|Year : 2016 | Volume
| Issue : 2 | Page : 676-680
Meta-analysis of the relationship between microRNA-499 rs3746444 polymorphism and hepatocellular carcinoma risk in Asians
Weiyu Wang1, Hanlin Qin1, Lei Zhou1, Jinliang Ma2
1 Department of Radiology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, China
2 Department of Hepatic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, China
|Date of Web Publication||25-Jul-2016|
Department of Hepatic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, 17 LuJiang Road, Hefei 230001
Source of Support: None, Conflict of Interest: None
Objective: Numerous studies have reported the role of microRNA-499 rs3746444 polymorphism with hepatocellular carcinoma. (HCC) risk in Asians, but the specific association is still controversial.
Materials and Methods: To derive a more precise estimation of the relationship, a meta-analysis was performed. An electronic search of PubMed database was conducted to select relevant studies. Odds ratios. (ORs) with 95% confidence intervals. (CIs) were estimated to assess the relationship between microRNA-499 rs3746444 polymorphism and HCC risk in Asians.
Results: Eight relevant studies including 2196 cases and 2701 controls were included in this meta-analysis. When all the eligible studies were pooled into this meta-analysis, no significant association of HCC risk with microRNA-499 rs3746444 polymorphism was found in Asians (TT vs. CC: OR = 1.00 95% CI = 0.54–1.83; TT vs. TC: OR = 0.89, 95% CI = 0.66–1.20; dominant model: OR = 1.13, 95% CI = 0.81–1.58; recessive model: OR = 0.99, 95% CI = 0.56–1.76).
Conclusion: This meta-analysis suggests that the microRNA-499 rs3746444 polymorphism is not contributed to the risk of HCC in Asians. However, more studies should be performed in the future to confirm this association.
Keywords: Hepatocellular carcinoma, microRNA-499, polymorphism, susceptibility
|How to cite this article:|
Wang W, Qin H, Zhou L, Ma J. Meta-analysis of the relationship between microRNA-499 rs3746444 polymorphism and hepatocellular carcinoma risk in Asians. J Can Res Ther 2016;12:676-80
|How to cite this URL:|
Wang W, Qin H, Zhou L, Ma J. Meta-analysis of the relationship between microRNA-499 rs3746444 polymorphism and hepatocellular carcinoma risk in Asians. J Can Res Ther [serial online] 2016 [cited 2021 Jul 31];12:676-80. Available from: https://www.cancerjournal.net/text.asp?2016/12/2/676/154002
| > Introduction|| |
Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor and is the second leading cause of cancer-related deaths worldwide. There are >660,000 new HCC cases every year, and it has an increasing incidence. This disease is strongly associated with several risk factors: Alcoholism, hepatitis B and C, liver cirrhosis, hemochromatosis, aflatoxin and type 2 diabetics. Although several major risk factors above have been shown to contribute to hepatocarcinogenesis, the etiology is still unclear. With developments of molecular biology in recent years, researchers provide strong evidence that genetic factors are important in the pathogenesis of HCC, such as LAPTM4B and CYP2E1 gene.,,
MicroRNAs are a group of endogenous small noncoding RNA molecules with length of around 22 nucleotides. Most microRNAs located at cancer-associated genomic regions or fragile sites. Previous studies showed that microRNAs are involved in multiple pivotal processes of cancer development and progression including cell differentiation, proliferation, apoptosis, migration, and invasion. Abnormal expression of microRNAs has been correlated with several pathophysiologic events including HCC. Therefore, it was hypothesized that genetic polymorphisms in microRNAs may be associated with the development of HCC. The human microRNA-499 gene was mapped to 20q11.22. An A to G single-nucleotide polymorphism has been found in the microRNA-499 gene, and the polymorphism is located in the stem region opposite to the mature microRNA-499 sequence (SNP: rs3746444). The microRNA-499 rs3746444 polymorphism has been reported to be the biomarker of several cancers, such as breast cancer and gastric cancer.,
Several studies found an association between rs3746444 polymorphism in the microRNA-499 gene and risk of HCC so far. However, the published results have been inconsistent. Since individual study may be underpowered and biased for effective evaluation of potentially slight effects of the polymorphism due to relatively limited study population, a meta-analysis was performed to achieve more comprehensive estimation of relationship between the microRNA-499 rs3746444 polymorphism and susceptibility to HCC in Asians.
| > Materials and Methods|| |
Relevant papers published before December 2014 were identified through a search of PubMed and Google scholar databases using the following terms: “MicroRNAs,” “HCC,” “polymorphism,” “single nucleotide polymorphism” and “genetic polymorphism.” The reference lists of major textbooks, reviews, and included articles were identified through manual searches to find other potentially eligible studies.
