Kaohsiung Journal of Medical Sciences (2017) 33, 359e364

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ORIGINAL ARTICLE

Glutathione peroxidase 3 gene polymorphisms

and the risk of sudden sensorineural hearing loss
Chen-Yu Chien a,b, Tzu-Yen Huang c, Shu-Yu Tai d,e, Ning-Chia Chang a,f,
Hsun-Mo Wang f, Ling-Feng Wang a,c,*, Kuen-Yao Ho a,b

a
Department of Otorhinolaryngology, School of Medicine, College of Medicine,
Kaohsiung Medical University, Kaohsiung City, Taiwan
b
Department of Otorhinolaryngology, Kaohsiung Medical University Hospital,
Kaohsiung Medical University, Kaohsiung City, Taiwan
c
Department of Otorhinolaryngology, Kaohsiung Municipal Ta-Tung Hospital,
Kaohsiung Medical University, Kaohsiung City, Taiwan
d
Department of Family Medicine, School of Medicine, College of Medicine,
Kaohsiung Medical University, Kaohsiung City, Taiwan
e
Department of Family Medicine, Kaohsiung Municipal Ta-Tung Hospital,
Kaohsiung Medical University, Kaohsiung City, Taiwan
f
Department of Otorhinolaryngology, Kaohsiung Municipal Hsiao-Kang Hospital,
Kaohsiung Medical University, Kaohsiung City, Taiwan

Received 12 December 2016; accepted 5 April 2017

Available online 9 May 2017

KEYWORDS Abstract The glutathione peroxidase 3 gene (GPX3) is reported to be a risk factor for arte-
Glutathione rial ischaemic stroke and cerebral venous thrombosis. GPX3 may be one of the aetiologies of
peroxidase 3; sudden sensorineural hearing loss (SSNHL), which might be attributed to the genetic effect
Polymorphism; of GPX3 by influence reactive oxygen species (ROS). Unbalanced ROS have been associated
Sudden sensorineural with susceptibility to SSNHL. Therefore, we conducted a caseecontrol study with 416 SSNHL
hearing loss cases and 255 controls. Five single nucleotide polymorphisms (SNPs) were selected. The ge-
notypes were determined using TaqMan genotyping assays. Each SNP was tested using the
HardyeWeinberg equilibrium (HWE), and the genetic effects were evaluated using three in-
heritance models. All five SNPs were in HWE. As the result, the AG genotype of rs3805435 had
an adjusted odds ratio (OR) of 0.54 (95% confidence interval Z 0.37e0.79, p Z 0.001)
compared with the AA genotype in the SSNHL cases. The GG and AG genotypes of the SNP

Conflicts of interest: All authors declare no conflicts of interest.

* Corresponding author. Department of Otorhinolaryngology, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung
City 807, Taiwan.
E-mail address: lifewang@kmu.edu.tw (L.-F. Wang).

