†These authors contributed equally.
Evidence suggests that there is a close association between myeloperoxidase
(MPO) gene rs2333227 G
Alzheimer’s disease (AD) is a chronic, progressive and irreversible neurodegenerative disease. The prevalence of AD is continuously rising due to the increasing longevity of the global population [1]. AD is the most common cause of dementia and is considered one of the largest health challenges worldwide. According to a recent epidemiological report, 4.7 million individuals aged 65 years or older are estimated to have AD dementia, and the disease will cause more than 600,000 deaths, comprising 32% of all older adult deaths in the US. By 2050, the number of people with AD dementia is projected to be 13.8 million, causing approximately 1.6 million deaths, thereby accounting for 43% of all older adult deaths [2, 3]. AD cases are likely to increase among developing and developed countries, and their complications will place tremendous mental and economic burdens on patients and families. Globally, AD and other dementias are considered to be one of the most important causes of disability adjusted life years (DALYs), accounting for 28.8 million DALY sin 2016 [4].
To date, the etiology and pathogenesis of AD have been extensively explored, but
still, the underlying mechanisms remain unclear. Increasing evidence suggests
that the accumulation of abnormally folded amyloid
Myeloperoxidase (MPO) is an oxidative lysosomal enzyme released by activated
polymerphonuclear neutrophils. MPO participates in the defense mechanisms of an
organism through its catalytic activities in the hydrogen peroxide-halide
reaction to kill infectious pathogens [13]. Studies have reported that chronic
inflammation with oxidative stress contributes to the development of numerous
neurodegenerative conditions, such as AD, Parkinson’s disease, multiple sclerosis
and stroke. Epidemiological studies have demonstrated a positive association
between aberrant MPO plasma levels, and AD and cardiovascular disease
susceptibility [14]. The MPO gene is located on the long arm of chromosome
17q23.1 in humans, is 14kb in length, and comprises 12 exons and 11 introns [15].
To date, many single nucleotide polymorphisms (SNPs) loci have been identified in
the MPO gene and the rs2333227 G
Since 1999, several case-control studies have been conducted to investigate the
role of this polymorphism and AD susceptibility, but their results were
inconsistent. In 2002, Combarros et al. [18] conducted the first
meta-analysis on the association between MPO rs2333227 G
This current meta-analysis was conducted with the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. All collected data were extracted from published studies; hence, there were no ethics issues to consider.
Online databases (PubMed, Embase, Web of Science, CNKI and Wanfang) were
searched for all published case-control studies on the association between MPO
rs2333227 G
#1 myeloperoxidase
#2 MPO
#3 #1 OR #2
#4 -463
#5 rs2333227
#6 polymorphism
#7 variant
#8 mutation
#9 #4 OR #5 OR #6 OR #7 OR #8
#10 Alzheimer’s disease
#11 dementia
#12#10 OR #11
#15 #3 AND #9 AND #12
Studies were included if they were: (1) case-control studies that examined the
association between MPO rs2333227 G
Two authors (Fang and Mao) reviewed the included studies independently, and the following information was extracted and listed for analysis: the first authors’ name, publication date, study country, sample sizes of the cases and controls, control design, genotyping method, frequency data of the genotype distribution, and assessment of hardy-weinberg equilibrium (HWE) in the control group. The newcastle-ottawa scale (NOS) was employed to evaluate the quality of all included studies. The scores ranged from 0 (worst) to 9 (best). Studies with a score of 7 points or higher indicated that they were of good research quality [19].
Overall, pooled ORs and 95% CIs were calculated to evaluate the association
between MPO rs2333227 G
The selection process is presented in Fig. 1. In the first step of the literature
search, 496 potential case-control studies were identified. A total of 169
studies were excluded due to duplication, 306 studies were deleted through
full-text review or title and abstract screening, and 12 studies were excluded
for other deficiencies. Then, nine publications (10 independent case-control
studies) involving 1630 patients and 1630 controls were included to assess the
association between MPO rs2333227 G
Flow diagram of the study selection process.