Studies included in current meta-analysis had to meet all the following criteria: (1) Case-control studies that addressed HCC cases and healthy controls; (2) studies on the association of rs3746444 polymorphism in the microRNA-499 gene and susceptibility to HCC and (3) studies that included sufficient genotype data for extraction. Studies were excluded if they were: (1) Not a case-control study; (2) duplicates of previous publications; (3) based on incomplete data; and (4) meta-analyses, case reports, letters, reviews, or editorial articles.
Two investigators (Weiyu Wang and Hanlin Qin) independently extracted data from the included studies using a standard protocol and data-collection form according to the inclusion criteria listed above, and reached consensus on all items. The following characteristics were collected from each study:First author, year of publication, country, nationality, number of patients and controls, polymorphisms of gene and evidence of Hardy–Weinberg equilibrium (HWE).
Hardy–Weinberg equilibrium for the microRNA-499 rs3746444 polymorphism distribution in controls was tested using Pearson's χ2 test (P < 0.05 was considered representative of a departure from HWE). The strength of the associations between rs3746444 polymorphism and susceptibility to HCC were estimated by odds ratio (OR) and 95% confidence interval (95% CI) under a homozygote comparison (TT vs. CC), a heterozygote comparison (TT vs. TC), a dominant model (CC + TC vs. TT) and a recessive mode (TT + TC vs. CC) between groups. The heterogeneity was assessed using the I2 test. I2 ranges between 0% and 100% and represents the proportion of inter-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, respectively. When I2 > 50% indicated heterogeneity across studies, the random effects model was used for meta-analysis, or else the fixed effects model was used. Subgroup analysis based on sample size (subjects >500) and the studies in agreement with HWE were used to explain the diversity among the results of different studies. The sensitivity analysis was performed by omitting one study at a time to determine the magnitude of influence on the overall summary estimate. Publication bias was investigated using funnel plot and Begg's test. The process of statistical analysis was performed with the Stata software (version 12.0; Stata Corporation, College Station, TX, USA).
| > Results|| |
Characteristics of eligible studies
All studies relevant to the searching words were retrieved. According to the inclusion and exclusion criteria, eight studies including 2196 cases and 2701 controls were included in our work.,,,,,,, The flowchart of study selection is summarized in [Figure 1]. All the cases were diagnosed as HCC while controls were mainly healthy populations. The published year of the included studies ranged from 2000 to 2014. When we performed HWE test on controls of each study, it showed that there were four studies with PHWE > 0.05, and four studies with PHWE < 0.05. The main characteristics of the studies included in this meta-analysis related to this polymorphism and HCC susceptibility are listed in [Table 1].
All the eligible studies were pooled into this meta-analysis; there was no statistically significant association between microRNA-499 rs3746444 polymorphism and HCC risk in Asians. (TT vs. CC: OR = 1.00 95% CI = 0.54–1.83; TT vs. TC: OR = 0.89, 95% CI = 0.66–1.20; dominant model: OR = 1.13, 95% CI = 0.81–1.58; recessive model: OR = 0.99, 95% CI = 0.56–1.76). To explore the sources of heterogeneity, we performed further subgroup analyses by sample size (subjects >500) and the studies in agreement with HWE. Similarly, there were no significant associations in the subgroup analyses. [Table 2] shows the detailed results [Table 2] and [Figure 2].
|Figure 2: Forest plot for meta-analysis of the association between microRNA-499 rs3746444 polymorphism and hepatocellular carcinoma risk|
Click here to view
Sensitivity analysis was performed to assess the influence of each study on the pooled OR by deleting one single study each time. When omitting each data set in the meta-analysis, the pooled ORs were always persistent. The results showed that no individual study affected the pooled OR significantly, suggesting stability of this meta-analysis [Figure 3].
|Figure 3: One-way sensitivity analysis of the pooled odds ratios and 95% confidence interval for microRNA-499 rs3746444 polymorphism, omitting each dataset in the meta-analysis|
Click here to view
Publication bias of the literature was assessed by Begg's funnel plot. There was no evidence of publication bias visually from the funnel plot, which implied that the publication bias was low in the present meta-analysis [Table 2] and [Figure 4].
