Original Paper

Digestion 2018;97:146–153 Received: April 18, 2017

Accepted: October 12, 2017
DOI: 10.1159/000484202 Published online: January 8, 2018

Serotonin Transporter Gene (SLC6A4)

Polymorphism May Be Associated with Chinese
Globus Pharyngeus and Its Antidepressant Effects
Yao Liu a Lin Jia a Shu-man Jiang a Dong-yun Chen a Jiang-shun Song b
         

Jian Xu c  

a Department
of Gastroenterology, The Second Affiliated Hospital, South China University of Technology,
Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China; b Department of  

Otorhinolaryngology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China;
c Department of Psychology, The Second Affiliated Hospital, South China University of Technology, Guangzhou First
 

People’s Hospital, Guangzhou Medical University, Guangzhou, China

Keywords anxiety compared to that without anxiety (χ2 = 14.579, p =

Globus pharyngeus · SLC6A4 · Antidepressants · Effect
Abstract
Background: Although globus pharyngeus is not rare in clin-
ical practice, little is known about its associated gene poly-
morphism. We investigated the association between the SL-
C6A4 polymorphism and globus pharyngeus and its re-
sponse to treatment with antidepressants. Methods: A total
of 84 patients were diagnosed with globus pharyngeus ac-
cording to Rome III, and 160 healthy controls were geno-
typed for the SLC6A4 polymorphism using polymerase chain
reaction amplification and agarose gel electrophoresis. All
patients with globus were studied using high-resolution ma-
nometry pre-therapy. Globus patients were randomized into
paroxetine or amitriptyline groups for a 6-week treatment
and asked to complete the following pre- and post-therapy
questionnaires: the Glasgow Edinburgh Throat Scale (GETS),
the Pittsburgh Sleep Quality Index, and the Hamilton Rating
Scale Anxiety/Depression. Treatment response was defined
as a >50% reduction in the GETS scores. Results: A significant
difference was observed in the globus S/S genotype with
0.006). The L/S genotype showed a significant difference be-
tween high upper esophageal sphincter pressure (>104 mm
Hg) and non-high upper esophageal sphincter pressure pa-
tients (χ2 = 14.433, p = 0.006). A significant association be-
tween the S/S genotype and the response to antidepressant
treatment was also observed, while patients with sleep dis-
orders or depression showed no association. Conclusion: A
significant association was observed between the S/S geno-
type of the SLC6A4 polymorphism and globus pharyngeus,
suggesting that SLC6A4 is a potential candidate gene in-
volved in the pathogenesis of globus pharyngeus.
© 2018 S. Karger AG, Basel
Introduction
Globus pharyngeus, a sensation of a lump or tightness
in the throat, is a well-defined clinical symptom that is
typically long lasting, difficult to treat, and has a tendency
to recur. More than half of globus patients suffer from
potential psychological disorders, such as anxiety and de-
pression [1], and patients with functional gastrointestinal
130.241.16.16 - 1/9/2018 2:18:12 PM

© 2018 S. Karger AG, Basel Prof. Lin Jia, MD, Department of Gastroenterology
The Second Affiliated Hospital, South China University of Technology
Guangzhou First People’s Hospital, Guangzhou Medical University
Göteborgs Universitet

E-Mail karger@karger.com
No. 1 Panfu Road, Guangzhou, Guangdong Province 510180 (China)
www.karger.com/dig
Downloaded by:

