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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 9  |  Page : 282-287

Myeloperoxidase -463 G/A polymorphism is associated with lung cancer risk: A meta-analysis with 7420 cases and 9132 controls


1 The Third People's Hospital of Zhenjiang Affiliated to Jiangsu University; School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
2 School of Medicine, Jiangsu University; Department of Medical Section, Zhenjiang Emergency Medical Center, Zhenjiang, Jiangsu, China
3 Department of Medical Section, Zhenjiang Emergency Medical Center, Zhenjiang, Jiangsu, China

Date of Web Publication29-Jun-2018

Correspondence Address:
Xin Pan
No. 1-19 Dingmaoqiao Road, Zhenjiang, Jiangsu
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.235341

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 > Abstract 

Aims: Several studies evaluated the association between myeloperoxidase (MPO) -463 G/A polymorphism and the risk of lung cancer. However, the results were not stable.
Materials and Methods: Online electronic databases (PubMed, EMBASE, and Wanfang database) were searched. The strength of association between the MPO -463 G/A polymorphism and lung cancer risk was assessed by calculating odds ratios (OR) with 95% confidence interval (CI).
Results: A total of 22 studies with 7420 cases and 9132 controls on the association between MPO -463 G/A polymorphism and lung cancer risk were included for this meta-analysis. MPO -463 G/A polymorphism was associated with a significantly decreased risk of lung cancer (OR = 0.91; 95% CI: 0.85–0.98; I 2 = 25%). In the race subgroup analysis, Asians with MPO -463 G/A polymorphism had decreased lung cancer risk (OR = 0.81; 95% CI: 0.70–0.93; I 2 = 0%). However, Caucasians did not show significant result (OR = 0.93; 95% CI: 0.86–1.02; I 2 = 36%). In the subgroup analysis according to source of control, both population-based studies and hospital-based studies were marginally significantly associated with decreased risk of lung cancer (OR = 0.90; 95% CI: 0.82–1.00; I 2 = 41% and OR = 0.91; 95% CI: 0.82–1.01; I 2 = 0%).
Conclusion: The present meta-analysis suggested that the MPO -463 G/A polymorphism carriers had a protective role in lung cancer.

Keywords: Association, lung cancer, myeloperoxidase, polymorphism


How to cite this article:
Zou S, Pan X, Hua C, Wu M, He B, Chen Z. Myeloperoxidase -463 G/A polymorphism is associated with lung cancer risk: A meta-analysis with 7420 cases and 9132 controls. J Can Res Ther 2018;14:282-7

How to cite this URL:
Zou S, Pan X, Hua C, Wu M, He B, Chen Z. Myeloperoxidase -463 G/A polymorphism is associated with lung cancer risk: A meta-analysis with 7420 cases and 9132 controls. J Can Res Ther [serial online] 2018 [cited 2018 Jul 16];14:282-7. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/282/235341


 > Introduction Top


Lung cancer is a dangerous tumor that threatens human health and life with high morbidity and mortality.[1] The incidence and mortality of lung cancer have significantly increased worldwide.[1] Chemotherapy is the primary treatment for lung cancer and is applied in most cases because this disease is usually diagnosed at an advanced stage.[2],[3] However, the efficiency of traditional chemotherapeutic drugs such as cisplatinum is poor. The 5-year overall survival of patients treated with traditional chemotherapeutic drugs is not ideal because of adverse effects and drug resistance.[4]

Myeloperoxidase (MPO) is the most abundant proinflammatory enzyme stored in the azurophilic granules of neutrophilic granulocytes, accounting for approximately 5% of their dry mass.[5] It catalyzes the formation of hypochlorous acid from hydrogen peroxide, generates other highly reactive molecules such as tyrosyl radicals, and cross-links proteins.[6] Recently, MPO has been found to be implicated in a multitude of diseases including lung cancer.[7]

