Abstract
The −251T/A (rs4073), a single nucleotide polymorphism, has been identified in the promoter region of the interleukin-8 (IL-8) gene. It’s presence could influence the production of IL-8 protein by regulating the transcriptional activity of the gene. A large number of studies have been performed to evaluate the role of −251T/A polymorphism on various cancers, with inconsistent results being reported. In this paper, we summarized 13,189 cases and 16,828 controls from 42 case–control studies and attempted to assess the susceptibility of −251T/A polymorphism to cancers by a comprehensive meta-analysis. Pooled odds ratios and 95% confidence intervals were calculated by using the random-effects model. Publication bias, subgroup, and sensitivity analysis were also performed. Results showed that the carriers of the −251A allele had about a 12–21% increased risk for the reviewed cancer, in total. The carriers of −251A had an elevated risk to breast cancer, gastric cancer and nasopharyngeal cancer and a reduced risk to prostate cancer, but no evidence was found to indicate that the −251A allele predisposed its carriers to colorectal and lung cancers. When stratified separately by ‘racial descent’ and ‘study design’, it was found that the carriers of the −251A allele among the African group, Asian group and hospital-based case–control study group were at a higher risk for cancer, but not in European group and population-based case–control study. These results show that −251A allele is susceptible in the development of low-penetrance cancers.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Tumorigenesis is a complex, multi-step process that includes cellular neoplastic transformation, resistance to apoptosis, autonomous growth signaling, emergence of a vascular supply, evasion of immunologic surveillance, and the acquisition of invasive/metastatic properties [1]. Soluble factors in the tumoral environment which are derived not only from tumor cells, but also from stroma, inflammatory cells, and endothelial cells, are critical determinants of tumor processes. Direct and indirect evidence strongly implicates that chemokines, a subset of soluble factors, play a key role in tumorigenesis [2, 3].
As a member of the chemokine family, interleukin-8 (IL-8) is well known for its leukocyte chemotactic properties and its tumorigenic and proangiogenic activities [4, 5]. It is produced by a wide range of normal cells including monocytes, neutrophils, fibroblasts, and endothelial cells [6]. Initially characterized for its leukocyte chemotactic activity, it is mainly involved in the initiation and amplification of acute inflammatory reactions as well as in the maintenance of chronic inflammatory processes [7]. In addition, IL-8 is produced by several types of tumor cells [8] and has been involved in angiogenesis and neovascularization-dependent tumor growth [9, 10]. It is also overexpressed in a variety of human tumors and is involved in tumor invasion and metastasis [11–13]. Therefore, IL-8 may constitute a risk factor in the development and progression of tumors.
IL-8 gene is located on chromosome 4q13-21 and consists of four exons, three introns, and a proximal promoter region. It’s gene coding exhibits several functional polymorphisms, fifteen of them have been characterized [14]. Among these, a T/A single nucleotide polymorphism was identified in the promoter region of the IL-8 gene −251 base pairs upstream of the transcriptional start site and in vitro assays performed show that it influences the production of IL-8 and affects the transcriptional activity of the IL-8 promoter [15, 16]. However, the relationship between the −251T/A polymorphism and IL-8 gene transcriptional activity has been inconsistent. Most all reports have demonstrated that the −251A allele is directly associated with higher IL-8 transcription activity [16–18]. However, in gastric carcinoma cell line, Lee et al. [19] found that −251T possessed transcription activity 2- to 5-fold stronger than its −251A counterpart.
A large number of molecular epidemiology studies have been preformed to evaluate the role of −251T/A polymorphism on various cancers such as breast, colorectal, gastric, lung, prostate, etc. [15, 18–66]. The frequency of the −251A allele varies in different geographic areas and ethnic populations. Moreover, genetic effects of the polymorphism have been shown to vary from one type of cancer to the other. Even at the same tumor site, the results are conflicting. Consequently, the statistical power of an individual study could be very limited for efficient assessment of the −251A allele. Integration of these data sets may provide improved statistical power to detect the significance.
With an aim of addressing inconsistencies in the findings of these studies, we adopted a meta-analysis based on published case–control studies attempting to assess the association between the IL-8-251 T/A polymorphism and cancer susceptibility.
Materials and methods
Primary search strategy
We searched MEDLINE (US National Library of Medicine, Bethesda, MD) for all genetic association studies on the rs4073 polymorphism of IL-8 and the susceptibility of cancer published before November 2010 using the PubMed search engine. The search used the keywords and subject terms “IL-8” or “interleukin-8,” “−251T/A” or “rs4073,” “polymorphism,” or “SNPs,” and “cancer and/or carcinoma and/or neoplasm” and was limited to English-language papers. The references of all computer-identified publications were searched. In addition, the PubMed option “Related Articles” and the publications on same topic in the reference lists of the reviewed articles were retrieved to search for potentially relevant publications.