E-Mail 13925012853 @ 139.com

disorders (FGIDs) have psychological disorders, such as
functional dyspepsia (FD) patients with weight loss [2].
Antidepressants have been used in the treatment of
FGIDs and showed promising efficacy. A previous study
showed that low-dose amitriptyline (AMT) is well toler-
ated and effective for general globus pharyngeus patients
[3]. Previous studies have suggested that AMT could
modify brain-gut axis function, thereby upregulating
brain-gut peptides, reducing the visceral sensitivity, and
regulating the secretory and motor functions of the gas-
trointestinal (GI) tract [4]; thus, GI symptoms and emo-
tional well-being could be significantly improved. Sero-
tonin 5-hydroxtryptamine (5-HT) is an important factor
in gut function, playing a key role in intestinal peristalsis,
secretion, and sensory signaling in the brain-gut axis [5,
6]. Several studies have investigated the association be-
tween SLC6A4 and FGIDs, including IBS (irritable bowel
syndrome) [7, 8] and FD [9]. Additionally, the association
between various complex behavioral traits and disorders
were also studied, including anxiety [10], major depres-
sion [11], suicide [12], smoking behavior [13], and alco-
hol dependence [14]. A single gene (SLC6A4) located on
human chromosome 17q11.1–17q12 encodes the sero-
tonin transporter (5-HTT). The polymorphism of this
gene is characterized by the insertion or deletion of a 44-
bp sequence, and this mutation is associated with differ-
ences in the transcriptional activity of this gene. Alleles
with the 44-bp deletion (short allele) are characterized by
3 times lower transcriptional activity than alleles with the
44-bp insertion (long allele).
Compared to other FIGDs, studies concerning globus
are rare. The pathogenesis of globus pharyngeus remains
unknown. To our knowledge, these findings are the first
to establish an association between the SLC6A4 gene
polymorphism and globus.
Materials and Methods
Subjects
Between September 2015 and June 2016, 84 patients (32 men
and 52 women) were recruited from either the Department of Gas-
troenterology or the Department of Otorhinolaryngology at
Guangzhou Nansha Central Hospital and Guangzhou First Peo-
ple’s Hospital. All patients were diagnosed with globus pharyngeus
according to Rome III diagnostic criteria [15]. All patients under-
went high-resolution manometry, otolaryngological assessment,
neck/thyroid palpation, and upper GI endoscopy or laryngoscopy
to exclude the presence of any organic disease.
The following exclusion criteria were considered: (1) age below
18 or over 80 years; (2) known allergy to AMT or paroxetine (PAR);
(3) severe hepatic or renal dysfunction; (4) prostatic disease; (5)
Serotonin Transporter Gene (SLC6A4)
Polymorphism
known glaucoma; (6) serious heart disease; (7) history of seizures;
(8) pregnancy or breast feeding; (9) recent use of monoamine oxi-
dase inhibitors; and (10) absence of informed consent or refusal to
join the study. A total of 160 subjects (63 men and 97 women) with-
out globus pharyngeus were enrolled as a control group during the
same period at routine annual physical examination.
Ethics Statement
The present study was approved by the hospital ethics commit-
tee and registered in the Chinese Clinical Trial Registry Center
(Registration number: ChiCTR-COC-15006827). Written in-
formed consent was obtained from all subjects.
Study Design and Procedures
The 84 globus patients were divided into 2 subgroups accord-
ing to the results of upper esophageal sphincter pressure (UES)
examined by high-resolution manometry (liquid-state assemblies
with 26 circumferential sensors, MedKinetic, Ningbo, China), and
104 mm Hg was used to divide the subgroups [16]. The present
study initially included 90 patients with globus, but 4 participants
dropped out because of adverse events (unbearable sleepiness, dry
mouth, and malaise). Another 2 patients were excluded from the
final analysis because of blood storage problems. An independent
investigator randomly assigned the 84 eligible patients into 2
groups using a computer-generated random numbers table, in-
cluding an AMT group, receiving 12.5 mg AMT (25 mg/tablet;
HuNanDongTing Pharmaceutical Co., Ltd., HuNan, China) once
daily before bedtime; and the PAR group, receiving PAR (Seroxat;
20 mg/tablet; Glaxo SmithKline Pharmaceutical Co., Ltd.) 20 mg
once daily in the morning. The treatment period was 6 weeks. All
patients underwent high-resolution pre- and post-therapy ma-
nometry (MedKinetic, Ningbo, China) and were asked to com-
plete the following pre- and post-therapy questionnaires: the
Glasgow Edinburgh Throat Scale (GETS), the Pittsburgh Sleep
Quality Index (PSQI), and the Hamilton Rating Scale Anxiety/De-
pression. Among the 182 subjects who completed the same ques-
tionnaires, 160 subjects (63 men and 97 women) did not have any
globus symptoms or psychological disorders as a control group.
Treatment response [4] was defined as a >50% reduction in the
GETS score. The response was calculated as follows: ([score at
treatment – score at baseline]/score at baseline) ×100%. All en-
rolled subjects provided informed consent and a 5-mL peripheral
blood sample.
Assessments
The following assessments were performed at entry (regarded
as baseline) and at the end of the 6-week trial:
Glasgow Edinburgh Throat Scale
The GETS [17], which provided both the primary and second-
ary outcomes, is a validated questionnaire used to assess throat
symptom severity. Higher scores represent more severe symp-
toms.
Pittsburg Sleep Quality Index
Prepared by psychiatrist Buysse (PSQI) [18], the PSQI assesses
7 areas, including sleep quality, the time to fall asleep, sleep time,
sleep efficiency, sleep disturbance, use of sleep medication and
daytime dysfunction. Higher scores represent worse sleep quality,
and scores >7 points indicate the presence of a sleep disorder.
130.241.16.16 - 1/9/2018 2:18:12 PM
Digestion 2018;97:146–153 147
DOI: 10.1159/000484202
Göteborgs Universitet
Downloaded by:
 Table 1. Demographic of study subjects
Female
Male
Age
Alcohol consumption
Cigarette smoking
Hamilton Anxiety Rating Scale
The 14-item Hamilton Anxiety Rating Scale (HAMA) [19] was
used to evaluate the degrees of anxiety symptoms. Higher scores
indicate more severe anxiety, and scores >7 indicate the presence
of anxiety.
Hamilton Rating Scale of Depression
The Hamilton Rating Scale of Depression (HAMD) [20] is the
most widely used clinician-administered depression scale. Higher
scores indicate more severe depression, and scores >7 indicate the
presence of depression.
Data Collection
Data were collected during face-to-face interviews conducted
in a quiet environment (20–30 min per subject). During each in-
terview, the measures described in the above section were com-
pleted, and high-resolution manometry results were recorded. All
subjects were interviewed by trained psychologists and digestive
physicians.
Genotyping
Genomic DNA from blood samples was isolated using a com-
mercially available kit (Biospin Whole Blood Genomic DNA Ex-
traction Kit, BioFlux, Japan) according to the manufacturer’s in-
structions. The primers for SLC6A4 (SERT-P repeats) were for-
ward: 5′-ATGCCAGCACCTAACCCCTAATGT-3′
(reversed) 5′-GGACCGCAAGGTGGGCGGGA-3′. Polymerase
chain reaction amplification was performed in a final volume of 20
μL, comprising 0.2 μg of genomic DNA, 400 μmol/L deoxy ribo-
nucleotides, and 0.2 μmol/L of each primer. Reflecting the high
guanine and cytosine content in the amplified region of the SERT
gene (SLC6A4), the polymerase chain reaction reactions were per-
formed using the TaKaRa La Taq polymerase (0.8 U/reaction) with
guanine and cytosine Buffer I (TaKaRaBiomedicals, Shiga, Japan).
After denaturing all DNA samples at 94 ° C for 1 min, the cycling
    