A number of studies have implicated MPO in the development of malignancies. A polymorphic site is located 463 bp upstream of the MPO gene (-463 G/A) in the Alu hormone-responsive element of the promoter region. The G allele acts as a strong SP1 transcription factor-binding site, which reacts with SP1 to increase MPO expression.[8] This allele is enhanced in patients with acute myeloid leukemia in association with high levels of MPO mRNA and expression.[9] The G-to-A nucleotide base shift, which is associated with decreased SP1 binding, and thus, lower MPO gene expression, has been associated with an overall decreased risk of lung cancer by some investigators.[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29] However, the results remained inconclusive. A meta-analysis is a useful method for investigating associations between genetic factors and diseases because a quantitative approach is used to combine the results from different studies on the same topic, thereby providing more reliable conclusions. Thus, we performed a meta-analysis to clarify the association of MPO -463 G/A polymorphism and lung cancer risk.


 > Materials and Methods Top


Publication search

Online electronic databases (PubMed, EMBASE, and Wanfang database) was searched using the search terms: (“Myeloperoxidase” or “OSAHS” or “MPO”) and “lung cancer.” Additional studies were identified by a hand search from the reference of original studies or review articles on this topic. There was no language restriction.

Inclusion and exclusion criteria

The following inclusion criteria were used: (1) The study should have evaluated the association between the MPO -463 G/A polymorphism and lung cancer risk; (2) the study should have a case-control or cohort design; (3) sufficient data should have been provided in order to calculate odds ratios (OR) and 95% confidence interval (CI). Studies were excluded if any of the following conditions applied: (1) Only abstracts or reviews were available, without sufficient data; (2) animal studies; (3) studies were repeated or publications overlapped.

Data extraction

The following data were recorded from each article:First author, years of publication, ethnicity of participants, the source of control, numbers of subjects. The data were extracted by two of the authors independently. Discrepancies between these two authors were resolved by discussion.

Statistical analysis

The strength of association between the MPO -463 G/A polymorphism and lung cancer risk was assessed by calculating OR with 95% CI. A statistical test for heterogeneity was performed based on the Q-test statistic. The P > 0.10 of the Q-test indicated a lack of heterogeneity among studies. The summary OR estimate of each study was calculated by the random-effects model. Stratified analysis was performed by race and source of control. Potential publication bias was examined by funnel plot and Egger's test. All statistical tests were performed with the software RevMan version 5.1 (Nordic Cochrane Center, Copenhagen, Denmark) and STATA version 11.0 (Stata Corporation, College station, TX, USA). A P < 0.05 was considered statistically significant.


 > Results Top


Study characteristics

A total of 22 studies [Figure 1] with 7420 cases and 9132 controls on the association between MPO -463 G/A polymorphism and lung cancer risk were included in this meta-analysis. There were 8 studies of the Asian population and 13 studies of the Caucasian population. The characteristics of each study are presented in [Table 1].
Figure 1: Flow chart for the literature selection

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Table 1: Characteristics of the included studies

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Results of meta-analysis

MPO -463 G/A polymorphism was associated with a significantly decreased risk of lung cancer [OR = 0.91; 95% CI: 0.85–0.98; I2 = 25%; [Figure 2]. In the race subgroup analysis, Asians with MPO -463 G/A polymorphism had decreased lung cancer risk [OR = 0.81; 95% CI: 0.70–0.93; I2 = 0%; [Figure 3]. However, the Caucasians did not show significant result [OR = 0.93; 95% CI: 0.86–1.02; I2 = 36%; [Figure 3]. In the subgroup analysis according to source of control, both population-based studies and hospital-based studies were marginally significantly associated with decreased risk of lung cancer [OR = 0.90; 95% CI: 0.82–1.00; I2 = 41% and OR = 0.91; 95% CI: 0.82–1.01; I2 = 0%; [Figure 4].
Figure 2: Meta-analysis for the association between myeloperoxidase -463 G/A polymorphism and lung cancer risk

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Figure 3: Subgroup-analysis by race for the association between myeloperoxidase -463 G/A polymorphism and lung cancer risk

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Figure 4: Subgroup-analysis by source of control for the association between myeloperoxidase -463 G/A polymorphism and lung cancer risk

