Introduction
Prostate cancer is the most common type of cancer diagnosis in males and the estimated new prostate cancer cases and mortalities in 2013 were 238,590 and 29,720, respectively (1). Several studies have been performed and their results suggested that the etiology of prostate cancer was extremely complicated, and may be associated with several factors, including smoking, environment, dietary habits, endocrine system, age and ethnicity (2–7). However, the accurate etiology and pathogenesis remain inconsistent. Recently, a number of studies suggested that inflammation and genetic factors may play an important role in the etiology of prostate cancer (8–14). The prostaglandin-endoperoxide synthase 2 gene that encodes the cyclooxygenase-2 enzyme has been verified to play an important role in the development of prostate cancer in numerous studies (15–18). The study by Woo et al (19) observed that tumor infiltrating B-cells were increased in prostate cancer tissue. The Lv et al (20) study suggested that hypoxia promoted the invasiveness of prostate cancer PC3 cells via hypoxia-inducible factor-1α- and tumor necrosis factor-α-induced stabilization of Snail. McDonald et al (21) investigated the associations between systemic inflammatory markers and serum prostate-specific antigen (PSA) in 3,164 healthy males and found that elevated serum PSA (194 males, 6.1% of the total) was significantly associated with plasma fibrinogen, suggesting that the markers of systemic inflammation were associated with elevated PSA in males without a known prostate disease.
Among the cytokines involved in inflammation, interleukin-6 (IL-6) plays a key role in the inflammation process. IL-6 is one of the most potent proinflammatory cytokines during acute inflammation, inducing and regulating the production of acute phase proteins (22). Previously, several studies have shown that the IL-6 polymorphism is significantly associated with a number of diseases and plays an important role in the etiology of diseases (23–29). With regards to prostate cancer, the Mandić et al (30) study indicated that the IL-6 -174 single-nucleotide polymorphism (SNP) distribution may vary between ethnicities and that a single cytokine-gene polymorphism probably has only a minor influence on prostate cancer susceptibility. The study by Pierce et al (31) suggested that circulating IL-6 and its gene polymorphism did not influence the prostate cancer risk, whereas Mandal et al (32) had an opposing opinion. Due to these conflicting results, the present meta-analysis was conducted to provide a comprehensive assessment of the associations of the IL-6 (-174 G/C) gene polymorphism with the risk of prostate cancer.
Materials and methods
Search strategy
Databases, including PubMed, Embase, Web of Science, the Cochrane Library, Chinese Biomedical Literature Database and Wanfang database, were searched between January 1994 and March 2014 for all the possible studies using an analytical design (including case-control and cohort studies) that mainly studied the association between the IL-6 (-174 G/C) gene polymorphism and the susceptibility of prostate cancer. The search terms used included: ‘Prostate cancer’ or ‘PCa;’ ‘interleukin 6’ or ‘IL-6;’ and ‘polymorphism,’ ‘single-nucleotide polymorphism,’ ‘SNP’ or ‘variation;’ and there was no language restriction in the literature search. To find more eligible studies that may not have been included in the initial search, the references of the candidate studies were examined and searches of unpublished literature were conducted.
Inclusion and exclusion criteria
The studies in the meta-analysis were included according to the following criteria: i) Analytical design (including case-control and cohort studies); ii) evaluation of the prostate cancer risk and IL-6 (-174 G/C) gene polymorphism; iii) sufficient data, including the number or frequency of alleles and genotypes; and iv) genotype frequencies in control groups should be abided by the Hardy-Weinberg equilibrium (HWE). The exclusion criteria included: i) Case studies and reviews; ii) no sufficient data reported; and iii) duplicated studies.
Data extraction
The quantitative data of all the eligible studies were extracted according to the inclusion and exclusion criteria by two investigators independently and a consensus was attempted if the data for one investigator was inconsistent with the other. The following characteristics of each study were collected: Authors, year of publication, study design, ethnicity, group, sample size, alleles and IL-6 genotypes. Certain studies included more than one ethnicity, therefore the information data were extracted separately according to the ethnicity.
