|Year : 2018 | Volume
| Issue : 8 | Page : 105-113
Cyclooxygenase-2 gene polymorphisms and susceptibility to hepatocellular carcinoma: A meta-analysis based on 10 case-control studies
Wei Xu1, Yaping Huang1, Ting Zhang1, Lingyun Zhao2, Jun Fan1, Lanjuan Li1
1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medical College, Zhejiang University, Hangzhou 310003, Zhejiang, China
2 Zhejiang-California International Nanosystems Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China
|Date of Web Publication||26-Mar-2018|
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medical College, Zhejiang University, Hangzhou 310003
Source of Support: None, Conflict of Interest: None
Objective: The association between cyclooxygenase-2 (COX-2) gene polymorphisms and hepatocellular carcinoma (HCC) has been widely reported, but the results are still controversial. To clarify the effect of COX-2 −1195G/A (rs689466), −765G/C (rs20417), and +8473T/C (rs5275) polymorphisms on HCC risk, a meta-analysis was performed.
Materials and Methods: The PubMed, Embase, Cochrane Library, Web of Science, Chinese BioMedical Literature, Wanfang, and Chinese National Knowledge Infrastructure databases were systematically searched to identify potential studies published up to October 10, 2014. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association. A total of eight studies with 2060 HCC cases and 2610 controls for −1195G/A, six studies with 1295 cases and 2193 controls for −765G/C, and four studies with 1477 cases and 1747 controls for +8473T/C were included in this meta-analysis.
Results: Overall, the COX-2 −1195G/A, and +8473T/C polymorphisms were both significantly associated with an increased risk of HCC (rs689466 GA + AA vs. GG: OR = 1.390, P = 0.006, 95% CI: 1.099–1.759, I2 = 50.7%, Pheterogeneity = 0.048; rs5275 CC vs. TT + TC: OR = 1.484, P = 0.041, 95% CI: 1.017–2.165, I2 = 0.0%, Pheterogeneity = 0.416). In the subgroup analyses stratified by ethnicity, the COX-2 −1195G/A, −765G/C, and +8473T/C were all associated with an increased HCC risk in Asian populations (rs689466 A vs. G: OR = 1.346, P = 0.001, 95% CI: 1.137–1.595, I2 = 0.0%, Pheterogeneity = 0.869; rs20417 CC vs. GG + GC: OR = 3.069, P = 0.013, 95% CI: 1.265–7.447; rs5275 CC vs. TT + TC: OR = 1.626, P = 0.020, 95% CI: 1.079–2.452, I2 = 0.0%, Pheterogeneity = 0.495).
Conclusions: Our meta-analysis suggests that −1195G/A, −765G/C, and +8473T/C in COX-2 may contribute significantly to HCC risk.
Keywords: Cyclooxygenase-2, hepatocellular carcinoma, meta-analysis, polymorphism, susceptibility
|How to cite this article:|
Xu W, Huang Y, Zhang T, Zhao L, Fan J, Li L. Cyclooxygenase-2 gene polymorphisms and susceptibility to hepatocellular carcinoma: A meta-analysis based on 10 case-control studies. J Can Res Ther 2018;14, Suppl S1:105-13
|How to cite this URL:|
Xu W, Huang Y, Zhang T, Zhao L, Fan J, Li L. Cyclooxygenase-2 gene polymorphisms and susceptibility to hepatocellular carcinoma: A meta-analysis based on 10 case-control studies. J Can Res Ther [serial online] 2018 [cited 2019 Sep 19];14:105-13. Available from: http://www.cancerjournal.net/text.asp?2018/14/8/105/172110
| > Introduction|| |
Hepatocellular carcinoma (HCC) is one of the most serious health problems worldwide. Sub-Saharan Africa and Eastern Asia are the regions with the highest incidence of HCC (>20/100,000 people), and China alone accounts for more than 50% of the world's cases,, which was considered as a genetic and environmental disease.