http://dx.doi.org/10.1016/j.kjms.2017.04.003
1607-551X/Copyright ª 2017, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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360
rs3805435 were associated with SSNHL under the dominant model (p Z 0.002, OR Z 0.58).
In conclusion, these results suggest that GPX3 polymorphisms influence susceptibility to
SSNHL in southern Taiwan.
Copyright ª 2017, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).
Introduction
Sudden sensorineural hearing loss (SSNHL) is defined as a
loss of at least 30 dB in three contiguous frequencies over 3
days or less [1]. The incidence rates per 100,000 popula-
tion in Taiwan are 8.85 for men and 7.79 for women [2].
The aetiology and pathogenesis of SSNHL are unknown, but
its causes may include viral infection, vascular disease,
and autoimmunity [3]. SSNHL, a complex multifactorial
disease, may also be associated with genetic factors
including heat shock protein 70 (HSP70), phosphodies-
terase 4D (PDE4D), factor V Leiden G1691A, prothrom-
bin G20210A, and methylene-tetrahydrofolate reductase
(MTHFR) C677T [3e6].
Glutathione peroxidase (GPX) is an oxygen radical-
metabolising enzyme. Four major GPX isoenzymes
(GPX1e4) are encoded by distinct genes, and the iso-
enzymes vary in tissue distribution and substrate specificity
[7]. The decreased activity of these antioxidant enzymes
may increase oxidative stress. GPX3 is a member of the
selenocysteine-containing GPX family. GPX3 is the only GPX
isoform found in the extracellular space.
Oxidative stress plays a key role in endothelial dysfunc-
tion and results in damage to the terminal microvas-
cular system. Berjis et al. revealed an association between
endothelial dysfunction and SSNHL by measuring flow-
mediated dilation [8]. Capaccio et al. noted unbalanced
reactive oxygen species (ROS) levels in SSNHL patients [9]. A
significantly higher ROS level was observed in SSNHL pa-
tients than in a group of controls [9]. Antioxidant enzymes
such as GPX function as the primary cellular defence
mechanism against ROS by reducing oxidative stress.
GPX3 plays a pivotal role in arterial and venous throm-
bosis [10,11]. GPX3 maintains the bioavailability of nitric
oxide (NO) in the vascular system, and GPX3 deficiency
leads to the decreased vascular bioavailability of NO, which
attenuates its effect on platelet function and subsequently
results in a prothrombotic state. Decreased GPX3 levels
may lead to the loss of antioxidant effects, promoting
oxidative modification of fibrinogen, thereby facilitating
fibrin thrombus formation [12]. Akhter et al. reported
decreased plasma GPX3 levels in stroke patients compared
with a group of controls [12].
Therefore, in the present study, we hypothesise that
single nucleotide polymorphisms (SNPs) of GPX3 are asso-
ciated with the risk of SSNHL. GPX3 polymorphisms may
play a role in the pathogenesis of SSNHL. No study has
investigated the relationship between GPX3 polymorphisms
and the risk of SSNHL. Thus, we conducted a caseecontrol
study to investigate whether GPX3 SNPs are risk factors for
SSNHL for people in southern Taiwan.
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C.-Y. Chien et al.
Material and methods
Study population
We recruited 416 SSNHL patients and 255 controls from our
hospital between October 2010 and July 2014. The diag-
nostic criteria of SSNHL were sensorineural hearing loss of
at least 30 dB in three contiguous frequencies detected
using a pure tone audiogram, with an onset within 3 days
[2]. Healthy volunteers without a history of hearing loss or
any ear disorders were enrolled as controls. Demographic
information was collected.
SSNHL patients underwent audiometric testing,
including pure tone audiometry and auditory brainstem-
evoked responses, and computed tomography or magnetic
resonance imaging (to exclude acoustic neuroma).
The study protocol was approved by the Institutional
Review Board of our hospital, and all subjects provided
informed consent.
SNP selection and genotyping
We selected all tagging SNPs (tSNPs) of GPX3 from the
release 2.0 phase II data of the HapMap Project (www.
hapmap.org) [13] by using the tagger pairwise method
[14]. tSNPs were selected according to the following
criteria: r2 of 0.8 or higher and a minor allele frequency of
more than 10% in the Han Chinese population. Five tSNPs of
GPX3 met the aforementioned criteria and were selected for
genotyping: rs3763013, rs8177412, rs3805435, rs3828599,
and rs2070593.
Genomic DNA was extracted from peripheral blood
through a standard method. Genotyping was performed
using TaqMan technology (7500 Real-Time PCR System,
Applied Biosystems, Foster City, CA, USA), and reactions
were performed in 96-well microplates in ABI 9700 thermal
cyclers (Applied Biosystems, Foster City, CA, USA). Fluo-
rescence was measured using the ABI 7500 Real-Time PCR
System and analysed using System SDS software version
1.2.3 (Applied Biosystems, Foster City, CA, USA). All SNPs
were typed in each subject.
Statistical analysis
Continuous variables were analysed using independent t
tests, the results of which are presented as means
SD.
The allele frequency was obtained through direct gene
counting. The HardyeWeinberg equilibrium (HWE) was
examined in the controls by using the chi-squared test. The
effect of the minor allele of each SNP was examined in
GPX3 polymorphisms in SSNHL
three genetic models: dominant, additive, and recessive.