conditions were set at 30 cycles at 94 ° C for 30 s, 60 ° C for 30 s, and
72 ° C for 2 min, with a 10-min final cycle extension at 72 ° C. To
determine the presence of length variations of the alleles, the am-
plified products were electrophoresed on 3.0% agarose and visual-
ized using ethidium bromide staining.
Statistical Analysis
The chi-square test and Hardy-Weinberg equilibrium theory
were used to compare the genotype and allele frequencies between
the globus and control group and among the globus subgroups.
Chi-square test and Fisher’s exact test were used to assess the rela-
tionship between clinical factors and genotype. Bonferroni’s test
148 Digestion 2018;97:146–153
DOI: 10.1159/000484202
Globus Controls p value
(n = 84), n (%) (n = 160), n (%)
52 (61.90) 94 (58.75) 0.633
32 (38.10) 66 (41.25) 0.633
46.25±12.52 45.23±13.56 0.415
13 (15.47) 23 (14.68) 0.870
12 (14.28) 23 (14.47) 0.903
was used for multiple comparisons. Statistical analysis was per-
formed using the SPSS 13.0 statistical software, and p values <0.05
were considered statistically significant. Bonferroni’s test was used
for multiple comparisons. Significance tests were 2-tailed and
managed at the 0.05 significance level.
Results
Demographic Characteristics
Participant demographics and SLC6A4 genotype dis-
tributions are summarized in Table 1. The median age of
the subjects with globus and the controls were 46.25
(range 21–75) and 45.23 (range 19–73) years (p = 0.415),
respectively. No significant bias was observed between
the groups in sex, smoking habit, and drinking habit.
Comparisons Concerning the SLC6A4 Polymorphism
Genotype Frequencies between the Globus Patients
and the Controls
A total of 84 globus patients and 160 healthy volun-
teers were enrolled in the present study, and peripheral
and
blood samples were obtained for genotyping. Genotype
distributions for the SLC6A4 polymorphisms were as-
sessed for deviation from Hardy-Weinberg equilibrium,
and no deviation was observed (SLC6A4 χ2 = 1.1159, p >
0.05). Allele frequencies are shown in Table 2. A com-
parison of the genotype distributions between globus
and controls (Table 2) showed significant differences for
SLC6A4 (χ2  = 33.880, p  = 0.001). The S/S genotype in
globus was significantly higher than that in the control
group (60.7 vs. 25.0%, p = 0.001); however, the L/S geno-
type in the control group was significantly higher than
that in the globus (60.0 vs. 26.2%, p = 0.001). A significant
difference was observed in the S allele (76.79 vs. 57.50%),
L allele (19.04 vs. 37.5%), and XL allele (4.17 vs. 5.00%)
of globus patients compared to the control group (χ2 =
18.593, p = 0.001). In globus, the S allele had a higher fre-
quency than in the control group (76.79 vs. 57.50%, p =
0.001).
130.241.16.16 - 1/9/2018 2:18:12 PM
Liu/Jia/Jiang/Chen/Song/Xu
Göteborgs Universitet
Downloaded by:
Table 2. SLC6A4 polymorphism genotype frequencies between the globus patients and the controls