Cyclooxygenase-2 (COX-2) also known as prostaglandin-endoperoxide synthase 2 (PTGS2) is a rate-limiting enzyme that converts arachidonic acid to prostaglandins, and plays a key role in many biological processes such as inflammation, immune function, cell proliferation, and angiogenesis, which are all crucial in the development and progression of neoplasms. Besides, accumulating evidence shows that COX-2 overexpression contributes to tumorigenesis of a variety of human malignancies by stimulating cell proliferation, inhibiting apoptosis, enhancing invasiveness, and mediating immune suppression. The human COX-2 gene is located on chromosome 1q25.2-q25.3 and contains 10 exons and 9 introns spanning 8.3 kb, and there are many different polymorphism sites in the COX-2 gene. Of them, −1195G/A (rs689466) and −765G/C (rs20417) in the promoter region, and +8473T/C (rs5275) in the 3'-untranslated region of the COX-2 gene have been widely investigated. These three single nucleotide polymorphisms could affect gene transcription and/or mRNA stability, and consequently cause individual variation in susceptibility to cancers.
Meta-analysis offers a powerful means of overcoming the problems associated with small sample size, and particularly, of overcoming the inadequate statistical powers of genetic studies on complex traits. Therefore, we performed a meta-analysis of all eligible studies to clarify the relationship between COX-2 −1195G/A, −765G/C, and +8473T/C polymorphisms and HCC risk.
| > Materials and Methods|| |
This meta-analysis was designed and reported according to the preferred reporting items for systematic reviews and meta-analyses statement [Supplementary Table 1] [Additional file 1] .
Literature searching strategy
A computerized literature search of PubMed, Embase, Cochrane Library, Web of Science, Chinese BioMedical Literature, Wanfang, and Chinese National Knowledge Infrastructure databases were conducted to identify all potential studies published up to October 10, 2014. The following keywords and subject terms were included in searching: “COX-2” or “PTGS2,” “liver cancer” or “HCC,” and “polymorphism” or “variant” or “allele.” References of retrieved articles and review articles were also screened.
Studies included in the meta-analysis had to meet all the following criteria: (1) Evaluating the association between COX-2 −1195G/A, −765G/C, and +8473T/C polymorphisms and HCC risk; (2) using case-control design; (3) using unrelated individuals; (4) providing sufficient data for estimating an odds ratio (OR) with its 95% confidence interval (95% CI); (5) published in English or Chinese. The corresponding authors were contacted to obtain missing information, and studies were excluded if the critical missing information was not retrievable. Case reports, case-only studies, reviews, animal studies, simple commentaries, and studies without sufficient data were all excluded. If more than one article was published using the same subjects, only the study with the largest sample size was selected.
Two investigators extracted data independently. When it came to conflicting evaluations, an agreement was reached after a discussion. The following data were extracted: Authors, name of journal, year of publication, ethnicity and country of study population, study design, inclusion and exclusion criteria, HCC confirmation, numbers of HCC cases and controls, characteristics of cases and controls, matching criteria, genotyping methods, genotype frequency of cases and controls, and interactions between environmental factors or genes.
Quality score assessment
Two investigators assessed the quality of studies independently, according to a set of predetermined criteria [Supplementary Table 2] [Additional file 2] . Any disagreement was resolved by discussion between the two investigators. The total scores ranged from 0 (worst) to 24 (best). Studies scoring <16 were classified as “low quality,” and those scoring ≥16 as “high quality.”
The unadjusted OR with 95% CI was used to assess the strength of the association between COX-2 polymorphisms (−1195G/A, −765G/C and +8473T/C) and HCC risk. The pooled ORs were calculated under the allelic contrast (−1195G/A: A vs. G, −765G/C: C vs. G, +8473T/C: C vs. T), homozygote comparison (−1195G/A: AA vs. GG, −765G/C: CC vs. GG, +8473T/C) and heterozygote comparison (−1195G/A: GA vs. GG, −765G/C: GC vs. GG, +8473T/C: TC vs. TT), dominant model (−1195G/A: GA + AA vs. GG, −765G/C: GC + CC vs. GG, +8473T/C: TC + CC vs. TT), and recessive model (−1195G/A: GG + GA vs. AA, −765G/C: GG + GC vs. CC, +8473T/C: TC + TT vs. CC), respectively. The Q-statistic test and I2 statistic were used to measure between-study heterogeneity., P < 0.10 was considered representative of significant statistical heterogeneity because of the low power of the statistic. I2 ranges between 0% and 100%, and represents the proportion of between-study variability that can be attributed to heterogeneity rather than chance. I2 values of 25%, 50%, and 75% were defined as low, moderate, and high estimates. If the significant Q-statistic indicated heterogeneity across studies, the random-effects model (DerSimonian and Laird method) was utilized; otherwise, the fixed-effect model (Mantel–Haenszel method) was adopted to pool the results. The Z-test was used to assess the significance of the pooled OR and P < 0.05 was considered significant.