Criteria for inclusion and exclusion
Any human associated study, regardless of sample size, was included if it met the following criteria: (a) the study used an unrelated case–control design; (b) the study investigated the association between −251T/A polymorphisms of IL-8 and the risk of cancer; and (c) the genotype distribution of control population must be in Hardy–Weinberg equilibrium [goodness of fit test, degree of freedom (df) = 1]. For the articles with same population resource or overlapping data sets, the publication reporting the largest or most recent data set was included.
Data extraction
Two investigators independently extracted data and reached a consensus on all of the items. The following information was sought from each article: author, journal and year of publication, country of origin, selection and characteristics of cancer cases and controls, demographics, ethnicity, study design, genotyping methods and genotyping information. For subjects of different ethnicities, data were extracted separately and categorized as European, Asian, and African (Table 1).
Statistical analysis
Firstly, we tested significance of deviation of genotype distribution at the polymorphic site from that expected from Hardy–Weinberg equilibrium in the control sample for each of the selected case–control data sets. The random-effects model was used to calculate the pooled odds ratio to estimate genotype AA, genotype TA, and A-allele carriers (AA + TA) against the TT genotype. In addition to comparisons for total subjects, studies were categorized into different subgroup analyses according to the ethnicity and tumor site (if a particular tumor type includes only one published study, it was categorized into the “other cancer” group). For each subgroup, we estimated the between-study heterogeneity across the eligible comparisons using the χ2-based Q test [67] and the heterogeneity was considered significant if P < 0.05. We also used the statistic of I 2 to efficiently test for the heterogeneity [68], with I 2 < 25%, 25–75% and >75% to represent low, moderate and high degree of inconsistency, respectively. When heterogeneity was not an issue, fixed effect model with Mantel–Haenszel method was used. Otherwise, a random effect model with Inverse variance method was used.
Publication bias was investigated with funnel plot, which is used as the main graphical method. To supplement the funnel plot approach, the Begg and Mazumdar adjusted rank correlation test [69] and the Egger regression asymmetry test [70] were adopted. To evaluate the stability of the results, we performed a one-way sensitivity analysis. The scope of this analysis reflects the influence of an individual data set by estimating the average odds ratio in the absence of each data set [71]. Statistical tests performed in the present analysis were considered significant whenever the corresponding null-hypothesis probability was P < 0.05.
All analyses were done with review manager software (RevMan; version 5.0, The Cochrane Collaboration, Oxford, England) and STATA software (version 10.0, Stata Corporation, College Station, TX). All the P values were two-sided.
Results
Meta-analysis results
A total of 58 published studies investigated the relationship between IL-8-251T/A polymorphism and cancer risk, three of which were excluded because they did not present detailed genotyping information [64, 65] or they investigated the same population of reported articles [66]. Eight studies were excluded because they were not a case–control study [72–79]. Another five studies were excluded because their genotype distributions in control population significantly deviate from HWE [59–63]. Hence, 42 case–control studies [15, 18–58], including 13,189 cancer cases and 16,828 controls, were used in this analysis, study characteristics were summarized in Table 1.
Overall data analysis
For all 43 data sets extracted from the 42 case–control studies, −251A allelic frequency in the pooled cases was moderately higher than that in the corresponding controls (Z = 2.63, P = 0.008). The pooled odds ratio estimate was 1.12 (95% confidence interval (CI) 1.03–1.23), suggesting that carriers of the −251A allele would have a moderately higher risk of being predisposed to developing cancer (Table 2). Both Cochran’s Q test (Q = 105.82 with 42 df, P < 0.00001) and the estimate of I 2 (60%) revealed a significant heterogeneity among the constituent studies (Table 3). To assess the cause of heterogeneity, we carried out subgroup analyses for ‘cancer type’, ‘racial descent’ and ‘study design’. Table 2 summarizes the odds ratio estimates and the corresponding 95% CIs for the subgroups. Table 3 summarizes Q tests and I 2 estimates for the subgroups. When stratified separately by ‘racial descent’, we found that −251A homozygote, heterozygote and −251A allele carriers increased cancer risk among the African and Asian group but not the European group. Subgroup analysis of ‘study design’ indicated that significantly increased risks were found among hospital-based case–control studies but not in population-based case–control studies. Because of the existence of heterogeneity, we carried out one-way sensitivity analyses and found that the results in odds ratio estimates were consistent with previous results when heterogeneity was removed, which confirmed the stability of the odds ratio estimates. The analyses for each type of cancer are detailed later in this text. The P values for the Begg and Mazumdar test and the Egger test were all higher than 0.05 for −251A homozygote, heterozygote and −251A allele carriers (Table S1, on-line supplementary data), both suggesting a negligible publication bias. In addition, to explore sources of heterogeneity, we carried out meta-regression analysis by covariate ‘cancer type’, ‘racial descent’, ‘genotyping methods’ and ‘study design’. Results indicated that covariates ‘racial descent’, ‘genotyping methods’ and ‘study design’ could explain 54% (AA vs. TT), 100% (AT vs. TT) and 83.29% ((AA + AT) vs. TT) of heterogeneity (Table S2, on-line supplementary data).