Data synthesis and statistical analysis
The pooled odds ratio (OR) with 95% confidence interval (95% CI) was calculated to assess the associations between the IL-6 (-174 G/C) gene polymorphism and prostate cancer according to allele contrast (C vs. G), homozygote (CC vs. GG), heterozygote (GC vs. GG), dominant (GC/CC vs. GG) and recessive (CC vs. GC/GG) models, and P<0.05 was considered to indicate a statistically significant difference. The subgroup analysis was also performed to determine whether there was a significant association between the IL-6 (-174 G/C) gene polymorphism and prostate cancer in different ethnicities. The heterogeneity assumption was checked by a χ2-based Q statistic test and quantified by the I2 metric value. When I2>50% or P<0.10, suggesting that a clear heterogeneity existed, the ORs were pooled by the random-effect model, but for other cases the fixed-effect model was used. In addition, the sensitivity analysis was performed by individually removing the included studies to assess the impact of each study on the combined effect of the present meta-analysis. Stata 12.0 software (StataCorp, College Station, TX, USA) was used to analyze the data in the study.
Results
Study characteristics
In the initial search, the total studies were identified and 11 studies (30–40) with 10,745 cases and 13,473 controls eventually satisfied the eligibility criteria (Fig. 1). Among these studies, 10 (30,32–40) were case-control studies and only one (31) was a cohort study. Three studies (31,32,40) were conducted in Caucasian and African-American patients; five (30,34–36,39) reported the results in Caucasian patients only, two studied Asian patients (37,38) and one (33) was conducted in a mixed population (Caucasian and African-American). Additionally, 10 studies (31–40) reported the alleles and genotypes of IL-6 (-174 G/C) and one (30) reported only the number of CC and GG+GC genotypes. The general demographical characteristics of the studies included in the meta-analysis are summarized in Table I. The genotype distributions in the controls of all the studies were consistent with HWE.
Meta-analysis results
In the meta-analysis, there were no associations found between the IL-6 (-174 G/C) polymorphism and prostate cancer susceptibility in the overall population in all the genetic models indicated in Table II (allele contrast: C vs. G; heterozygote model: GC vs. GG; and homozygote model: CC vs. GG), Fig. 2 (dominant model: GC/CC vs. GG) and Fig. 3 (recessive model: CC vs. GG/GC). The subgroup analysis suggested that the IL-6 (-174 G/C) polymorphism was not significantly associated with prostate cancer in Asian, Caucasian and mixed population patients under the allele contrast, homozygote, heterozygote, dominant and recessive models. However, in African-American patients, the subgroup analysis suggested that there was a slightly significant association between the IL-6 (-174 G/C) polymorphism and prostate cancer risk in the homozygote and recessive models (CC vs. GG: OR, 3.43; 95% CI, 1.01–11.71; P=0.049; CC vs. GG/GC: OR, 3.51; 95% CI, 1.04–11.82; P=0.042, respectively) (Figs. 3 and 4) and no significant association was found in the allele contrast, heterozygote and dominant models (Table II and Fig. 2).
Sensitivity analysis
To evaluate the stability of the meta-analysis, a leave-one-out sensitivity analysis was performed. The sensitivity analysis suggested that the independent study by Mandal et al (32) influenced the interpretation of the results in the homozygote and recessive models for African-American patients. When the Mandal et al (32) study was removed from the present meta-analysis, no significant association was found between the IL-6 (-174 G/C) polymorphism and the risk of prostate cancer in African-American patients under the homozygote (OR, 2.67; 95% CI, 0.69–10.36; P=0.17) and recessive models (OR, 2.64; 95% CI, 0.70–9.98; P=0.15). However, no single study influenced the results in the overall population by the sensitivity analysis.
Publication bias
The Begg’s test was performed and the results did not reveal any evidence of clear asymmetry (C vs. G, P=0.95; CC vs. GG, P=0.73; GC vs. GG, P=0.54; GC/CC vs. GG, P=0.63; and CC vs. GC/GG, P=0.06), suggesting the absence of publication bias in the meta-analysis.
