Shinshu Med J, 68⑴：41～48, 2020

Myeloperoxidase (MPO) Gene Polymorphisms are not
Associated with Japanese Patients with COPD
Michiko Ito, Masanori Yasuo＊, Yunden Droma
Nobumitsu Kobayashi and Masayuki Hanaoka
The First Department of Internal Medicine, Shinshu University School of Medicine

Background : The pathogenesis of chronic obstructive pulmonary disease (COPD) is suggested to be involved
with systemic inflammation and influenced by genetic factors. Myeloperoxidase (MPO) is secreted by activatedpolymorphonuclear neutrophils and plays a crucial role in the inflammation response. This study attempts to
examine the associations of the genetic variants of the MPO gene with susceptibility to COPD in Japanesepatients.
Methods : Six single nucleotide polymorphisms (SNPs) within the MPO were genotyped, including rs2107545 (A/G) and rs2243828 (A/G, variants of expression quantitative trait loci : eQTL) in the promotor region, rs7208693(C/A, Val53Phe) in exon 2, rs35921530 (C/A, eQTL) in intron 7, rs35670089 (C/T, Arg604Cys) in exon 11, andrs2071409 (T/G, eQTL) in intron 11, in 260 patients with COPD and 129 non-COPD smokers. These 6 SNPs wereable to capture at least more than 50 SNPs throughout the length of MPO gene. In addition, the plasma MPO
concentrations were measured in both groups.
Results : There were no significant differences of allele frequencies of the six SNPs between the COPD and nonCOPD groups. In addition, the plasma MPO concentration was not significantly different between the two groups.
Conclusion : The genetic variants of MPO were not associated with the susceptibility to COPD in the Japanese
population. The MPO biomolecule is not involved with the pathogenesis of COPD. Shinshu Med J 68 : 41―48,
2020(Received for publication July 30, 2019 ; accepted in revised form October 15, 2019)
Key words : COPD, myeloperoxidase, gene, single nucleotide polymorphism (SNP), inflammation

Ⅰ

Introduction

ucts, resulting in lung parenchymal destruction andairway remodeling2）. MPO is a mediator for tissue

Chronic obstructive pulmonary disease (COPD) isdamage and it affects neutrophil functions including

characterized by an abnormal persistent inflammato­

cytokine production3）. Meanwhile, it is also a major

ry response to noxious environmental stimuli, mostenzymatic source of endogenous acrolein4）. The irri­

commonly cigarette smoke1）. Inflammation is sug­tant acrolein is a pathological reactive aldehyde ingested to be one of the mechanisms in the pathogen­the airway with toxicity directly affecting the devel­

esis of COPD, for example, the recruitment andopment of COPD5）6）. Thus, we hypothesize that MPO

regulation of neutrophils potentially activate poly­

plays an important role in the pathogenesis of COPD.

morphonuclear neutrophils (PMNs) that release my­

It has been well demonstrated that the develop­

eloperoxidase (MPO) and other intracellular prod­

ment of COPD is influenced by ethnicity, gender, andenvironmental factors as well as genetic factors7）.

＊

Corresponding author : Masanori Yasuo
First Department of Internal Medicine,
Shinshu University School of Medicine, 3-1-1
Asahi, Matsumoto, Nagano 390-8621, Japan
E-mail : yasumasa@shinshu-u.ac.jp

No. 1, 2020

The marked variability in lung function and riskof COPD in people with similar cigarette smoking
histories, together with studies of familial aggregation,
support an important role for genetics in COPD7）8）.
41

Ito・Yasuo・Droma et al.

The MPO gene contains 12 exons and spans aboutal.12）. We defined the emphysema phenotype as a

13 kb locating in chromosome 17q229）. The genetic

total score ≥ 7 in lung fields.

variants of MPO were reported to be associated with

Subjects with the following disorders were exclud­

susceptibility to diseases involved with inflammation,

ed from the study : late sequelae of pulmonary tuber­such as vascular diseases10）. Thus, we performed thisculosis, diffuse panbronchiolitis, sinobronchitis, bron­study in order to observe associations of the genetic

chiectasis, bronchiolitis obliterans due to autoimmune

variants of MPO with susceptibility to COPD in Japa­

disease, and bronchial asthma.

nese patients.