Breast cancer
Five studies investigated the susceptibility of −251A carriers to breast cancer, comprising 1,454 patients and 1,366 normal controls [20–24]. Overall meta-analysis showed that the −251A heterozygotes had a moderately increased risk of developing breast cancer (OR 1.28, 95% CI 1. 00–1.64). However, statistical tests showed a significant heterogeneity among these studies (Q = 10.78 with 4 df, P = 0.03; I 2 = 63%). To evaluate the stability of the results, we performed a one-way sensitivity analysis. The heterogeneity was effectively removed (Q = 2.80 with 3 df, P = 0.42; I 2 = 0%) after exclusion of the data of Vogel et al. [23], and the results were consistent with our previous results without omission. The OR estimates for −251A heterozygotes and −251A alleles were 1.45 (95% CI 1.18–1.79) and 1.52 (95% CI 1.25–1.85), respectively. So, our meta-analysis result provided evidence that IL-8 −251A carriers are associated with an increased risk of breast cancer.
Colorectal cancer
Five studies investigated the susceptibility of −251A carriers to colorectal cancer in Europeans, comprising 1,242 patients and 1,880 normal controls [25–29]. When these data sets were analyzed together, there was no significant heterogeneity (Q = 6.72 with 4 df, P = 0.15; I 2 = 40%). The odds ratio for the risk of cancer for the −251A carriers was estimated as 1.00 (95% CI 0.81–1.25), and it showed no significant association of the −251A allele with progression of colorectal cancer.
Gastric cancer
Eighteen studies investigated −251T/A polymorphism in relation to gastric cancer [15, 18, 19, 30–44], which involved 4,274 cases and 6,498 controls. Meta-analysis showed that the −251A alleles had a significantly increased risk of developing gastric cancer (OR 1.17, 95% CI 1. 01–1.36). The odds ratio estimates for −251A homozygote and heterozygote were 1.28 (95% CI 1. 02–1.62) and 1.13 (95% CI 0.98–1.30), respectively. However, statistical tests showed a significant heterogeneity among these studies (Q = 48.17 with 17 df, P < 0.0001; I 2 = 65%). To avoid the influence of the genetic heterogeneity on the association analysis, we separated the meta-analysis according to Asian and European groups. Significantly elevated risks were observed in all comparison models in the Asian group but not in the European group (Table 2). However, heterogeneity in the Asian group was still high (P = 0.01), which could be directly attributed to the data set from Lee et al. [19]. After exclusion of this data set, the heterogeneity was effectively removed (Q = 12.05 with 11 df, P = 0.36; I 2 = 9%). Sensitivity analysis got similar results in odds ratio estimates after excluding this data set [Compared with TT genotype, OR for AA, AT genotypes and A allele carriers were 1.65 (1.39–1.95), 1.26 (1.09–1.45) and 1.34 (1.19–1.51), respectively], indicating that our results were statistically reliable. These results demonstrated that the −251A allele was an ethnicity-dependent risk factor for gastric cancer.
Lung cancer
Three studies addressed the relationship of the −251T/A polymorphism to lung cancer in Europeans [45–47], which involved 2,786 cases and 3,070 controls. The heterogeneity tests were not statistically significant (Q = 0.94 with 2 df, P = 0.62; I 2 = 0%). The odds ratio estimate from the pooled data sets for the −251A carriers was 0.98 (95% CI 0.87–1.10). There were no significant difference in allelic and genotypic frequency distribution between patients and controls, suggesting that the −251A allele carriers were not susceptible to lung cancer.
Nasopharyngeal cancer
Two studies involving 440 patients and 459 controls detected the −251T/A polymorphism in nasopharyngeal cancer patients in Tunisia [48] and China [49]. The heterogeneity tests showed no statistical significance (Q = 0.10 with 1 df, P = 0.75; I 2 = 0%). The odds ratio estimate from the pooled data sets was 2.04 (95% CI 1.38–2.99) for −251A homozygote, 1.59 (95% CI 1.19–2.13) for −251A heterozygote, and 1.70 (95% CI 1.30–2.24) for the −251A carriers, respectively. This showed that IL-8 −251A allele carriers have an increased risk to nasopharyngeal cancer.
Prostate cancer
Four studies focused on the association between the −251A allele and prostate cancer in Europeans, with 1,496 patients and 1,518 controls [50–53]. The odds ratio estimate for the −251A allele carriers showed no significance (odds ratio (OR) 0.95, 95% CI 0.72–1.25). However, statistical tests indicated a significant heterogeneity among these studies (Q = 8.06 with 3 df, P = 0.04; I 2 = 63%). This finding can be attributed to the data set from McCarron et al. [53], in which gender and age were statistically significant in patients and controls. The heterogeneity was effectively removed after exclusion of this data set (Q = 0.82 with 2 df, P = 0.66; I 2 = 0%). Sensitivity analysis detected significant changes in the pooled odds ratio estimates after excluding this data set. The pooled odds ratio estimates for −251A allele carriers were 0.83 (95% CI 0.70–0.99), which indicated that IL-8 −251A allele carriers have a decreased risk to prostate cancer.
