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vol. 16
Letter to the Editor

Association between myeloperoxidase rs2333227 polymorphism and susceptibility to coronary heart disease

Yi-Qing Zhang
Yu-Feng Jiang
Min Chen
Nan-Nan Zhang
Ya-Feng Zhou

Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, P.R. China
Arch Med Sci 2020; 16 (5): 1231–1238
Online publish date: 2020/05/27
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Coronary heart disease (CHD) accounts for the most morbidity and mortality all over the world [1]. Heritable factors account for 30–60% of the susceptibility to coronary heart disease, and therefore genotypic variants are potential modifiers of predisposition to coronary heart disease. Our previous study demonstrated that apolipoprotein A1 polymorphism was associated with coronary artery disease [2]. Recently, researchers have revealed myeloperoxidase (MPO) as a new potential mutation associated with the pathogenesis of CHD [3]. In Piedrafita et al.’s study, MPO rs2333227 was reported to be associated with significantly decreased transcriptional activity due to the disruption of an SP1 (speci­ficity protein-1)-binding site in an Alu hormone-responsive element [4]. To date, there have been many researchers studying the association between MPO rs2333227 and coronary heart disease. But the results were not consistent. Given the conflicting evidence on this issue, we conducted the present meta-analysis of all available studies to evaluate the association between MPO rs2333227 genetic polymorphism and the risk of coronary heart disease.
We performed our meta-analysis according to the “Meta-analysis Of Observational Studies in Epidemiology” (MOOSE) proposal [5]. To identify eligible studies for this meta-analysis, two investigators (Yi-Qing Zhang and Yu-Feng Jiang) searched the PubMed, Web of Science, Embase, CNKI (Chinese National Knowledge Infrastructure) and WanFang database in all languages up to March 31, 2017, combined with a manual search of reference lists from identified studies. For the article search, the following combination of medical subject heading or suitable key words was used: coronary heart disease, coronary artery disease, ische­mic heart disease, angina or myocardial infarction and myelope­roxidase rs2333227 and polymorphism. The inclusion criteria were pre-established: 1) case-control designed studies; 2) studies that evaluated the association of myeloperoxidase polymorphism and susceptibility to CHD; 3) provided detailed information on genotype frequency and 4) studies that provided sufficient data to calculate odds ratios (ORs) and 95% confidential intervals for extraction. Useful data in all eligible studies were extracted by two authors (Yi-Qing Zhang and Yu-Feng Jiang). Conflicts were discussed with a third investigator (Ya-Feng Zhou). Study quality was assessed according to the 9-point Newcastle-Ottawa Scale (NOS) [6]. We performed Hardy-Weinberg equilibrium (HWE) tests to evaluate the controls in all the included studies in this meta-analysis. We combined ORs and 95% confidence intervals (95% CI) under a fixed or random effect model to evaluate the association between myeloperoxidase polymorphism and susceptibility to CHD according to the I2 value. To identify the potential heterogeneity, we also conducted subgroup analyses according to ethnicity, source of control, study sample size and disease subtypes (including stable angina pectoris (SAP), defined as chest pain with typical features occurring at predictable levels of exertion, and acute coronary syndrome (ACS), which occurs when an atherosclerotic plaque disrupts and results in activation of thrombocytes and coagulation factors and ultimately the formation of a thrombus). Five genetic models – allele, recessive, dominant, additive and codominant models – were used in subgroup and overall analyses. We performed a sensitivity analysis to identify latent alternation of the overall meta result by combining ORs repeatedly with omission of each study. Publication bias was shown by calculating Egger’s test and drawing Begg’s funnel plot, and there was no statistically significant publication bias (p > 0.05). All statistical tests were performed with Stata version 14.0 (Stata Corporation, USA).
Eventually, there were nineteen studies [7–25] containing 4008 cases and 3460 controls eligible for this meta-analysis. The sample sizes ranged from 128 to 2471 of all eligible studies, containing 3554 Asian (n = 13) and 3914 Caucasian (n = 6), and all but three [13, 18, 19] of them conformed to the Hardy-Weinberg equilibrium test. Moreover, all eligible studies were checked by NOS and scores were more than 6 points, showing the studies to be of high quality. Studies’ characteristics are presented in Table I.