First author | Year | Country/Ethnicity | Control design | Case | Control | Genotype distribution | P for HWE | Genotyping method | MAF | NOS | |||||
Case | Control | ||||||||||||||
GG | GA | AA | GG | GA | AA | ||||||||||
Reynolds-1 | 1999 | US | Not available | 69 | 160 | 43 | 25 | 1 | 96 |
64 |
NA | NA | PCR-RFLP | NA | 5 |
Reynolds-2 | 2000 | Finnish | Hospital-based | 127 | 174 | 77 | 45 | 5 | 117 | 54 | 3 | 0.25 | PCR-RFLP | 0.17 | 7 |
Crawford-A | 2001 | US | Population-based | 226 | 166 | 138 | 70 | 18 | 83 | 62 | 21 | 0.09 | PCR-RFLP | 0.31 | 8 |
Crawford-B | 2001 | US | Population-based | 59 | 75 | 26 | 27 | 6 | 42 | 29 | 4 | 0.73 | PCR-RFLP | 0.25 | 8 |
Combarros | 2002 | Spain | Hospital-based | 315 | 327 | 160 | 142 | 13 | 168 | 139 | 20 | 0.21 | PCR-RFLP | 0.27 | 7 |
Styczynska | 2003 | Poland | Not available | 100 | 100 | 71 | 10 | 19 | 72 | 17 | 11 | PCR-RFLP | 0.20 | 6 | |
Leininger-Muller | 2003 | Europe | Hospital-based | 265 | 246 | 147 | 101 | 17 | 157 | 84 | 5 | 0.10 | PCR-RFLP | 0.19 | 6 |
Zappia | 2004 | Italy | Healthy-based | 148 | 158 | 84 | 60 | 4 | 67 | 74 | 17 | 0.61 | PCR-RFLP | 0.34 | 7 |
Usui | 2006 | Japan | Population-based | 205 | 92 | 166 | 38 | 1 | 75 | 15 | 0 | 0.39 | PCR-RFLP | 0.08 | 8 |
Ji | 2017 | China | Hospital-based | 116 | 134 | 68 | 41 | 7 | 95 | 34 | 5 | 0.08 | PCR-RFLP | 0.16 | 7 |
HWE in control. |
Overall, the pooled results did not show any significant association between MPO
rs2333227 G
OR and 95% CIs of the associations between MPO rs2333227 G
N* | A vs. G | GA vs. GG | AA vs. GG | GA + AA vs. GG | AA vs. GG + GA | |||||||||||||||||
OR | 95% CI | P | I |
OR | 95% CI | P | I |
OR | 95% CI | P | I |
OR | 95% CI | P | I |
OR | 95% CI | P | I | |||
Total | 10 | 1.09 | 0.85–1.40 | 0.51 | 73.9 | 1.04 | 0.83–1.31 | 0.75 | 47.5 | 1.16 | 0.61–2.19 | 0.65 | 68.5 | 1.06 | 0.83–1.34 | 0.65 | 59.3 | 1.14 | 0.64–2.02 | 0.65 | 62.3 | |
HWE-yes | 8 | 1.07 | 0.81–1.40 | 0.64 | 76.5 | 1.07 | 0.85–1.35 | 0.55 | 48.2 | 1.09 | 0.53–2.25 | 0.81 | 69.9 | 1.08 | 0.81–1.43 | 0.60 | 68.0 | 1.05 | 0.56–1.98 | 0.87 | 62.1 | |
Ethnicity | ||||||||||||||||||||||
Caucasian | 8 | 1.03 | 0.77–1.37 | 0.85 | 77.4 | 0.97 | 0.75–1.25 | 0.81 | 49.5 | 1.08 | 0.52–2.25 | 0.83 | 75.0 | 0.99 | 0.76–1.29 | 0.94 | 61.3 | 1.09 | 0.56–2.11 | 0.80 | 70.7 | |
Asian | 2 | 1.44 | 1.00–2.06 | 0.05 | 0 | 1.44 | 0.94–2.19 | 0.09 | 0 | 1.87 | 0.61–5.71 | 0.27 | 0 | 1.48 | 0.98–2.23 | 0.06 | 0 | 1.61 | 0.54–4.87 | 0.40 | 0 | |
Design | ||||||||||||||||||||||
HB | 5 | 1.10 | 0.78–1.55 | 0.59 | 80.3 | 1.12 | 0.85–1.48 | 0.40 | 51.5 | 1.15 | 0.41–3.19 | 0.79 | 78.1 | 1.12 | 0.80–1.59 | 0.51 | 71.5 | 1.10 | 0.44–2.77 | 0.84 | 73.9 | |
PB | 3 | 1.02 | 0.59–1.78 | 0.94 | 73.6 | 0.99 | 0.60–1.66 | 0.95 | 51.0 | 0.99 | 0.31–3.20 | 0.98 | 51.7 | 1.01 | 0.56–1.81 | 0.97 | 67.6 | 0.79 | 0.44–1.40 | 0.42 | 26.4 | |
NA | 2 | 1.30 | 0.81–2.10 | 0.28 | NA | 0.60 | 0.26–1.39 | 0.23 | NA | 1.75 | 0.78–3.94 | 0.18 | NA | 0.97 | 0.64–1.48 | 0.90 | 0 | 1.90 | 0.85–4.23 | 0.12 | NA | |
NOS evaluation | ||||||||||||||||||||||
7 | 1.01 | 0.76–1.36 | 0.92 | 74.2 | 1.04 | 0.80–1.36 | 0.77 | 51.0 | 0.87 | 0.44–1.73 | 0.70 | 60.3 | 1.03 | 0.75–1.41 | 0.85 | 67.7 | 0.84 | 0.47–1.49 | 0.55 | 46.9 | ||
3 | 1.41 | 1.09–1.81 | 0.01 | 0 | 0.97 | 0.47–2.00 | 0.93 | 62.3 | 2.38 | 1.27–4.45 | 0.01 | 16.9 | 1.21 | 0.92–1.59 | 0.17 | 0 | 2.35 | 1.25–4.40 | 0.01 | 0 | ||
* Numbers of comparisons. I |
Initially, some heterogeneity was observed among the included studies in the
general population under all five genetic models (A vs. G: I
Funnel plot analysis to detect publication bias for GA + AA vs.