Other cancers
Six studies [40, 54–58] involving 1,497 patients and 2,037 controls had detected the −251T/A polymorphism in cancer patients, including; cutaneous malignant melanoma, esophageal squamous cell carcinoma, tongue cancer etc. The results of the heterogeneity tests showed no statistically significant difference (Q = 5.88 with 5 df, P = 0.32; I 2 = 15%). The odds ratio estimate from the pooled data sets for the −251A carriers was 1.04 (95% CI 0.87–1.23). No significant difference was detected in allelic and genotypic frequency distribution between patients and controls, implying that the −251A allele bears no susceptibility to these six cancers.
Discussion
Our meta-analysis, based on 42 case–control studies with 13,189 cases and 16,828 controls, showed that the carriers of −251A allele had about a 12–21% increased risk for the reviewed cancer in total. The carriers of −251A had a higher risk to breast cancer, gastric cancer and nasopharyngeal cancer and lower risk to prostate cancer. When stratified separately by ‘racial descent’ and ‘study design’, it was found that carriers of the −251A allele demonstrated an increased risk to cancer among the African group, the Asian group and hospital-based case–control group.
Three meta-analyses [80–82] on the association of IL-8 −251T/A polymorphism with various cancers was published in 2010, two of which [80, 81] were based on roughly the same published data from 10 to 12 individual case–control studies [15, 18, 19, 33, 35, 36, 38–40, 42–44] and were restricted to gastric cancer risk. The meta-analysis of Wang et al. [80] analyzed 10 case–control studies with 2,195 cases and 3,505 controls and concluded that −251A homozygote has a significant association with the risk of gastric cancer. Subgroup analysis of ‘racial descent’ indicated that significantly increased risks were found among the Asian group but not the European group. These results were consistent with ours but were inconsistent with the results of Liu et al., which concluded that the carriers of −251A allele were not associated with the risk of gastric cancer.
The meta-analysis by Gao et al. [82] analyzed 14,876 cases with different cancer types and 18,465 controls from 45 case–control studies, 36 of them met our inclusion criteria and were included in our meta-analysis. When compared, the results of the two meta-analysis showed that the carriers of −251A exhibited high risk among the African group and the hospital-based case–control study to nasopharyngeal cancer. However, there were also inconsistent between the analyses. Our results showed that the carriers of −251A had a higher risk to breast cancer and gastric cancer and lower risk to prostate cancer, but Gao et al. found no significant risks to these three cancers. Also, Gao et al. reported that the −251A allele decreased cancer risk among population-based studies with no significant risks being observed in all comparison models for the Asian group only, whereas, our results indicated that there were no significant cancer risks among population-based studies but significantly increased risk in all comparison models for the Asian group. Maybe these differences were mainly caused by the inclusion criteria of the two articles. Firstly, the studies published in English (41 articles) or Chinese (4 articles) were all included in meta-analysis by Gao et al., whereas, only English-language papers were included in ours. Secondly, five studies which did not present detailed genotyping information [64, 65] or which genotype distributions in control population significantly deviate from HWE [61–63] were excluded in our meta-analysis but included in meta-analysis by Gao et al. Thirdly, the data from six newly published papers [20, 28, 30–32, 37] were included in our meta-analysis but not in meta-analysis of Gao et al.
One of the major concerns in meta-analysis is heterogeneity between the component studies. Lack of attention to this commonly occurring problem may cause a misleading statistical inference. To test the significance of heterogeneity, we carried out Cochran’s Q test and calculated the quantity I 2 that describes the magnitude of heterogeneity across the constituent studies. To explore the sources of heterogeneity, we carried out meta-regression analysis and found that covariates ‘racial descent’, ‘genotyping methods’ and ‘study design’ could explain about 54–100% of heterogeneities in all comparison models. For (AA vs. TT) model and [(AA + AT) vs. TT] model, not all the heterogeneity could be explained by the covariates, which is common in a meta-regression analysis but the data was permitted. Thus, we also carried out subgroup analyses for ‘racial descent’ and observed significantly elevated risks in all comparison models among the African group and the Asian group, but not in the European group, which may indicate that the −251A allele is an ethnicity-dependent risk factor for cancer. In a subgroup analysis of ‘study design’, we observed significantly increased risk among hospital-based case–control studies but not in the population-based case–control studies. Because hospital-based controls were less representative of the general population than population-based controls, there maybe exist a selection bias and we must draw a conclusion carefully.