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A funnel plot was performed to assess the publication bias of literatures. The shape of the funnel plot showed symmetry [Figure 5]. Egger's test found no evidence of publication bias (P = 0.164).
Figure 5: Funnel plot for the association between myeloperoxidase -463 G/A polymorphism and lung cancer risk

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 > Discussion Top


Although many studies reported the results about the MPO -463 G/A polymorphism and lung cancer risk, definite conclusions cannot be drawn. Therefore, we did this meta-analysis to estimate the relationship between MPO -463 G/A polymorphism and lung cancer risk. The meta-analysis involved 22 case-control articles. The results of this meta-analysis showed that the MPO -463 G/A polymorphism had a significant protective effect against lung cancer. However, this polymorphism did not show a protective effect against lung cancer in the Caucasian. We found that the result was marginal significant. Thus, more studies are still needed to assess the relationship between MPO -463 G/A polymorphism and lung cancer risk in the Caucasian.

MPO -463 G/A polymorphism was also reported to be associated with other cancers. Cascorbi et al. suggested that MPO -463 A variant is a protective factor in the etiology of larynx cancer, but possibly not of pharyngeal cancer.[30] Hung et al. found that MPO G-463 A homozygous variant was associated with a reduced risk of bladder cancer with an OR of 0.31 (95% CI = 0.12–0.80).[31] Pakakasama et al. observed that MPO -463 A allele is a protective factor with regard to the risk of hepatoblastoma.[32] Although G/A polymorphism alters transcription rates, there are few studies indicating corresponding changes in MPO protein or enzyme activity. The MPO system, in cell-free form or in intact, stimulated neutrophils, can catalyze the conversion of certain procarcinogens to their carcinogenic and in this way, may contribute to the development of malignancies.[33] Further, the formation of 5-chlorouracil and 5-bromouracil by the MPO (or EPO) system and their incorporation into nuclear DNA can be mutagenic.[34]

Some limitations of this meta-analysis should be acknowledged. First, potential pleiotropic effects of genes may influence the results when a naturally occurring single nuclear polymorphism is used as an instrument to evaluate disease causality. Although single genetic variation is relative to extensive diseases, many of these associations are false positives because the gene has been more generally characterized than most in population investigations of genetic association studies. Second, in the subgroup analyses, the sample sizes in some subgroup were relatively small, not having enough statistical power to explore the real association. Third, lung cancer is a complex disease and involves potential interactions of gene-environment. However, many eligible studies included in this meta-analysis did not consider the environmental factors. Therefore, studies with larger sample sizes and better design are needed.

The present meta-analysis suggested that the MPO -463 G/A polymorphism carriers had a protective role in lung cancer. However, the results should be interpreted with caution because of its limitations. Further studies with large sample size, especially with the consideration of gene-gene and gene-environment interactions, are needed to confirm our findings.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.  Back to cited text no. 1
[PUBMED]    
2.
Mao Y, Li W, Chen K, Xie Y, Liu Q, Yao M, et al. B7-H1 and B7-H3 are independent predictors of poor prognosis in patients with non-small cell lung cancer. Oncotarget 2015;6:3452-61.  Back to cited text no. 2
[PUBMED]    
3.
Kong J, Xu F, Qu J, Wang Y, et al. Genetic polymorphisms in the vitamin D pathway in relation to lung cancer risk and survival. Oncotarget 2015;6:2573-82.  Back to cited text no. 3
    
4.
Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med 2004;350:379-92.  Back to cited text no. 4
[PUBMED]    
5.
Schultz J, Kaminker K. Myeloperoxidase of the leucocyte of normal human blood. I. Content and localization. Arch Biochem Biophys 1962;96:465-7.  Back to cited text no. 5
    