GG model of MPO rs2333227 G
Accumulative analyses (Fig. 4 for GA + AA vs. GG) and sensitivity analyses (Fig. 5 for GA + AA vs. GG) were conducted based on the published date of each study. No significant fluctuations were found in the results, which indicated that the results were stable and credible.
Cumulative meta-analyses according to publication year in GA + AA
vs. GG model of MPO rs2333227 G
Sensitivity analysis through deleting each study to reflect the
influence of the individual dataset to the pooled ORs in GA + AA vs. GG model of
MPO rs2333227 G
TSA was conducted in the dominant model. An overall type I error rate of 5% and type II error rate of 20% were used. The total number of participants in this meta-analysis did not exceed the required information size of 11,452 (Fig. 6 for GA + AA vs. GG). The TSA indicated that the cumulative z-curve neither crossed the trial monitoring boundary nor reached the required information size, indicating that the current evidence is insufficient and further studies are necessary.
Trial sequential analysis of MPO rs2333227 G
AD is one of the most important neurodegenerative diseases and has been
considered the most common cause of aging-associated dementia. The World Health
Organization predicts that AD and other causes of dementia will overtake cancer
and become the second leading cause of death [31]. The accumulation of plaques
formed by A
In term of rs2333227 G
Firstly, Reynolds et al. [24] conducted acase-control study and
reported that the MPO rs2333227 GG genotype increased the risk for AD in females
in a US population in 1999. Since then, many studies that focused on the
relationship between MPO rs2333227 G
These discrepancies among published studies may have been derived from the
following: (1) the study population came from different countries or ethnicities;
(2) small sample size in the studies; (3) the quality of the included studies,
which was inconsistent according to NOS evaluation; and (4) the controls of each
study comprised population-based and hospital-based controls. So, our
meta-analysis was therefore conducted to investigate and clarify the precise
association. The pooled results, using general and stratified analyses based on
the current evidence, indicated that no significant association exists between
MPO rs2333227 G
Compared with previous meta-analyses, five additional studies were enrolled in the present meta-analysis and a more comprehensive stratified analysis was conducted. In addition, cumulative and sensitivity analyses were conducted, as well as tests for publication bias, and the influence of NOS evaluation differences. Finally, a TSA was conducted to guarantee the stability and accuracy of our results. Furthermore, our meta-analysis had the following advantages: (1) a larger sample size contributing to more reliable results; (2) the use of a more scientific retrieval strategy and rigorous methodologies; (3) more subgroup analyses to explore potential relationships; (4) the use of TSA, which indicated that the current evidence is insufficient and further studies are necessary; and (5) no significant publication bias was identified that might have influenced the results.
Nevertheless, this meta-analysis had some limitations that should be addressed:
(1) only nine studies could be found that focused on the association
between rs2333227 G
In summary, the current meta-analysis suggested that the MPO rs2333227 G
GLY and LZ designed the research study. ZCF and CCM performed the data curation. CCM, YJH analyzed the data. ZCF, CCM, YJH, GLY and LZ wrote the manuscript. All authors contributed to editorial changes in the manuscript.
Not applicable.
Not applicable.
This study was supported by the Science and Technology Department of Hubei Province (No. 2020CFB747) and HuBei Provincial Department of Science and Technology Innovation Group Programme (No.2019CFA034).
The authors declare no conflict of interest.