Subgroup analyses were stratified by ethnicity, study design, type of controls, study quality, genotyping methods, and number of cases, respectively. Sensitivity analyses were performed by sequential omission of individual studies and by excluding data in which Hardy–Weinberg equilibrium (HWE) tested by the χ2 test was violated to evaluate the stability of the results. Furthermore, both Begg's test and Egger's test were performed to test whether publication bias existed or not. All P values were two-sided. All of these analyses were performed using the software Stata software (version 11.0, StataCorp LP, College Station, TX, USA).
| > Results|| |
According to the searching strategy, there are several studies conducted to examine the association between COX-2 −1195G/A, −765G/C, and +8473T/C polymorphisms and HCC susceptibility, but the results remain controversial and inconclusive.,,,,,,,,,
The details of the literature search and study selection procedures were presented in a flow chart in [Figure 1]. The literature search yielded a total of 407 potentially relevant records. After removing 73 duplications, 306 records were excluded because of obvious irrelevance to our study aim by checking the titles and abstracts. Eighteen of the remaining 28 records further were excluded based on the selection criteria (flow diagram as flowed), and 10 studies were included in the meta-analysis.,,,,,,,,, Among them, eight studies with 2060 HCC cases and 2610 controls were available for −1195G/A polymorphism, six studies with 1295 cases and 2193 controls for −765G/C polymorphism, and four studies with 1477 cases and 1747 controls for +8473T/C polymorphism.
Characteristics of studies and subjects
The main characteristics of the eligible studies were listed in [Table 1]. Among the 10 included studies, seven were performed in Asian populations, one in European populations, and two in African populations. Six studies are used healthy subjects as controls while four studies included both healthy subjects and patients with chronic liver diseases (hepatitis B virus [HBV] infection, hepatitis C virus infection, cirrhosis) as controls. The sample size of the total participants ranged from 200 to 1560, with a mean of 669. The quality scores of the individual studies ranged from 11.5 to 20.5, with 8 out of the 10 studies classified as high quality. The genotype distribution in the controls was consistent with HWE for all selected studies, except for 1 study for −1195G/A, 1 study for −765G/C, and 1 study for +8473T/C. The frequency of −1195A allele was 50% in Asian controls, 86% in European controls, and 55% in African controls. The frequency of −765C allele was 6% in Asian controls, 27% in European controls, and 20% in African controls. There were significant differences among the three major ethnicities in terms of −1195A and −765C allele frequency, respectively (P < 0.001). The frequency of +8473C allele was 19% in Asian controls, and 31% in European controls. There were significant differences in terms of +8473C allele frequency between the two major ethnicities (P < 0.001).
|Table 1: Main characteristics of eligible studies included in the meta-analysis|
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[Table 2] and [Figure 2]a indicate the associations between COX-2 −1195G/A polymorphism and HCC risk. Overall, the −1195G/A polymorphism was significantly associated with an increased HCC risk under the dominant model (OR = 1.390, P= 0.006, 95% CI: 1.099–1.759, I2 = 50.7%, Pheterogeneity = 0.048), homozygote comparison (OR = 1.422, P= 0.021, 95% CI: 1.054–1.918, I2 = 57.8%, Pheterogeneity = 0.020), and heterozygote comparison (OR = 1.500, P= 0.021, 95% CI: 1.063–2.115, I2 = 73.5%, Pheterogeneity < 0.001). In the subgroup analyses by ethnicity, the pooled results showed that −1195G/A polymorphism was significantly associated with HCC in Asian populations (AA vs. GG: OR = 1.442, P= 0.034, 95% CI: 1.028–2.022, I2 = 67.7%, Pheterogeneity = 0.015; A vs. G: OR = 1.199, P= 0.031, 95% CI: 1.016–1.414, I2 = 66.8%, Pheterogeneity = 0.017); and African populations (GA + AA vs. GG: OR = 2.144, P= 0.002, 95% CI: 1.323–3.477, I2 = 0.0%, Pheterogeneity = 0.595), but not in European populations (GA + AA vs. GG: OR = 1.000, P= 1.000, 95% CI: 0.139–7.209). When stratifying by study design in Asian populations, a significantly elevated association between −1195G/A polymorphism and HCC risk was observed in population-based studies (A vs. G: OR = 1.346, P= 0.001, 95% CI: 1.137–1.595, I2 = 0.0%, Pheterogeneity = 0.869), but not in hospital-based studies (A vs. G: OR = 1.121, P= 0.302, 95% CI: 0.902–1.394, I2 = 72.1%, Pheterogeneity = 0.028). Furthermore, according to chronic liver disease status in Asian controls, a significant association between −1195G/A polymorphism and HCC risk was obtained both in healthy controls (A vs. G: OR = 1.255, P= 0.001, 95% CI: 1.098–1.435, I2 = 50.2%, Pheterogeneity = 0.134) and controls with chronic liver diseases (A vs. G: OR = 1.388, P= 0.019, 95% CI: 1.057–1.823).