Another crucial question for meta-analysis is publication bias. To assess this problem, we presented the relation between the odds ratio estimates in a logarithmic scale and their corresponding standard errors across all constituent data sets. The results showed that no obvious publication bias was detected in this analysis. In fact, both the Begg and Mazumdar adjusted rank correlation analysis and the Egger regression asymmetry test revealed no correlation between the estimate of odds ratio and sample size.
It is well established that environmental factors including tobacco use, alcohol consumption and dietary habits are associated with cancer risks [83]. In addition, virus infections such as helicobacter pylori and hepatitis B virus play a key role in gastric cancer risk and hepatocellular carcinoma risk [84, 85]. Furthermore, several studies suggested a possible interaction between −251A and family history on cancer risk [51], and the effect of IL-8 was perhaps best represented by its haplotypes [49]. However, the lack of original data from of the meta-analysis limited our further evaluation of potential gene-to-gene and gene-to-environment interactions. In spite of this, our meta-analysis holds some key benefits in two aspects. Firstly, large numbers of cases and controls were pooled from different studies, which significantly increased statistical power of the analysis. Secondly, the quality of case–control studies included in our meta-analysis was good. In fact, all included studies were embodied by SCI (Science Citation Index) magazine.
In conclusion, our meta-analysis supports growing evidence that the −251A allele in the promoter region of the IL-8 gene is emerging as a low-penetrance cancer susceptibility allele in the development of cancers. To further evaluate the interactions on −251T/A polymorphisms and cancer risks, a single larger study with thousands of subjects and tissue-specific biochemical and biological characterizations is required.
References
Brat DJ, Bellail AC, Van Meir EG (2005) The role of interleukin-8, its receptors in gliomagenesis, tumoral angiogenesis. Neuro-Oncology 7(2):122–133
Balkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4(7):540–550
Vicari AP, Caux C (2002) Chemokines in cancer. Cytokine Growth Factor Rev 13(2):143–154
Harada A, Sekido N, Akahoshi T et al (1994) Essential involvement of interleukin-8 (IL-8) in acute inflammation. J Leukoc Biol 56(5):559–564
Xie K (2001) Interleukin-8, human cancer biology. Cytokine Growth Factor Rev 12(4):375–391
Rollins BJ (1997) Chemokines. Blood 90(3):909–928
Du H, Bay BH, Mahendran R et al (2002) Endogenous expression of interleukin-8, interleukin-10 in nasopharyngeal carcinoma cells, the effect of photodynamic therapy. Int J Mol Med 10(1):73–76
Heinzmann A, Ahlert I, Kurz T et al (2004) Association study suggests opposite effects of polymorphisms within IL8 on bronchial asthma, respiratory syncytial virus bronchiolitis. J Allergy Clin Immunol 114(3):671–676
van Aken BE, Reitsma PH, Rosendaal FR (2002) Interleukin 8, venous thrombosis: evidence for a role of inflammation in thrombosis. Br J Haematol 116(1):173–177
Koch AE, Polverini PJ, Kunkel SL et al (1992) Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258(5089):1798–1801
Kitadai Y, Haruma K, Mukaida N et al (2000) Regulation of disease-progression genes in human gastric carcinoma cells by interleukin 8. Clin Cancer Res 6(7):2735–2740
Bendre MS, Gaddy-Kurten D, Mon-Foote T et al (2002) Expression of interleukin 8 and not parathyroid hormone-related protein by human breast cancer cells correlates with bone metastasis in vivo. Cancer Res 62(19):5571–5579
Li A, Dubey S, Varney ML et al (2003) IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 170(6):3369–3376
Hull J, Rowlands K, Lockhart E et al (2004) Haplotype mapping of the bronchiolitis susceptibility locus near IL8. Hum Genet 114(3):272–279
Canedo P, Castanheira-Vale AJ, Lunet N et al (2008) The interleukin-8-251*T/*A polymorphism is not associated with risk for gastric carcinoma development in a Portuguese population. Eur J Cancer Prev 17(1):28–32
Hull J, Thomson A, Kwiatkowski D (2000) Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families. Thorax 55(12):1023–1027
Hull J, Ackerman H, Isles K et al (2001) Unusual haplotypic structure of IL8, a susceptibility locus for a common respiratory virus. Am J Hum Genet 69(2):413–419
Taguchi A, Ohmiya N, Shirai K et al (2005) Interleukin-8 promoter polymorphism increases the risk of atrophic gastritis and gastric cancer in Japan. Cancer Epidemiol Biomarkers Prev 14(11 Pt 1):2487–2493