To assess the genetic effects, multivariate logistic regres-
sion analysis was performed to obtain the age- and sex-
adjusted odds ratio (OR) and 95% confidence interval (95%
CI). All statistical analysis were performed using the JMP
software version 9.0 and Stat View version 5.0 (SAS institute
Inc., Cary City, NC, USA) for Windows. Two-tailed P values
<0.05 were considered significant.
Ethical concerns
This study was approved by the Institutional Review Board
of our hospital, and informed written consent was obtained
from all subjects included in this study.
Results
Study population
Table 1 summarises the demographic characteristics of the
study population. The mean age of the 416 patients [218
(52%) men and 198 (48%) women] was 50.7
14.8 years,
and the mean age of the 255 controls [127 (50%) men and
128 (50%) women] was 46.2
15.3 years. The SSNHL pa-
tients were significantly older than controls (p Z 0.0002).
The sex distribution was 1.1:1.0 (male: female) among the
SSNHL patients. The sex characteristics did not differ
significantly between the two groups.
Single SNP results
Using a p value of 0.05 as the cutoff point, we found that
the distribution of GPX3 genotypes in the controls was in
HWE. The adjusted ORs were calculated to determine the
associations between GPX3 genotypes and SSNHL. Table 2
summarises the distributions of genotypes and allele fre-
quencies of the GPX3 SNPs. No significant differences were
observed in the genotype and allele distributions between
the SSNHL patients and controls for the SNPs rs3763013,
rs8177412, rs3828599, and rs2070593 (Table 2). The intronic
SNP rs3805435 (intron 1) was significantly associated with
SSNHL.
The proportion of the G allele of rs3805435 was lower
in the SSNHL patients than in the controls (42% vs. 49%,
p Z 0.019). The multivariate logistic regression model yiel-
ded sex- and age-adjusted ORs of 0.54 (95% CI Z 0.37e0.79,
Table 1 Baseline demographic characteristics of the
subjects.
SSNHL case Control
(n Z 416) (n Z 255)
Age (mean
SD, y/o) 50.7
14.8 46.2
15.3 0.0002*a
Sex (n, %)
Male 218 (52) 127 (50) 0.5131b
Female 198 (48) 128 (50)
*p < 0.05.
a oxidative stress and cause damage to DNA, proteins, and
Independent t test.
b lipids. ROS accumulation and unrepaired DNA damage
Chi-squared test.
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361
p Z 0.001) for the AG genotype and of 0.66 (95%
CI Z 0.42e1.05, p Z 0.081) for the GG genotype compared
with the AA genotype (Table 2). The dominant model yielded
a significant result (Table 3), with an adjusted OR of 0.58
(95% CI Z 0.40e0.82, p Z 0.002) for the GG þ AG and AA
genotypes of rs3805435 after adjusting for age and sex
(Table 4). Subjects who carried at least one protective G
allele (i.e., AG or GG genotype) of rs3805435 exhibited a
decreased risk of SSNHL compared with those who carried
the AA homozygote.
Discussion
This study investigated the relationship of the five SNPs of
GPX3 with SSNHL in a southern Taiwanese population and
found that GPX3 exerts an evident genetic effect on the
development of SSNHL. Significant results were obtained
for the rs3805435 polymorphism of GPX3, highlighting the
protective role that this rare G allele of rs3805435 has
against SSNHL in southern Taiwan. We found no significant
differences between the SSNHL patients and controls for
the SNPs rs3763013, rs8177412, rs3828599, and rs2070593.
This study is the first report the potential contribution of
GPX3 variants to susceptibility to SSNHL.
Furthermore, our dominant model yielded a significant
adjusted OR of 0.58 (p Z 0.002) for the GG þ AG and AA
genotypes of rs3805435 after adjusting for age and sex. This
result reveals that subjects carrying the G allele (GG þ AG)
tend to have a lower incidence of SSNHL than those with
the AA genotype, suggesting that subjects with the GG and
AG genotypes are conferred a degree of protection. The G
allele of rs3805435 may be a protective allele with a
dominant effect on SSNHL in people in southern Taiwan.
The SNP rs3805435 has not been previously associated with
hearing impairment.
Previous studies have shown that the intronic SNP
rs3805435 is associated with thyroid cancer in patients aged
45 years as well as in those with gastric cancer and an
average age of 66.3
13.9 years [15,16]. In this study, the
mean age of the SSNHL patients was 50.7
14.8 years.
Wang et al. revealed that functional GPX3 polymorphisms
(AC haplotype and rs3805435ers3928599) are associated
with an increased risk of gastric cancer in Taiwanese pa-
tients [16]. Patients carrying the protective haplotype
(allele G of rs3805435 and T of rs3828599) exhibit two-fold
higher luciferase activity than those carrying the risk
haplotype (allele A of rs3805435 and C of rs3828599)
(p Z 0.004) [16]. The reporter assay also revealed that the
GT haplotype (rs3805435ers3928599) increases gene
expression by two-fold compared with the AC haplotype. To
the best of our knowledge, no relevant study has investi-
P value gated the relationship of GPX3 polymorphisms with SSNHL.
The G allele of the intronic SNP rs3805435 likely increases
GPX3 expression, leading to a protective effect against
SSNHL.
Oxidative stress is observed in SSNHL patients; howev-
er, the mechanism underlying the association between
GPX3 and SSNHL is not well known. ROS can increase
may lead to SSNHL [9]. Antioxidant enzymes such as GPX,
362 C.-Y. Chien et al.