6.
Heinecke JW. Mechanisms of oxidative damage by myeloperoxidase in atherosclerosis and other inflammatory disorders. J Lab Clin Med 1999;133:321-5.  Back to cited text no. 6
[PUBMED]    
7.
Klebanoff SJ. Myeloperoxidase: Friend and foe. J Leukoc Biol 2005;77:598-625.  Back to cited text no. 7
[PUBMED]    
8.
Piedrafita FJ, Molander RB, Vansant G, Orlova EA, Pfahl M, Reynolds WF. An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid hormone-retinoic acid response element. J Biol Chem 1996;271:14412-20.  Back to cited text no. 8
[PUBMED]    
9.
Reynolds WF, Chang E, Douer D, Ball ED, Kanda V. An allelic association implicates myeloperoxidase in the etiology of acute promyelocytic leukemia. Blood 1997;90:2730-7.  Back to cited text no. 9
[PUBMED]    
10.
London SJ, Lehman TA, Taylor JA. Myeloperoxidase genetic polymorphism and lung cancer risk. Cancer Res 1997;57:5001-3.  Back to cited text no. 10
[PUBMED]    
11.
Le Marchand L, Seifried A, Lum A, Wilkens LR. Association of the myeloperoxidase -463G->a polymorphism with lung cancer risk. Cancer Epidemiol Biomarkers Prev 2000;9:181-4.  Back to cited text no. 11
[PUBMED]    
12.
Schabath MB, Spitz MR, Zhang X, Delclos GL, Wu X. Genetic variants of myeloperoxidase and lung cancer risk. Carcinogenesis 2000;21:1163-6.  Back to cited text no. 12
[PUBMED]    
13.
Feyler A, Voho A, Bouchardy C, Kuokkanen K, Dayer P, Hirvonen A, et al. Point: Myeloperoxidase -463G -> a polymorphism and lung cancer risk. Cancer Epidemiol Biomarkers Prev 2002;11:1550-4.  Back to cited text no. 13
[PUBMED]    
14.
Dally H, Gassner K, Jäger B, Schmezer P, Spiegelhalder B, Edler L, et al. Myeloperoxidase (MPO) genotype and lung cancer histologic types: The MPO -463 A allele is associated with reduced risk for small cell lung cancer in smokers. Int J Cancer 2002;102:530-5.  Back to cited text no. 14
    
15.
Lu W, Xing D, Qi J, Tan W, Miao X, Lin D. Genetic polymorphism in myeloperoxidase but not GSTM1 is associated with risk of lung squamous cell carcinoma in a Chinese population. Int J Cancer 2002;102:275-9.  Back to cited text no. 15
[PUBMED]    
16.
Schabath MB, Spitz MR, Delclos GL, Gunn GB, Whitehead LW, Wu X. Association between asbestos exposure, cigarette smoking, myeloperoxidase (MPO) genotypes, and lung cancer risk. Am J Ind Med 2002;42:29-37.  Back to cited text no. 16
[PUBMED]    
17.
Xu LL, Liu G, Miller DP, Zhou W, Lynch TJ, Wain JC, et al. Counterpoint: The myeloperoxidase -463G->a polymorphism does not decrease lung cancer susceptibility in Caucasians. Cancer Epidemiol Biomarkers Prev 2002;11:1555-9.  Back to cited text no. 17
[PUBMED]    
18.
Kantarci OH, Lesnick TG, Yang P, Meyer RL, Hebrink DD, McMurray CT, et al. Myeloperoxidase -463 (G->A) polymorphism associated with lower risk of lung cancer. Mayo Clin Proc 2002;77:17-22.  Back to cited text no. 18
[PUBMED]    
19.
Wu XM, Zhou YK, Ren S, Hao QL. Gene polymorphism of myeloperoxidase and genetic susceptibility to lung cancer. Ai Zheng 2003;22:912-5.  Back to cited text no. 19
[PUBMED]    
20.
Chevrier I, Stücker I, Houllier AM, Cenée S, Beaune P, Laurent-Puig P, et al. Myeloperoxidase: New polymorphisms and relation with lung cancer risk. Pharmacogenetics 2003;13:729-39.  Back to cited text no. 20
    