Ｂ

Ⅱ
Ａ

Controls

Controls were non-COPD smokers and they were

Subjects and Methods

recruited from people for health screening at ouraffiliated hospitals (Misayama Hospital and Shinmachi

Subjects
This study was approved by the Ethics Committee

Hospital, Japan). The selection criteria for non-COPD

of Shinshu University. The study protocols were per­smokers included former or current smokers (all theformed in accordance with the principles outlined incontrols had over 10 pack-years in smoking history),

the Declaration of Helsinki of the World Medical As­

Japanese ethnicity, 50 years old or older, and FEV1/sociation. We obtained written informed consent

FVC≧71 ％ and ％FEV1＞81 ％. Generally, they werefrom all subjects of cases and controls. Patients withhealthy Japanese individuals.

COPD were recruited from the Department of Respi­

Ｃrology and Infectious Disease and Allergology in

Genotyping

DNA was extracted from whole blood with theShinshu University Hospital (Matsumoto, Japan). All

QuickGene-800 kit (FUJIFILM, Tokyo, Japan).

participants were Japanese. COPD was diagnosed by

Genomic DNA was prepared at concentrations ofsmoking history (99.2 ％ of the patients had over 10

5-15 ng/μl for the TaqMan SNP genotyping assay.

pack-years in smoking history), chronic respiratory

Six single nucleotide polymorphisms (SNPs) with‑symptoms (cough, sputum, breathlessness), and spiro­i n M P O w e r e g e n o t y p e d , i n c l u d i n g r s 2107545

metric measurements that indicated an irreversible(A/G) and rs2243828 (A/G) in the promotor region,

airflow limitation according to the Global Initiative

rs7208693 (C/A) in exon 2, rs35921530 (C/A) in intron 7,

1）

for Chronic Obstructive Lung Disease (GOLD) . Spi­

rs35670089 (C/T) in exon 11, and rs2071409 (T/G) inrometry measurements were performed with a pul­intron 11. These SNPs covered a length of 11.888

monary function test system (Chestac-55 V, Chest Co.

kb of MPO with minor allele frequency＞5 ％ in theLtd., Tokyo, Japan). An airflow limitation was definedJapanese population according to the National Centeras the ratio of forced expiratory volume in 1 secondfor Biotechnology Information SNP database (Table(FEV1) to forced vital capacity (FVC) less than 70 ％1). Among them, rs7208693 (Val53Phe) and rs35670089(FEV1/FVC＜70 ％) and the percentage of the pre­(Arg604Cys) are SNPs of nonsynonymous substitutions

dicted value for FEV1 less than 80 ％ (％FEV1＜80

in MPO ; the rs2243828, rs35921530 and rs2071409％) (1). The severity of the airflow limitation was de­are variants of the expression quantitative trait locitermined according to spirometric classifications of(eQTL). These (eQTLs) are genomic loci that explain

1）

all or a fraction of variations in the expression levels

GOLD .

The patients with COPD present two phenotypes,of mRNA13）14）. In addition, setting the threshold of

one is termed as small airway disease (obstructive

correction coefficient (r2) at 0.8, these 6 SNPs served

bronchiolitis) and the other is parenchymal destruction

as tag SNPs and were able to capture at least more(emphysema) based on the images on high-resolution

than 50 SNPs in the MPO gene in the Japanese

11）

computed tomography (HRCT) . Low attenuation

population according to the 1000 Genomes data inareas (LAA) were visually evaluated in three bilater­

Ensembl (http://grch37.ensembl.org/Homo_sapiens/

al lung fields according to the method of Goddard etInfo/Index) (Table 2). The tag SNPs act as direct

42

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MPO in COPD
Table 1

The genetic information of the SNPs of MPO in the study

rs number

Major/Minor
alleles

Position

Genomic
RegionCharacterof Variant

rs2107545
rs2243828
rs7208693
rs35921530
rs35670089
rs2071409

A/G
A/G
C/A
C/A
C/T
T/G

Chr17 : 58282757
Chr17 : 58281523
Chr17 : 58280457
Chr17 : 58276230
Chr17 : 58271875
Chr17 : 58270869

Promotor
Promotor
Exon 2Intron 7
Exon 11
Intron 11

Intergenic
Intergenic
Missense
IntronMissense
IntronFunctioneQTL
Val53PheeQTL
Arg604CyseQTL

Abbreviations : Chr, chromosome ; eQTL, expression quantitative trait loci ; MPO, myeloperoxidase ; SNP,
single nucleotide polymorphism.
Table 2 Tagging efficiency of SNPs of rs2107545, rs2243828, rs7208693, rs35921530, rs35670089, rs2071409
in MPO in JTP population
Alleles captured＊