Table 2 Association of three SNPs of GPX3 with SSNHL in the study population.
SNP Overall, n (%)
SSNHL case Control P-valuea Adjusted OR (95% CI)b, P-valuea
rs3763013
Genotypes
AA 239 (57) 139 (55) 0.543 1.00c
AG 143 (34) 98 (38) OR Z 0.84 (0.60e1.17), P Z 0.294
GG 34 (8) 18 (7) OR Z 1.08 (0.59e2.03), P Z 0.812
Alleles
A 621 (75) 376 (74) 0.710
G 211 (25) 134 (26)
rs8177412
Genotypes
TT 283 (68) 175 (69) 0.982 1.00c
TC 117 (28) 70 (27) OR Z 1.03 (0.72e1.47), P Z 0.877
CC 16 (4) 10 (4) OR Z 0.93 (0.41e2.19), P Z 0.864
Alleles
T 683 (82) 420 (82) 0.903
C 149 (18) 90 (18)
rs3805435
Genotypes
AA 148 (36) 60 (23) 0.003* 1.00c
AG 183 (44) 140 (55) OR Z 0.54 (0.37e0.79), P Z 0.001*
GG 85 (20) 55 (22) OR Z 0.66 (0.42e1.05), P Z 0.081
Alleles
A 479 (58) 260 (51) 0.019*
G 353 (42) 250 (49)
rs3828599
Genotypes
CC 122 (29) 57 (22) 0.133 1.00c
CT 201 (48) 138 (54) OR Z 0.70 (0.47e1.02), P Z 0.067
TT 93 (23) 60 (24) OR Z 0.74 (0.47e1.18), P Z 0.206
Alleles
C 445 (53) 252 (49) 0.147
T 387 (47) 258 (51)
rs2070593
Genotypes
AA 168 (40) 106 (41) 0.435 1.00c
AG 199 (48) 127 (50) OR Z 0.97 (0.69e1.35), P Z 0.842
GG 49 (12) 22 (9) OR Z 1.41 (0.81e2.52), P Z 0.225
Alleles
A 535 (64) 339 (66) 0.435
G 297 (36) 171 (34)
*p < 0.05.
a
Chi-squared test.
b
Adjusted for age and sex.
c
Reference group.