|Figure 4: Begg's funnel plot analysis to detect potential publication bias|
Click here to view
| > Discussion|| |
Hepatocellular carcinoma is one of the most common malignancies worldwide. In addition to common risk factors such as hepatitis B and hepatitis C, recent studies have shown that gene factors also play an important role in the development of HCC. Recombinant adenovirus-p53 (Gendicine) is a newly developed medicine of gene therapy that relies on the function of wild-type p53, which is safe and could prolong the survival time of the patients with HCC., Evidence has demonstrated that microRNAs are essential for normal development and cellular homeostasis and thereby, dysfunctions in these molecules have been associated with various cancers. To date, several research studies have evaluated the association between rs3746444 polymorphism in the microRNA-499 gene and HCC, but the specific association is still controversial. This led us to perform the present meta-analysis, which could quantify the synthesis of all the available data and might help us to explore a more robust estimate of the role of the rs3746444 polymorphism with hepatic carcinogenesis.
Our meta-analysis quantitatively assessed the association between microRNA-499 rs3746444 polymorphism and susceptibility to HCC in Asians. Finally, 8 case-control studies were included and assessed, involving a total of 2196 HCC cases and 2701 healthy controls. The main meta-analysis results showed no association of microRNA-499 rs3746444 polymorphism with susceptibility to HCC. For all included studies aiming at Asians, further investigation may be needed in Caucasians and Africans. In addition, we performed a subgroup analysis based on sample size >500, the results detect no significant association with HCC, suggesting there was not have small-study bias in our meta-analysis. However, the potential function of polymorphism might be affected via gene-gene and gene-environment interactions. A previous study demonstrated that microRNA-499 rs3746444 polymorphism and smoking and alcohol synergistically increase the risk of HCC. So caution should be exercised when considering this conclusion.
Some limitations of this meta-analysis should be acknowledged. Firstly, the sample size is still relatively small, which might not provide sufficient power to estimate the association between-microRNA-499 rs3746444 polymorphism and HCC. Secondly, our results were based on unadjusted estimates while a more precise analysis should be conducted adjusted by other factors, such as smoking, drinking status, and other environmental factors. Thirdly, meta-analysis is retrospective research that is subject to methodological limitations.
In summary, the results of our meta-analysis indicate that microRNA-499 rs3746444 polymorphism may be not associated with HCC risk in Asians. Large studies with the pooling of individual data should be considered in future studies and to further evaluate the effect of gene-environment interactions of microRNA-499 rs3746444 polymorphism with HCC.
| > References|| |
Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis 2010;42 Suppl 3:S206-14.
Ferenci P, Fried M, Labrecque D, Bruix J, Sherman M, Omata M, et al
. World Gastroenterology Organisation Guideline. Hepatocellular carcinoma (HCC): A global perspective. J Gastrointestin Liver Dis 2010;19:311-7.
Niwa Y, Matsuo K, Ito H, Hirose K, Tajima K, Nakanishi T, et al.
Association of XRCC1 Arg399Gln and OGG1 Ser326Cys polymorphisms with the risk of cervical cancer in Japanese subjects. Gynecol Oncol 2005;99:43-9.
Moribe T, Iizuka N, Miura T, Kimura N, Tamatsukuri S, Ishitsuka H, et al.
Methylation of multiple genes as molecular markers for diagnosis of a small, well-differentiated hepatocellular carcinoma. Int J Cancer 2009;125:388-97.
Kato S, Tajiri T, Matsukura N, Matsuda N, Taniai N, Mamada H, et al
. Genetic polymorphisms of aldehyde dehydrogenase 2, cytochrome p450 2E1 for liver cancer risk in HCV antibody-positive Japanese patients and the variations of CYP2E1 mRNA expression levels in the liver due to its polymorphism. Scand J Gastroenterol 2003;38:886-93.
Wang S, Zhang QY, Zhou RL. Relationship between LAPTM4B gene polymorphism and susceptibility of primary liver cancer. Ann Oncol 2012;23:1864-9.
Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004;116:281-97.
Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, et al.
Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A 2004;101:2999-3004.
Murakami Y, Tanaka M, Toyoda H, Hayashi K, Kuroda M, Tajima A, et al.
Hepatic microRNA expression is associated with the response to interferon treatment of chronic hepatitis C. BMC Med Genomics 2010;3:48.
Ryan BM, Robles AI, Harris CC. Genetic variation in microRNA networks: The implications for cancer research. Nat Rev Cancer 2010;10:389-402.