Test SNP
rs2107545 (eQTL)
in the promotor region

rs79720816, rs4401102, rs2243828, rs2333227, rs71365871, rs59377187, rs62083750,
rs73993644, rs16942914, rs12938133, rs11079344, rs77472986, rs569425179, rs9908667,
rs115013689, rs11649901, rs2240261, rs72839983, rs3744102

rs2243828 (eQTL)
in the promotor region

rs2333227, rs2107545, rs79720816, rs4401102, rs71365871, rs59377187, rs62083750,
rs73993644, rs16942914, rs12938133, rs11079344, rs77472986, rs569425179, rs9908667,
rs115013689, rs11649901, rs2240261, rs72839983, rs3744102

rs7208693 (Val53Phe)in exon 2

rs62083752, rs62084578, rs3744099, rs62084580, rs34212101, rs11575868, rs8178377,
rs11656836, rs11652686, rs8178340, rs8178307, rs7219860, rs8178290, rs11654568,
rs62083746, rs62083745, rs11337012, rs8178409, rs62084581

rs35921530 (eQTL)
in intron 7

r s 2071409 , r s 8178392 , r s 8178375 , r s 60650460 , r s 2301869 , r s 2301870 , r s 8178350 ,rs11871239, rs8178348, rs8178345, rs540966028, rs12942443, rs148318946, rs12953025,
rs79822084, rs10853005, rs12944679, rs79706658, rs76781940, rs8178326, rs2240262

rs35670089 (Arg604Cys)
in exon 11

Not available

rs2071409 (eQTL)
in intron 11

Not available

Abbreviations : eQTL, expression quantitative trait loci ; MPO, myeloperoxidase ; SNPs, single nucleotide
polymorphisms ; JPT, Japanese population in Tokyo.
＊

tag SNPs (r2＞0.8) based on the 1000 Genomes data in Ensembl
http://grch37.ensembl.org/Homo_sapiens/Info/Index with JPT.

proxies for all other untyped SNPs because they are

lyzed using sequence detection software (SDS v1.3.1 ;highly correlated with one another by means of pair­

Applied Biosystems, Inc.).

wise tagging in the capture of the untyped SNPs

Ｄ

15）

Measurement of plasma MPO concentrations

The plasma MPO concentrations were measured

perfectly and efficiently .

The SNP genotyping was performed using theusing enzyme-linked immunosorbent assay (ELISA)

TaqMan®SNP Genotyping Assay Mix with the Ap­

kit specific for humans according to the manufacturer’s

plied Biosystems 7500 Fast Real-time PCR System

instructions (IDK®MPO ELISA, Immundiagnostik AG,(Applied Biosystems Inc. Foster City, CA, USA) fol­

Germany).

lowing the manufacturer’s instructions. After ther­Ｅ

mal cycling, genotype data were automatically ana­
No. 1, 2020

Statistical analysis

Continuous data are expressed as mean±standard
43

Ito・Yasuo・Droma et al.
Table 3

Phenotypes of patients with COPD and non-COPD smokers

Phenotypes

Patients with COPD

Number

Non-COPD smokers

260

129

Male/Female
Age (years)

255/5
71.0±7.7＊125/4
62.7±9.5

Smoking history(pack years)

59.4±29.6＊

38.7±18.3

FEV1 (Liter)

1.6±0.7＊

2.6±0.558.9±21.8＊

88.1±12.8

51.9±11.3＊
21.4±23.2

80.4±6.8
21.3±25.5

FEV1 (％ pred)

FEV1/FVC (％)

Plasma MPO level (ng/ml)

Data are expressed as mean±SD.
Abbreviations : FEV1, forced expiratory volume in 1 second ; ％ pred, percent of the predictedvalue ; FVC, forced vital capacity＊p＜0.01 versus non-COPD group by the Mann-Whitney U test

deviation (SD). The differences in the continuous data

III & IV and 103 patients presented the emphysema

between the two groups were analyzed by student’s

phenotype on HRCT. The plasma MPO concentrationt test, and the differences in the categorical data

was 21.4±23.2 ng/ml in the COPD group and 21.3±

were analyzed by a contingency table (2×2). Allele

25.5 ng/ml in the non-COPD groups. There was nofrequencies were calculated by allele counting andsignificant difference of the plasma MPO levels

were expressed as decimals. The Hardy-Weinberg

between the two groups.

equilibrium (HWE) was calculated individually for

The genotype distributions of the six SNPs in theeach SNP in the two groups using the Genepop soft­

COPD and non-COPD groups were in HWE (p＞0.2).