Discussion
Prostate cancer is a common cause of cancer mortality in males and it is widely considered that age, diet, ethnicity and environmental factors contribute to the prostate cancer etiology (2,5–7), but recently the genetic background and inflammation are considered as sensitive factors for the differences in prostate cancer susceptibility (37,40). Following the identification of the IL-6 (-174 G/C) polymorphism, attention to determine whether the IL-6 (-174 G/C) polymorphism is associated with prostate cancer, not only in the overall population but also in different ethnicities, has increased. Bao et al (37) used TaqMan polymerase chain reaction to gene-type the IL-6 (-174 G/C) polymorphism for comparing the prostate cases and controls in terms of allele frequency, genotype frequency and risk of prostate cancer. The results suggested that no significant association was found in the population of Han people in the Hubei region, which was also identified in Caucasian patients (36). Additionally, two meta-analyses (41,42) based on studies published 4–10 years ago also held the same conclusion. However, a recent study published in January 2014 by Mandal et al (32) suggested that the GG genotype may be associated with an increased risk of prostate cancer in Caucasian subjects, whereas the CC genotype was associated with an increased risk in the African-American subjects.
In order to determine whether the IL-6 (-174 G/C) polymorphism is associated with the prostate cancer risk in the overall population and different ethnic populations, the present meta-analysis of 11 independent studies was performed, which included 10,745 cases and 13,473 controls based on several recently published studies, whose results were inconsistent with former studies. In the meta-analysis, it was found that the IL-6 (-174 G/C) polymorphism is not a risk factor for prostate cancer in the overall population. However, the present study suggested that there was a slightly significant association between the IL-6 (-174 G/C) polymorphism and prostate risk in African-American patients under the homozygote and recessive models (CC vs. GG: OR, 3.43; 95% CI, 1.01–11.71; P=0.049; and CC vs. GG/GC: OR, 3.51; 95% CI, 1.04–11.82; P=0.042, respectively), which contradicts the results of the Magalhaes et al (41) meta-analysis. In addition, no significant associations were found in Asians and Caucasians, which is consistent with the Magalhaes et al (41) and Zhang et al (42) studies, suggesting that ancestral genetic factors in different populations may have an impact on prostate cancer susceptibility. Additionally, the removal of the Mandal et al (32) study from the present meta-analysis showed that no significant association was found between the IL-6 (-174 G/C) polymorphism and the risk of prostate cancer in African-American patients under the homozygote (OR, 2.67; 95% CI, 0.69–10.36; P=0.17) and recessive models (OR, 2.64; 95% CI, 0.70–9.98; P=0.15). The potential explanation for this may involve the different patients recruited in each independent study, as well as their different lifestyles, different experimental procedures and complex gene-gene and gene-environment interaction, which may also have contributed to these conflicting results.
Although the comprehensive analysis was conducted to show the association between the IL-6 (-174 G/C) gene polymorphism and prostate cancer risk, there are particular limitations that should be identified. Firstly, for the African-American patients, only three studies were conducted and the results of these studies were contradictory. Therefore, it may be difficult to explore the real association in African-American patients. Secondly, only two studies that were conducted in Asian patients fulfilled the inclusion criteria, which could not provide enough statistical power to detect the possible effects of the IL-6 (-174 G/C) gene polymorphism on prostate cancer in Asian patients. Thirdly, the studies included in the meta-analysis were conducted in Caucasian, Asian and African-American patients, which may not represent the negative associations in all the worldwide ethnicities. In addition, the possibility of gene-gene interactions or environmental factors or the possibility of linkage disequilibrium between the polymorphisms were also not considered in the study. Therefore, larger-scale and well-designed studies are necessary to estimate the association between the IL-6 (-174 G/C) polymorphism and the risk of prostate cancer.
In conclusion, although there were certain limitations in the meta-analysis, the study was based on a substantial number of cases and controls and suggested that there was no significant association between IL-6 (-174 G/C) polymorphism and the prostate cancer risk in the overall population, as well as in Caucasian and Asian patients, whereas the CC genotype may be associated with an increased prostate cancer risk in the African-American patients. Due to these limitations, more studies that consider lifestyle, complex gene-gene and gene-environment interactions or family history should be conducted to further assess the associations of the IL-6 (-174 G/C) gene polymorphisms with the risk of prostate cancer.