superoxide dismutase, and catalase function as protective
antioxidants for oxidative stress and neutralize ROS before
it can initiate the cell damage cascade [16]. Plasma GPX3
is a major antioxidant enzyme in the plasma and scav-
enges ROS generated during normal metabolism or after
oxidative insult. Deficiency of this enzyme increases
extracellular oxidant stress, promotes platelet activation,
and may promote oxidative posttranslational modification
of fibrinogen [11].
Previous studies have reported an association between
GPX3 polymorphisms and ischaemic stroke [10,12], factor V
Leiden [17], MTHFR [18], and stroke [19]. Voetsch et al.
revealed that GPX3 polymorphisms are an independent risk
factor for cerebral venous thrombosis (OR Z 10.7,
p < 0.0001) and arterial ischaemic stroke (OR Z 2.07,
p Z 0.034) [10,11]. The enzymes belonging to the GPX
family reduce ROS levels in the vasculature and maintain
the bioavailability of NO, thereby maintaining normal
endothelial function and a normal antithrombotic vascular
environment. GPX3 maintains the vascular bioavailability of
NO, a major vasorelaxant and inhibitor of platelet func-
tion, because NO can be rapidly inactivated by ROS [10].

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GPX3 polymorphisms in SSNHL 363

Table 3 Five SNPs and their relationships with SSNHL under three genetic models (dominant, additive, and recessive).
SNP SSNHL Genotype (n) p
Dominant Additive Recessive
rs3763013 Case AA (239) AG (143) GG (34) 0.403 0.515 0.633
Control AA (139) AG (98) GG (18)
rs8177412 Case TT (283) TC (117) CC (16) 0.927 0.970 0.848
Control TT (175) TC (70) CC (10)
rs3805435 Case AA (148) AG (183) GG (85) 0.002* 0.006* 0.908
Control AA (60) AG (140) GG (55)
rs3828599 Case CC (122) CT (201) TT (93) 0.067 0.179 0.772
Control CC (57) CT (138) TT (60)
rs2070593 Case AA (168) AG (199) GG (49) 0.847 0.392 0.176
Control AA (106) AG (127) GG (22)
Dominant, additive, or recessive model: the rare allele had a dominant, additive, or recessive effect.
All P values were adjusted by age and sex.
*p < 0.05.

The major limitation of the present study is that only

Table 4 Association between GPX3 SNP rs3805435 and
subjects from eastern Asia were included. Additional studies
SSNHL under the dominant model.
should include different ethnic groups to generalize the
SNP SSNHL, Control, Adjusted OR results of the current study. In addition, functional analysis
case n (%) n (%) (95% CI)b, P-valuea of the SNP rs3805435 in GPX3 in SSNHL patients is warranted.
rs3805435 In conclusion, the results of this study support that GPX3
Genotypes polymorphisms influence the risk of SSNHL in a southern
GG þ AG 268 (64) 195 (76) OR Z 0.58 (0.40e0.82), Taiwanese population. The GG and AG genotypes of the SNP
P Z 0.002* rs3805435 may be protective genotypes for SSNHL.
AA 148 (36) 60 (24) 1.00c
*p < 0.05. Ethical concerns
a
Chi-squared test.
b
Adjusted for age and sex. This study was approved by the Institutional Review Board
c
Reference group. of Kaohsiung Medical University Hospital (Approval No.
KMUH-IRB-990243)

Oxidative stress plays a key role in the pathogenesis of

venous thrombosis. Deficiency of plasma GPX3 is associated
with platelet-dependent thrombosis, coronary artery dis-
ease, and familial arterial ischaemic stroke. SNPs in the
promoter region of GPX3 are associated with ischaemic
stroke in the Caucasian population [12].
Baez-Duarte et al. revealed that serum levels of GPX3
are increased in subjects with metabolic syndrome (MetS).
GPX3 polymorphisms have been associated with cardiovas-
cular risk in a Mexican population [20]. A previous study
showed that MetS is an independent risk factor for SSNHL in
Taiwan after adjusting for potential confounding factors
(adjusted OR Z 3.54, p < 0.01) [21]. The T allele frequency
for rs3828599 of GPX3 is significantly lower in hypertensive
patients than in controls (35.6% vs. 40.8%, p Z 0.009) in the
Han Chinese population in China [22]. Individuals carrying
the T allele have a lower risk of hypertension than those
carrying the C allele in the Han Chinese population in
China. Hypertension is one of the most common and sig-
nificant risk factors for coronary heart disease, stroke, and
SSNHL [22]. A previous study conducted in Taiwan showed
that the prevalence of hypertension was higher in SSNHL
patients than in a group of controls (39.2% vs. 23.8%,
p < 0.01) [21]. A Japanese caseecontrol study found no
significant associations between GPX1 polymorphisms
(Pro198Leu and rs1050450) and SSNHL risk [23].
Acknowledgements
This study was supported by grants from Ministry of Science
and Technology (MOST 106-2314-B-037-000), and Kaohsiung
Medical University Hospital (KMUH106-6R00).
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