene (IL-18-607 and IL-18-137) may be associated with a worse prognosis for RCC. High levels of IL-18 production may play a major role in the growth, invasion and metastasis of renal cancer.

... pez等^[10]研究发现IL-18 基因-137 G/C和-607 C/A 两位点多态性与肾细胞癌都具有相关性 ...