21.
Liu G, Zhou W, Wang LI, Park S, Miller DP, Xu LL, et al. MPO and SOD2 polymorphisms, gender, and the risk of non-small cell lung carcinoma. Cancer Lett 2004;214:69-79.  Back to cited text no. 21
[PUBMED]    
22.
Larsen JE, Colosimo ML, Yang IA, Bowman R, Zimmerman PV, Fong KM. CYP1A1 Ile462Val and MPO G-463A interact to increase risk of adenocarcinoma but not squamous cell carcinoma of the lung. Carcinogenesis 2006;27:525-32.  Back to cited text no. 22
[PUBMED]    
23.
Park JH, Park JM, Kim EJ, Cha SI, Lee EB, Kim CH, et al. Myeloperoxidase -463G>A polymorphism and risk of primary lung cancer in a Korean population. Cancer Detect Prev 2006;30:257-61.  Back to cited text no. 23
[PUBMED]    
24.
Yang M, Choi Y, Hwangbo B, Lee JS. Combined effects of genetic polymorphisms in six selected genes on lung cancer susceptibility. Lung Cancer 2007;57:135-42.  Back to cited text no. 24
[PUBMED]    
25.
Yoon KA, Kim JH, Gil HJ, Hwang H, Hwangbo B, Lee JS. CYP1B1, CYP1A1, MPO, and GSTP1 polymorphisms and lung cancer risk in never-smoking Korean women. Lung Cancer 2008;60:40-6.  Back to cited text no. 25
[PUBMED]    
26.
Arslan S, Pinarbasi H, Silig Y. Myeloperoxidase G-463A polymorphism and risk of lung and prostate cancer in a Turkish population. Mol Med Rep 2011;4:87-92.  Back to cited text no. 26
[PUBMED]    
27.
Rotunno M, Yu K, Lubin JH, Consonni D, Pesatori AC, Goldstein AM, et al. Phase I metabolic genes and risk of lung cancer: Multiple polymorphisms and mRNA expression. PLoS One 2009;4:e5652.  Back to cited text no. 27
[PUBMED]    
28.
Bag A, Bag N, Jeena LM, Jyala NS. Glutathione S-transferase T1 and myeloperoxidase -463 G>A genotypes in lung cancer patients of Kumaun region. J Nat Sci Biol Med 2014;5:293-6.  Back to cited text no. 28
[PUBMED]    
29.
Kiyohara C, Horiuchi T, Takayama K, Nakanishi Y Genetic polymorphisms involved in the inflammatory response and lung cancer risk: A case-control study in Japan. Cytokine 2014;65:88-94.  Back to cited text no. 29
    
30.
Cascorbi I, Henning S, Brockmöller J, Gephart J, Meisel C, Müller JM, et al. Substantially reduced risk of cancer of the aerodigestive tract in subjects with variant-463A of the myeloperoxidase gene. Cancer Res 2000;60:644-9.  Back to cited text no. 30
    
31.
Hung RJ, Boffetta P, Brennan P, Malaveille C, Gelatti U, Placidi D, et al. Genetic polymorphisms of MPO, COMT, MnSOD, NQO1, interactions with environmental exposures and bladder cancer risk. Carcinogenesis 2004;25:973-8.  Back to cited text no. 31
[PUBMED]    
32.
Pakakasama S, Chen TT, Frawley W, Muller C, Douglass EC, Tomlinson GE. Myeloperoxidase promotor polymorphism and risk of hepatoblastoma. Int J Cancer 2003;106:205-7.  Back to cited text no. 32
[PUBMED]    
33.
Petruska JM, Mosebrook DR, Jakab GJ, Trush MA. Myeloperoxidase-enhanced formation of (+-)-trans-7, 8-dihydroxy-7,8-dihydrobenzo[a]pyrene-DNA adducts in lung tissue in vitro: A role of pulmonary inflammation in the bioactivation of a procarcinogen. Carcinogenesis 1992;13:1075-81.  Back to cited text no. 33
[PUBMED]    
34.
Henderson JP, Byun J, Takeshita J, Heinecke JW. Phagocytes produce 5-chlorouracil and 5-bromouracil, two mutagenic products of myeloperoxidase, in human inflammatory tissue. J Biol Chem 2003;278:23522-8.  Back to cited text no. 34
[PUBMED]    


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