|Table 2: Main results of meta-analysis for COX-2 -1195G/A polymorphism and HCC risk|
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|Figure 2: Forest plots of cyclooxygenase-2 −1195G/A (dominant), −765G/C and −1195G/A (recessive) to hepatocellular carcinoma risk. (a) Forest plots for the association between cyclooxygenase-2 −1195G/A and hepatocellular carcinoma risk under the dominant model. For each study, the estimate of odds ratio and its 95% confidence interval is plotted with a diamond and a horizontal line. (b) Forest plots for the association between cyclooxygenase-2 −765G/C and hepatocellular carcinoma risk under the dominant model. For each study, the estimate of odds ratio and its 95% confidence interval is plotted with a diamond and a horizontal line. (c) Forest plots for the association between cyclooxygenase-2 −1195G/A and hepatocellular carcinoma risk under the recessive model. For each study, the estimate of odds ratio and its 95% confidence interval is plotted with a diamond and a horizontal line|
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[Table 3] and [Figure 2]b indicate the associations between COX-2 −765G/C polymorphism and HCC risk. Overall, the COX-2 −765G/C polymorphism was not associated with HCC risk under any genetic model (C vs. G: OR = 1.314, P= 0.300, 95% CI: 0.784–2.202, I2 = 87.9%, Pheterogeneity < 0.001). In the subgroup analyses based upon ethnicity, the decreased association with HCC risk was significant in European populations (CC vs. GG + GC: OR = 0.243, P= 0.014, 95% CI: 0.078–0.754), but insignificant in African populations (CC vs. GG + GC: OR = 0.713, P= 0.607, 95% CI: 0.196–2.589). However, in Asian populations, a significantly elevated association between −765G/C polymorphism and HCC risk was found (CC vs. GG + GC: OR = 3.069, P= 0.013, 95% CI: 1.265–7.447). When stratifying by study design in Asian populations, the −765G/C polymorphism was significantly associated with an increased HCC risk both in population-based studies (C vs. G: OR = 2.671, P < 0.001, 95% CI: 1.772–4.027, I2 = 0.0%, Pheterogeneity = 0.380) and hospital-based studies (CC vs. GG + GC: OR = 3.069, P= 0.013, 95% CI: 1.265–7.447). Furthermore, according to chronic liver disease status in Asian controls, a significant association between −765G/C polymorphism and HCC risk was observed both in healthy controls (CC vs. GG + GC: OR = 5.138, P= 0.036, 95% CI: 1.116–23.651) and controls with chronic liver diseases (CC vs. GG + GC: OR = 3.069, P= 0.013, 95% CI: 1.265–7.447).
|Table 3: Main results of meta-analysis for COX-2 -765G/C polymorphism and HCC risk|
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[Table 4] and [Figure 2]c indicate the associations between COX-2 +8473T/C polymorphism and HCC risk. Overall, the pooled results of all the studies showed that the COX-2 +8473T/C polymorphism was significantly associated with an increased HCC risk (CC vs. TT + TC: OR = 1.484, P= 0.041, 95% CI: 1.017–2.165, I2 = 0.0%, Pheterogeneity = 0.416). When stratifying by ethnicity, the +8473T/C polymorphism was significantly associated with an elevated HCC risk in Asian populations (CC vs. TT + TC: OR = 1.626, P= 0.020, 95% CI: 1.079–2.452, I2 = 0.0%, Pheterogeneity = 0.495), but insignificantly associated with a reduced HCC risk in European populations (CC vs. TT + TC: OR = 0.882, P= 0.802, 95% CI: 0.329–2.361).