Okubo M, Tahara T, Shibata T, Yamashita H, Nakamura M, Yoshioka D, et al.
Association between common genetic variants in pre-microRNAs and gastric cancer risk in Japanese population. Helicobacter 2010;15:524-31.
Gao LB, Bai P, Pan XM, Jia J, Li LJ, Liang WB, et al.
The association between two polymorphisms in pre-miRNAs and breast cancer risk: A meta-analysis. Breast Cancer Res Treat 2011;125:571-4.
Wang WZ. Association between T174M polymorphism in the angiotensinogen gene and risk of coronary artery disease: A meta-analysis. J Geriatr Cardiol 2013;10:59-65.
Wang Z, Cao Y, Jiang C, Yang G, Wu J, Ding Y. Lack of association of two common polymorphisms rs2910164 and rs11614913 with susceptibility to hepatocellular carcinoma: A meta-analysis. PLoS One 2012;7:e40039.
Zintzaras E, Chatzoulis DZ, Karabatsas CH, Stefanidis I. The relationship between C677T methylenetetrahydrofolate reductase gene polymorphism and retinopathy in type 2 diabetes: A meta-analysis. J Hum Genet 2005;50:267-75.
Akkiz H, Bayram S, Bekar A, Akgöllü E, Üsküdar O. Genetic variation in the microRNA-499 gene and hepatocellular carcinoma risk in a Turkish population: Lack of any association in a case-control study. Asian Pac J Cancer Prev 2011;12:3107-12.
Xiang Y, Fan S, Cao J, Huang S, Zhang LP. Association of the microRNA-499 variants with susceptibility to hepatocellular carcinoma in a Chinese population. Mol Biol Rep 2012;39:7019-23.
Zhou J, Lv R, Song X, Li D, Hu X, Ying B, et al.
Association between two genetic variants in miRNA and primary liver cancer risk in the Chinese population. DNA Cell Biol 2012;31:524-30.
Kim WH, Min KT, Jeon YJ, Kwon CI, Ko KH, Park PW, et al.
Association study of microRNA polymorphisms with hepatocellular carcinoma in Korean population. Gene 2012;504:92-7.
Zou HZ, Zhao YQ. Positive association between miR-499A>G and hepatocellular carcinoma risk in a Chinese population. Asian Pac J Cancer Prev 2013;14:1769-72.
Shan YF, Huang YH, Chen ZK, Huang KT, Zhou MT, Shi HQ, et al.
miR-499A>G rs3746444 and miR-146aG>C expression and hepatocellular carcinoma risk in the Chinese population. Genet Mol Res 2013;12:5365-71.
Ma Y, Wang R, Zhang J, Li W, Gao C, Liu J, et al.
Identification of miR-423 and miR-499 polymorphisms on affecting the risk of hepatocellular carcinoma in a large-scale population. Genet Test Mol Biomarkers 2014;18:516-24.
Chu YH, Hsieh MJ, Chiou HL, Liou YS, Yang CC, Yang SF, et al.
MicroRNA gene polymorphisms and environmental factors increase patient susceptibility to hepatocellular carcinoma. PLoS One 2014;9:e89930.
Wu YJ, Yang X, Wang XX, Qiu MT, You YZ, Zhang ZX, et al.
Association of vitamin D receptor BsmI gene polymorphism with risk of tuberculosis: A meta-analysis of 15 studies. PLoS One 2013;8:e66944.
Xu C, Chen S, Gao H, Zhao K, You X, Zhang Y, et al.
Quantitative assessment of the influence of glutathione S-transferase M1 null variant on ovarian cancer risk. J Cancer Res Ther 2014;10 Suppl: C201-5.
Yang ZX, Wang D, Wang G, Zhang QH, Liu JM, Peng P, et al.
Clinical study of recombinant adenovirus-p53 combined with fractionated stereotactic radiotherapy for hepatocellular carcinoma. J Cancer Res Clin Oncol 2010;136:625-30.
Chen GX, Zhang S, He XH, Liu SY, Ma C, Zou XP. Clinical utility of recombinant adenoviral human p53 gene therapy: Current perspectives. Onco Targets Ther 2014;7:1901-9.
Wang J, Wang Q, Liu H, Shao N, Tan B, Zhang G, et al.
The association of miR-146a rs2910164 and miR-196a2 rs11614913 polymorphisms with cancer risk: A meta-analysis of 32 studies. Mutagenesis 2012;27:779-88.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]