16）

ware package . The inherited effects of the major

There were no significant differences of allele fre­alleles, assuming dominant mode or recessive mode

quencies of the SNPs between the COPD and non-in the COPD groups, were analyzed by Chi-squared

COPD groups (Table 4). The major alleles did not

test. The odds ratio (OR) was estimated with theshow any dominant mode or recessive mode of in­approximate 95 ％ confidence interval (CI). A P value

heritance on the COPD group (Table 4). Furtherof less than 0.05 was considered significant.

analyses showed that there were no significant asso­

Ⅲ
Ａ

Results

Characteristics of study subjects

ciations regarding the SNPs of MPO with patientswith severe COPD in Stage III & IV as well as withthe emphysema phenotype of COPD (Table 5). More­

Table 3 shows the characteristics, spirometry data

over, these SNPs also did not show any associations

and plasma MPO concentrations of the study subjects.

with the circulating MPO concentrations in both

The study subjects consisted of 260 patients with

COPD and non-COPD groups (data not shown).

COPD (255 males and 5 females) and 129 non-COPD
smokers (125 males and 4 females). The gender ratio

Ⅳ

Discussion

was matched between the two groups (p＝0.48), how­

The current study did not reveal associations of

ever, the age and smoking history were significantly

the six SNPs of MPO with susceptibility to COPD in

higher in patients with COPD compared to non-COPD

Japanese patients. The SNPs of the eQTL loci andsmokers (p＜0.01). In agreement with the selection

nonsynonymous substitutions were not associatedcriteria for the COPD group and non-COPD group,with airflow limitations in Japanese patients with

the FEV1/FVC and ％FEV1 were significantly differ­

COPD either. Moreover, these six SNPs did not show

ent between the two groups (p＜0.01). Among the

any associations with the severe airflow limitation as

patients with COPD, 87 patients were in GOLD stage

well as the emphysema phenotype. Furthermore, the44

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MPO in COPD
Table 4 Genotype distribution and allele frequencies of the six SNPs in MPO in the COPD group versus
non-COPD group
COPD group(n＝260)
Genotype(freq)

SNPs

non-COPD group(n＝129)Allele(freq)

Genotype(freq)

Allele(freq) P valueOR(95 ％CI)P value

P value

11

12

22

1

11

12

22

1

(1/2)

(1/2)

(11/12＋22)d(11＋12/22)e

rs2107545 (A/G)

0.78

0.21

0.01

0.89

0.77

0.23

0

0.88

0.82

1.06 (0.66－1.68)

0.67

0.31

rs2243828(A/G)a

0.78

0.21

0.01

0.89

0.77

0.23

0

0.88

0.82

1.06 (0.66－1.68)

0.67

0.31

rs7208693 (C/A)b

0.73

0.25

0.02

0.86

0.74

0.23

0.03

0.85

0.84

1.04 (0.69－1.59)

0.99

0.49

rs35921530 (C/A)a

0.82

0.18

0

0.91

0.83

0.16

0.01

0.91

0.81

0.94 (0.56－1.58)

0.66

0.16

rs35670089 (C/T)c

0.99

0.01

0

0.99

0.98

0.02

0

0.98

0.21

2.98 (0.49－17.93)

0.21

0.21

rs2071409 (T/G)a

0.83

0.17

0

0.92

0.84

0.15

0.01

0.92

0.95

0.98 (0.58－1.68)

0.79

0.16

Abbreviations : freq, frequency ; MPO, the gene encoding myeloperoxidase ; SNP, single nucleotide polymorphism ; OR,
odds ratio ; 95 ％ CI, 95 ％ confidence interval.
1 is for major allele and 2 is for minor allele, and the SNP variant is shown as the rs number (major allele/minor allele).
aExpression quantitative trait loci (eQTLs), the genomic loci contribute to variations in the mRNA expression levels of
the MPO.

b

The nonsynonymous substitution Val53Phe in the MPO.

c

The nonsynonymous substitution Arg604Cys in the MPO.
P values were calculated using the chi-square test (2×2 contingency table).

d

2×2 contingency table assuming the dominant mode with major allele (11/12＋22) of inheritance in COPD group.

e

2×2 contingency table assuming the recessive mode with major allele (11＋12/22) of inheritance in COPD group.

plasma MPO concentrations did not differ between

conclusive, despite meta-analysis attempts to clarify

the patients with COPD and non-COPD smokers.

these controversies10）19）. Korytina and colleagues hy­

COPD is a multifactorial disease and many factors,

pothesized that the MPO-derived oxidants pathogen­including genetic and environmental, interact to in­

ically promote inflammation and cause tissue damage involve with the pathogenesis and development of

the pathogenesis of COPD ; however, the case-control

COPD. The pathophysiology of COPD is characterized

study with 425 patients of COPD and 457 control

by a mixed pathology with phenotypes of small air­subjects did not find any association of genetic variants

way disease (chronic bronchiolitis) and parenchymal

in MPO with COPD20）. Similarly, the present study

destruction (emphysema), the relative contributions

did not detect any associations of the SNPs of MPO

11）

of which vary from person to person . Most patientswith COPD, the severity of airway limitation of COPD

with COPD have a combination of both phenotypes.

and the emphysema phenotype in Japanese patients.