|Table 4: Main results of meta-analysis for COX-2 +8473T/C polymorphism and HCC risk|
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The Q-statistic and I2 statistic indicated statistically significant heterogeneity among all studies under all genetic models for COX-2 −1195G/A and −765G/C polymorphisms [Table 2] and [Table 3]. Therefore, the random-effects model was adopted to analyze the OR. To explore the sources of heterogeneity, we performed subgroup analyses by ethnicity, study design, type of controls, study quality, genotyping methods, and number of cases, respectively. However, heterogeneity still existed in subgroups. For COX-2 +8473T/C polymorphism, there was no evidence for between-study heterogeneity in any genetic model [Table 4].
Sensitivity analysis and publication bias
Sensitivity analyses were performed by sequential omission of individual studies and by excluding data in which HWE was violated. The pooled ORs were consistently significant for COX-2 −1195G/A polymorphism in the dominant model suggesting the robustness of our results. However, the significant association turned to be negative for COX-2 −765G/C and +8473T/C polymorphisms in sensitivity analyses.
Funnel plots and Egger's test were performed to assess the publication bias of included literature. The shapes of funnel plot were symmetrical, which have not implied the existence of publication bias. The results of three polymorphisms were detected for COX-2 −1195G/A (A vs. G: T = 0.29, P= 0.779), −765G/C (C vs. G: T = −0.27, P= 0.804), and +8473T/C (C vs. T: T = −0.05, P= 0.966) [Figure 3]. All the P values were >0.05, and thus there was no obvious publication bias in the meta-analysis.
|Figure 3: Funnel plots for publication bias of cyclooxygenase-2 variants and hepatocellular carcinoma risk. (a) The cyclooxygenase-2 −1195G/A polymorphism. (b) The −765G/C −polymorphism.(c) The +8473T/C polymorphism|
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| > Discussion|| |
This article investigated the relationship between COX-2 −1195G/A, −765G/C, and +8473T/C polymorphisms and HCC susceptibility. A total of 2060 cases and 2610 controls available from eight studies concerning −1195G/A, 1295 cases and 2193 controls available from six studies concerning −765G/C, and 1477 cases and 1747 controls available from four studies concerning +8473T/C were finally included in this study. Overall, the combined results demonstrated that COX-2 −1195G/A and +8473T/C were both significantly associated with an increased risk of HCC. There was no evidence for an association between −765G/C and HCC risk in overall populations under any genetic model. Further subgroup analyses by ethnicity revealed that COX-2 −1195G/A, −765G/C, and +8473T/C were all associated with an increased HCC risk in Asian populations. Sensitivity analysis further strengthened the validity of the positive association in overall populations for −1195G/A, indicating the robustness of our results.
It is possible that genetic factors play different roles in HCC susceptibility across various ethnic populations. In this study, ethnicity was identified as a potential source of between-study heterogeneity by subgroup analyses. Although the underlying mechanisms are unclear, several factors may contribute to the discrepancy. First, different genetic backgrounds may cause the difference. In the present study, there were significant differences among the three major ethnicities in terms of −1195A, −765C, and +8473C allele frequency, respectively. The frequency of the minor allele among the controls of all studies was consistent with that in 1000 Genome Project, except for three studies for −1195G/A,,, and three studies for −765G/C polymorphism., The omission of these studies did not substantially alter the results, indicating the reliability of our results. Second, different linkage disequilibrium patterns may contribute to the discrepancy. The COX-2 polymorphisms may be in close linkage with different nearby causal variants in different populations. Third, different lifestyles may exert different influences on HCC. Different populations usually differ in dietary intake of nutrients, some of which may play important roles in the tumorigenesis and tumor metastasis by gene-environment interactions. Last but not least, owing to the limited number of studies in European and African populations included in this study, the ethnic discrepancy may be caused by chance. Consequently, more well-designed studies should be performed to investigate the cause of this discrepancy.