Lee WP, Tai DI, Lan KH et al (2005) The −251T allele of the interleukin-8 promoter is associated with increased risk of gastric carcinoma featuring diffuse-type histopathology in Chinese population. Clin Cancer Res 11(18):6431–6441
Snoussi K, Mahfoudh W, Bouaouina N et al (2010) Combined effects of IL-8 and CXCR2 gene polymorphisms on breast cancer susceptibility and aggressiveness. BMC Cancer 10:283
Snoussi K, Mahfoudh W, Bouaouina N et al (2006) Genetic variation in IL-8 associated with increased risk and poor prognosis of breast carcinoma. Hum Immunol 67(1–2):13–21
Kamali-Sarvestani E, Aliparasti MR, Atefi S (2007) Association of interleukin-8 (IL-8 or CXCL8) −251T/A and CXCR2 +1208C/T gene polymorphisms with breast cancer. Neoplasma 54(6):484–489
Vogel U, Christensen J, Nexo BA et al (2007) Peroxisome proliferator-activated [corrected] receptor-gamma2 [corrected] Pro12Ala, interaction with alcohol intake and NSAID use, in relation to risk of breast cancer in a prospective study of Danes. Carcinogenesis 28:427–434
Smith KC, Bateman AC, Fussell HM et al (2004) Cytokine gene polymorphisms, breast cancer susceptibility, prognosis. Eur J Immunogenet 31(4):167–173
Cacev T, Radosević S, Krizanac S et al (2008) Influence of interleukin-8 and interleukin-10 on sporadic colon cancer development and progression. Carcinogenesis 29(8):1572–1580
Wilkening S, Tavelin B, Canzian F et al (2008) Interleukin promoter polymorphisms and prognosis in colorectal cancer. Carcinogenesis 29:1202–1206
Vogel U, Christensen J, Dybdahl M et al (2007) Prospective study of interaction between alcohol, NSAID use and polymorphisms in genes involved in the inflammatory response in relation to risk of colorectal cancer. Mutat Res 624:88–100
Gunter MJ, Canzian F, Landi S et al (2006) Inflammation-related gene polymorphisms, colorectal adenoma. Cancer Epidemiol Biomarkers Prev 15(6):1126–1131
Theodoropoulos G, Papaconstantinou I, Felekouras E et al (2006) Relation between common polymorphisms in genes related to inflammatory response and colorectal cancer. World J Gastroenterol 12(31):5037–5043
Bo S, Dianliang Z, Hongmei Z et al (2010) Association of interleukin-8 gene polymorphism with cachexia from patients with gastric cancer. J Interferon Cytokine Res 30(1):9–14
Zhang L, Du C, Guo X et al (2010) Interleukin-8-251A/T polymorphism and Helicobacter pylori infection influence risk for the development of gastric cardiac adenocarcinoma in a high-incidence area of China. Mol Biol Rep 37(8):3983–3989
Song B, Zhang D, Wang S et al (2009) Association of interleukin-8 with cachexia from patients with low-third gastric cancer. Comp Funct Genomics 2009:212345
Ye BD, Kim SG, Park JH et al (2009) The interleukin-8 −251 A allele is associated with increased risk of noncardia gastric adenocarcinoma in Helicobacter pylori-infected Koreans. J Clin Gastroenterol 43:233–239
Ko KP, Park SK, Cho LY et al (2009) Soybean product intake modifies the association between interleukin-10 genetic polymorphisms and gastric cancer risk. J Nutr 139:1008–1012
Kang JM, Kim N, Lee DH et al (2009) The effects of genetic polymorphisms of IL-6, IL-8, and IL-10 on Helicobacter pylori-induced gastroduodenal diseases in Korea. J Clin Gastroenterol 43(5):420–428
Shirai K, Ohmiya N, Taguchi A et al (2006) Interleukin-8 gene polymorphism associated with susceptibility to non-cardia gastric carcinoma with microsatellite instability. J Gastroenterol Hepatol 21(7):1129–1135
Kamali-Sarvestani E, Bazargani A, Masoudian M et al (2006) Association of H. pylori cagA and vacA genotypes and IL-8 gene polymorphisms with clinical outcome of infection in Iranian patients with gastrointestinal diseases. World J Gastroenterol 12:5205–5210
Lu W, Pan K, Zhang L et al (2005) Genetic polymorphisms of interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor alpha and risk of gastric cancer in a Chinese population. Carcinogenesis 26(3):631–636
Ohyauchi M, Imatani A, Yonechi M et al (2005) The polymorphism interleukin 8 −251 A/T influences the susceptibility of Helicobacter pylori related gastric diseases in the Japanese population. Gut 54(3):330–335
Savage SA, Abnet CC, Mark SD et al (2004) Variants of the IL8, IL8RB genes, risk for gastric cardia adenocarcinoma, esophageal squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 13(12):2251–2257
Crusius JB, Canzian F, Capella G et al (2008) Cytokine gene polymorphisms and the risk of adenocarcinoma of the stomach in the European prospective investigation into cancer and nutrition (EPIC-EURGAST). Ann Oncol 19:1894–1902