The genetic variants are believed to contribute to theMoreover, more than 50 SNPs captured by the six tag

pathogenesis of COPD and related traits, including

SNPs were found to have no association with COPD

disease severity, extent of emphysema, exacerba­

in the Japanese population. Thus, it seems that thetions of COPD, lung function decline, and drug ef­

MPO gene and the MPO biomolecule are not likely

17）fects . By understanding that MPO is highly involved

to be involved with the pathogenesis and developmentwith the inflammation through activating PMNs, theof COPD. Further prospective confirmatory studies

genetic case-control studies concerning the asso­

beyond initial association studies would evaluate theciations of the genetic variants of MPO with inflam­true facts concerning this issue.

mation-related diseases, such as COPD, cardiovascular

The circulating MPO levels did not show a signifi­

disease, and coronary artery disease, have been per­cant difference between the COPD and non-COPD

10）
18）
19）

. However, most of

smokers and the SNPs of MPO were not significantly

the results were conflicting and remain generally in­associated with the circulating level in either theformed worldwide elsewhere

No. 1, 2020

45

Ito・Yasuo・Droma et al.
Table 5 Associations of the six SNPs in the MPO gene with the severity of COPD as
well as with the emphysema phenotype.

SNPs

rs2107545(A/G)
rs2243828(A/G)aStage III & IV in COPD
n＝87
Major/Minor alleles(freq)

Non-COPD smokers
n＝129
Major/Minor alleles(freq)P Value＊

0.88/0.12

0.88/0.12

0.94

0.88/0.12

0.88/0.12

0.94

rs7208693(C/A)b

0.83/0.17

0.85/0.15

0.59

rs35921530(C/A)a0.91/0.09

0.91/0.09

0.97

rs35670089(C/T)c0.99/0.01

0.99/0.01

0.54

rs2071409(T/G)a0.92/0.08

0.92/0.08

0.91

Emphysema in COPD
n＝103
Major/Minor alleles(freq)

Non-COPD smokers
n＝129
Major/Minor alleles(freq)P Value＊

0.87/0.13

0.88/0.12

0.77

SNPs

rs2107545(A/G)
rs2243828(A/G)a0.87/0.13

0.88/0.12

0.77

rs7208693(C/A)b

0.84/0.16

0.85/0.15

0.82

rs35921530(C/A)a0.89/0.11

0.91/0.09

0.58

0.99/0.01

0.99/0.01

0.86

0.91/0.09

0.92/0.08

0.73

rs35670089(C/T)crs2071409(T/G)aAbbreviations : freq, frequency ; MPO, the gene encoding myeloperoxidase ; SNP, single
nucleotide polymorphism.
aExpression quantitative trait loci (eQTLs), the genomic loci contribute to variations in themRNA expression levels of MPO.

b

The nonsynonymous substitution Val53Phe in MPO.

c

The nonsynonymous substitution Arg604Cys in MPO.
P values were calculated using the chi-square test (2×2 contingency table).

COPD group or non-COPD smokers. The MPO levels
21）

were measured in the sputum in COPD , in the serum22）in the present study. MPO activity may need to bemeasured to confirm the present results.

in healthy smokers and smokers with COPD , andSeveral potential limitations of this study have been

23）

in the serum in patients with exacerbations of COPD .

considered. The sample size was small with un-

The circulating level of MPO was suggested as amatched age and smoking history in the case andpotential systemic neutrophilic inflammation biomarker

control groups. The logistic regression statisticalin patients with COPD. However, the importance ofanalysis was not applied to the adjustments of age

the circulating MPO level in COPD was not verified

and smoking history for the two study groups

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MPO in COPD

because the results showed no significance andmeasured to confirm this result.

the sample size was less than 500. Regardless, theⅤodds ratio was very close to 1, which provided aConclusion

negative hint that these SNPs were not associated with

The genetic variants of the MPO gene were not

COPD. Another limitation was that the MPO mea­

associated with susceptibility to COPD in the Japa­

surements lacked precision with large variability ofnese population. The MPO biomolecule is not involved

measurements, and the MPO activity may need to bewith the pathogenesis of COPD.

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