In our meta-analysis, we found that the myeloperoxidase rs2333227 polymorphism could reduce the risk of coronary heart disease in Asians but not in Caucasians (Figure 1). Although there was a significant association in the overall population, high inter-study heterogeneity was observed. After conducting subgroup analysis by ethnicity, the results grew in disparity in Asians and Caucasians with lowered individual heterogeneity, which means ethnicity might be a confounding factor in this study. In the stratified analysis of population, we noted that A allele in the Asian population is significantly related to lower risk of CHD, but not in Caucasians. This may reflect differences in genetic background and gene-environment interaction. In addition, in terms of research characteristics, the allele frequency of control in the Asian population (28.3% on average) and Caucasian population (with an average frequency of 23.0%) was significantly different. As a result, results in Caucasians should be carefully explained, and further larger studies in Caucasians are needed to further evaluate the correlation. We also conducted subgroup analysis on CHD subtypes. There were three studies reporting data on subtypes. Results were shown in Table II. According to the analysis, we found the same condition in SAP and ACS subtypes. Three studies did not fit the HWE test in the control group. After omission of these studies during the sensitivity analysis, it did not alter the conclusions made in the meta-analysis. To evaluate the publication bias of literature, we performed Begg’s funnel plot and Egger’s test. There is no apparent asymmetry in the shape of the funnel plots. Subsequently, the symmetry of funnel plots and statistical evidence in Egger’s test indicated that in overall analyses there was no publication bias under the allele model (Egger’s test, p = 0.73). As a result, our meta-analysis results ought to be reliable.
In general, coronary heart disease is a complicated disease, which is mainly caused by atherosclerosis and relevant to many genes and environment factors [26]. At present the therapy of coronary heart disease still involves drugs and interventional treatment. The genetic therapy of coronary heart disease remains to be explored. Since Nikpoor reported that myeloperoxidase polymorphism may be associated with coronary heart disease [8], there has been a research upsurge, but the results are varied and controversial. Meta-analysis as a powerful statistical technique could improve the reliability of the inconsistent results and find out the reason for the variation. In order to estimate the relationship between MPO RS2333227 polymorphism and susceptibility to CHD, we thus did this updated meta-analysis. The myeloperoxidase gene is located on chromosome 17q23–q24, a functional polymorphism located in the promoter region of this gene that affects its transcription [8]. Myeloperoxidase plays an important role in pro-atherosclerosis [27, 28] by decreasing nitric oxide bioavailability, oxidizing low-density lipoprotein, generating dysfunctional high-density lipoprotein and other path­ways [29].
Myeloperoxidase gene polymorphism, which has been reported to be able to alter an SP1 transcription factor binding site, is a G to A replacement at a site 463 bp upstream of the transcription start site. Moreover, the presence of an A rather than G at this site disrupts the binding site for SP1 and reduces the expression of MPO enzyme in the cell [4]. Therefore, it seems that A in the 463 site will slow down the process of atherosclerosis. To date there have been no genome-wide association studies relevant to myeloperoxidase rs2333227. Previous meta-analyses [30–33] regarding to myeloperoxidase rs2333227 polymorphism and coronary heart disease gave controversial results. Compared to them, our meta-analysis has some strengths. First, we included more studies and as a result had a larger sample size in this study. Second, we performed HWE tests and sensitivity analysis to eliminate the possible bias. In addition, we did stratified analysis on the source of control to consider whether comorbidities could influence the results.
However, some limitations did exist. First, three studies did not fit the HWE test in the control group. After omission of these studies during the sensitivity analysis, it did not alter the conclusions made in the meta-analysis. Secondly, there were no studies including Africans. Third, the genetic susceptibility may also depend on the coincidence of several gene polymorphisms acting together, which may influence the results.
Our meta-analysis demonstrated that the mye­lo­peroxidase rs2333227 polymorphism could reduce the risk of coronary heart disease. Myeloperoxidase, as a kind of superoxide enzyme in the activated neutrophils, monocytes and macrophages in human atherosclerotic plaque, may be a promising gene therapy site of coronary heart disease in the future. However, more case-control studies are needed for further validation, and to reinforce the results of the present meta-analysis.


Yi-Qing Zhang and Yu-Feng Jiang contributed equally to this work.
This work was supported by grants from the National Natural Science Foundation of China (81170174), Natural Scientific Fund of Jiangsu province (BK20161226), Jiangsu Province’s Key Provincial Talents Program (RC2016056), and Jiangsu Province’s 333 High-Level Talents Project (BRA2017539).

Conflict of interest

The authors declare no conflict of interest.
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