Garza-Gonzalez E, Bosques-Padilla FJ, Mendoza-Ibarra SI et al (2007) Assessment of the toll-like receptor 4 Asp299Gly, Thr399Ile, interleukin-8-251 polymorphisms in the risk for the development of distal gastric cancer. BMC Cancer 7:70
Kamangar F, Abnet CC, Hutchinson AA et al (2006) Polymorphisms in inflammation-related genes, risk of gastric cancer (Finland). Cancer Causes Control 17(1):117–125
Savage SA, Hou L, Lissowska J et al (2006) Interleukin-8 polymorphisms are not associated with gastric cancer risk in a Polish population. Cancer Epidemiol Biomarkers Prev 15(3):589–591
Vogel U, Christensen J, Wallin H et al (2008) Polymorphisms in genes involved in the inflammatory response and interaction with NSAID use or smoking in relation to lung cancer risk in a prospective study. Mutat Res 639:89–100
Campa D, Hung RJ, Mates D et al (2005) Lack of association between −251T>A polymorphism of IL8, lung cancer risk. Cancer Epidemiol Biomarkers Prev 14(10):2457–2458
Campa D, Zienolddiny S, Maggini V et al (2005) Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. Carcinogenesis 25(2):229–235; Erratum in Carcinogenesis 26(6):1157
Ben Nasr H, Chahed K, Mestiri S et al (2007) Association of IL-8 (−251)T/A polymorphism with susceptibility to and aggressiveness of nasopharyngeal carcinoma. Hum Immunol 68(9):761–769
Wei YS, Lan Y, Tang RG et al (2007) Single nucleotide polymorphism and haplotype association of the interleukin-8 gene with nasopharyngeal carcinoma. Clin Immunol 125(3):309–317
Wang MH, Helzlsouer KJ, Smith MW et al (2009) Association of IL10 and other immune response- and obesity-related genes with prostate cancer in CLUE II. Prostate 69:874–885
Michaud DS, Daugherty SE, Berndt SI et al (2006) Genetic polymorphisms of interleukin-1B (IL-1B), IL-6, IL-8, and IL-10 and risk of prostate cancer. Cancer Res 66(8):4525–4530
Yang HP, Woodson K, Taylor PR et al (2006) Genetic variation in interleukin 8, its receptor genes, its influence on the risk, prognosis of prostate cancer among Finnish men in a large cancer prevention trial. Eur J Cancer Prev 15(3):249–253
McCarron SL, Edwards S, Evans PR et al (2002) Influence of cytokine gene polymorphisms on the development of prostate cancer. Cancer Res 62(12):3369–3372
Shimizu Y, Kondo S, Shirai A et al (2008) A single nucleotide polymorphism in the matrix metalloproteinase-1 and interleukin-8 gene promoter predicts poor prognosis in tongue cancer. Auris Nasus Larynx 35(3):381–389
Campa D, Hashibe M, Zaridze D et al (2007) Association of common polymorphisms in inflammatory genes with risk of developing cancers of the upper aerodigestive tract. Cancer Causes Control 18:449–455
Vogel U, Christensen J, Wallin H et al (2007) Polymorphisms in COX-2, NSAID use and risk of basal cell carcinoma in a prospective study of Danes. Mutat Res 617:138–146
van der Kuyl AC, Polstra AM, Weverling GJ et al (2004) An IL-8 gene promoter polymorphism is associated with the risk of the development of AIDS-related Kaposi’s sarcoma: a case–control study. AIDS 18:1206–1208
Howell WM, Turner SJ, Theaker JM et al (2003) Cytokine gene single nucleotide polymorphisms, susceptibility to, prognosis in cutaneous malignant melanoma. Eur J Immunogenet 30(6):409–414
Zhang J, Dhakal IB, Lang NP et al (2010) Polymorphisms in inflammatory genes, plasma antioxidants, and prostate cancer risk. Cancer Causes Control 21(9):1437–1444
Ahirwar DK, Mandhani A, Mittal RD (2010) IL-8 −251 T>A polymorphism is associated with bladder cancer susceptibility, outcome after BCG immunotherapy in a northern Indian cohort. Arch Med Res 41(2):97–103
Kury S, Buecher B, Robiou-du-Pont S et al (2008) Low-penetrance alleles predisposing to sporadic colorectal cancers: a French case–controlled genetic association study. BMC Cancer 8:326
Vairaktaris E, Yapijakis C, Serefoglou Z et al (2007) The interleukin-8 (−251A/T) polymorphism is associated with increased risk for oral squamous cell carcinoma. Eur J Surg Oncol 33(4):504–507
Landi S, Moreno V, Gioia-Patricola L et al (2003) Association of common polymorphisms in inflammatory genes interleukin (IL)6, IL8, tumor necrosis factor alpha, NFKB1, and peroxisome proliferator-activated receptor gamma with colorectal cancer. Cancer Res 63(13):3560–3566
Leibovici D, Grossman HB, Dinney CP et al (2005) Polymorphisms in inflammation genes and bladder cancer: from initiation to recurrence, progression, and survival. J Clin Oncol 23(24):5746–5756
Lee KM, Shen M, Chapman RS et al (2007) Polymorphisms in immunoregulatory genes, smoky coal exposure and lung cancer risk in Xuan Wei, China. Carcinogenesis 28:1437–1441