Although statistically significant associations were found in Asian populations for COX-2 −1195G/A, −765G/C, and +8473T/C polymorphisms, it should still be treated with caution because of between-study heterogeneity and small sample size. For −1195G/A polymorphism, the significant heterogeneity disappeared, and the pooled results reached significance in Asian populations under all genetic models when a study by Fan et al. were omitted. Different from other studies, this study included both healthy subjects and patients infected with HBV as controls and used Taqman method to genotype the polymorphism. Numerous epidemiology studies have suggested that infection with HBV contributed to the development and progression of HCC. Nevertheless, according to chronic liver disease status in Asian controls, a significant association between COX-2 −1195G/A polymorphism and HCC risk was observed both in healthy controls, and controls with chronic liver diseases indicating reliability of the pooled results in Asian populations. Moreover, the geographical discrepancy should be considered in the analyses because all Asian studies were based on Chinese populations. Therefore, our results with Chinese populations may not reflect the effects on HCC risk as accurately as those with the whole Asian populations. For −765G/C, the significant results in Asian populations were based on the study by He et al. of which the quality score was high, and the sample size was the largest of all the eligible studies. Although, we performed the subgroup analysis based on ethnicity to eliminate the heterogeneity among these studies, the heterogeneity still existed in Asian. Sensitivity analysis suggested that the pooled results for −765G/C and +8473T/C were not stable. Therefore, larger population-based studies were required to confirm further the association between COX-2 polymorphisms and HCC risk in Asian populations.
COX-2 is an inducible enzyme that converts arachidonic acid to prostaglandins, which are potent mediators of inflammation. Through the production of prostaglandins, COX-2 is thought to influence carcinogenesis by simulating cell proliferation, inhibiting apoptosis, promoting angiogenesis, enhancing invasiveness, and mediating immune suppression. The COX-2 −1195G/A polymorphism creates a c-myeloblastosis binding site, resulting in the higher transcription activity of the COX-2 gene. The COX-2 −765G/C polymorphism may change a putative stimulatory protein binding site in the promoter of COX-2, but it creates an E2 promoter factor binding site, leading to high transcription activity and increased COX-2 expressions. The COX-2 +8473T/C polymorphism may affect gene expression through altered messenger RNA stability and/or translational efficiency. Therefore, it has been speculated that COX-2 −1195G/A, −765G/C, and +8473T/C polymorphisms may have effects on HCC risk. This meta-analysis showed that COX-2 −1195G/A, −765G/C, and +8473T/C polymorphisms were all associated with an increased risk of HCC in Asian populations, which was consistent with the hypothesis. Further functional studies are required to explore the underlying mechanism of the COX-2 gene on HCC.
The current meta-analysis has several limitations that should be considered. First, publication bias might be possible, even though the statistical test did not show it because only published studies were included in the meta-analysis. Second, study designs varied across different studies. Three studies were population-based while seven were hospital-based. Subjects from hospital-based studies may not represent the general populations. The subgroup analyses indicated that COX-2 −1195G/A and −765G/C polymorphisms were all associated with HCC risk in population-based studies. Moreover, controls were divided into healthy controls and controls with chronic liver diseases. The subgroup analyses showed that the effect of COX-2 polymorphisms on HCC susceptibility seemed to be identical in healthy controls and controls with chronic liver diseases. Third, gene-gene and gene-environment interactions were not addressed in this meta-analysis due to lack of sufficient data. If individual data were available, adjusted ORs could be obtained to conduct a more precise analysis. Finally, the sample size was relatively small for European populations and African populations, which may lead to low statistical power and generate fluctuation in estimation.
Our meta-analysis suggests that COX-2 −1195G/A and +8473T/C polymorphisms are significantly associated with the increased risk of HCC in overall populations. For Asian populations, COX-2 −1195G/A, −765G/C, and +8473T/C polymorphisms are all associated with the elevated risk of HCC. Further well-designed and large-scale studies with the consideration of gene-gene and gene-environment interactions should be conducted to investigate the association in different ethnic populations.
Financial support and sponsorship
Supported by the opening foundation of the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medical College, Zhejiang University, grant NO. 2013KF04.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]