Vairaktaris E, Yapijakis C, Serefoglou Z et al (2008) Gene expression polymorphisms of interleukins-1 beta, -4, -6, -8, -10, and tumor necrosis factors-alpha, -beta: regression analysis of their effect upon oral squamous cell carcinoma. J Cancer Res Clin Oncol 134(8):821–832
Cochran WG (1954) The combination of estimates from different experiments. Biometrics 10:101–129
Higgins JP, Thompson SG, Deeks JJ et al (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560
Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50(4):1088–1101
Egger M, Davey Smith G, Schneider M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634
Tobias A (1999) Assessing the influence of a single study in the meta-analysis estimate. Stata Tech Bull 8:15–17
Zhang W, Stoehlmacher J, Park DJ et al (2005) Gene polymorphisms of epidermal growth factor receptor, its downstream effector, interleukin-8, predict oxaliplatin efficacy in patients with advanced colorectal cancer. Clin Colorectal Cancer 5(2):124–131
Lurje G, Husain H, Power DG et al (2010) Genetic variations in angiogenesis pathway genes associated with clinical outcome in localized gastric adenocarcinoma. Ann Oncol 21(1):78–86
Stocker G, Ott K, Henningsen N et al (2009) CyclinD1 and interleukin-1 receptor antagonist polymorphisms are associated with prognosis in neoadjuvant-treated gastric carcinoma. Eur J Cancer 45(18):3326–3335
Lurje G, Hendifar AE, Schultheis AM et al (2009) Polymorphisms in interleukin 1 beta, interleukin 1 receptor antagonist associated with tumor recurrence in stage II colon cancer. Pharmacogenet Genomics 19(2):95–102
Lurje G, Leers JM, Pohl A et al (2010) Genetic variations in angiogenesis pathway genes predict tumor recurrence in localized adenocarcinoma of the esophagus. Ann Surg 251(5):857–864
Reyes-Gibby CC, Shete S, Yennurajalingam S et al (2009) Genetic and nongenetic covariates of pain severity in patients with adenocarcinoma of the pancreas: assessing the influence of cytokine genes. J Pain Symptom Manage 38(6):894–902
Schultheis AM, Lurje G, Rhodes KE et al (2008) Polymorphisms and clinical outcome in recurrent ovarian cancer treated with cyclophosphamide and bevacizumab. Clin Cancer Res 14(22):7554–7563
Lin HC, Liu CC, Kang WY et al (2009) Influence of cytokine gene polymorphisms on prostate-specific antigen recurrence in prostate cancer after radical prostatectomy. Urol Int 83(4):463–470
Wang J, Pan HF, Hu YT et al (2010) Polymorphism of IL-8 in 251 allele and gastric cancer susceptibility: a meta-analysis. Dig Dis Sci 55(7):1818–1823
Liu L, Zhuang W, Wang C et al (2010) Interleukin-8 −251 A/T gene polymorphism and gastric cancer susceptibility: a meta-analysis of epidemiological studies. Cytokine 50(3):328–334
Gao LB, Pan XM, Jia J et al (2010) IL-8 −251A/T polymorphism is associated with decreased cancer risk among population-based studies: evidence from a meta-analysis. Eur J Cancer 46(8):1333–1343
Lee M, Lee Y, Cho HJ et al (2011) Copy number variations of chromosome 17p13.1 might be linked to high risk of lung cancer in heavy smokers. Mol Biol Rep. doi:10.1007/s11033-010-0672-3
Zhang Q, Li Y, Li X et al (2009) PARP-1 Val762Ala polymorphism, CagA+ H. pylori infection, risk for gastric cancer in Han Chinese population. Mol Biol Rep 36(6):1461–1467
Duan S, Zhang G, Han Q et al (2010) CTLA-4 exon 1 +49 polymorphism alone and in a haplotype with −318 promoter polymorphism may confer susceptibility to chronic HBV infection in Chinese Han patients. Mol Biol Rep. doi:10.1007/s11033-010-0660-7
Acknowledgments
We greatly acknowledge Dr. Vogel [23], Dr. Ko [34] and Dr. Zhang [59], for they have provided the frequencies of IL-8 −251 T/A polymorphism between the cases and controls in detail. We also greatly acknowledge Stacey Dial (Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Food and Drug Administration, USA) for her helpful comments. This work is supported by funds for the potentially distinguished scientific project construction program in Hebei universities.
Author information
Authors and Affiliations
Corresponding author
Additional information
Our study indicated that −251A allele of the interleukin-8 gene was emerging as a low-penetrance cancer susceptibility allele for the development of cancers.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Wang, N., Zhou, R., Wang, C. et al. −251 T/A polymorphism of the interleukin-8 gene and cancer risk: a HuGE review and meta-analysis based on 42 case–control studies. Mol Biol Rep 39, 2831–2841 (2012). https://doi.org/10.1007/s11033-011-1042-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-011-1042-5