SLC6A4 n Genotype χ2 p value Allele frequency χ2 p value

L/L L/S S/S XL/L XL/S S L XL

Globus 84 4 22 51 2 5 129 32 7
Controls 160 8 96 40 8 8 33.880 0.001 184 120 16 18.593 0.001
HUES 21 1 12 7 0 1 27 14 1
NUES 63 3 10 44 2 4 14.433 0.006 102 18 6 7.568 0.023
Anxiety 39 1 3 31 1 2 67 6 3
No anxiety 45 3 19 20 1 3 14.579 0.006 62 26 4 11.416 0.003
Depression 23 1 5 14 1 2 35 8 3
No depression 61 3 17 37 1 3 1.166 0.884 94 24 4 0.938 0.625
Sleep disorders 43 2 9 27 2 3 66 15 5
No sleep disorders 41 2 13 24 0 2 3.058 0.548 63 17 2 1.386 0.500

p < 0.05 was considered statistically significant.

HUES, high upper esophageal sphincter pressure group; NUES, non-high upper esophageal sphincter pressure group.

Comparing High Upper Esophageal Sphincter Pressure
Group with Non-High Upper Esophageal Sphincter
Pressure Group
The SLC6A4 polymorphism genotype frequencies in
the 2 subgroups, high upper esophageal sphincter pres-
sure group (HUES) and non-high upper esophageal
sphincter pressure group (NUES), showed a significant
difference (χ2 = 14.433, p = 0.006). In the HUES group (21
patients), the L/S genotype was higher than that in the
NUES group (63 patients).
Comparing Subgroups According to Psychological
Features in Globus
Among globus patients, there were 39 (46.4%) patients
with anxiety, 23 (27.3%) patients with depression, and 43
(51.8%) patients with sleep disorders. The S/S genotype
in globus patients with anxiety was significantly higher
than in those without (79.4 vs. 44.4%, p = 0.006). The S
allele in the anxiety group showed a frequency higher
than in patients without anxiety (χ2 = 11.416, p = 0.003).
No significant difference was observed between patients
with depression and those without depression (χ2 = 1.166,
p = 0.884). The same result was observed between patients
with sleep disorders and those without depression (χ2 =
3.058, p = 0.548).
Association between the SLC6A4 Polymorphism and
Effect of Antidepressants
We combined XL/L, XL/S, and L/L genotypes into one
group, as the number of these genotypes was small. In the
AMT group, there were 5 patients with (XL/L + XL/S +
L/L), 10 patients with L/S, and 26 patients with S/S, and
the treatment responders in these subgroups were 1, 2,
and 16, respectively (a total of 19 treatment responders).
As shown in Table 3, treatment response, the HAMA
score (11.71 ± 4.83 vs. 4.79 ± 2.67, p < 0.0167) and GETS
score (12.76 ± 3.22 vs. 5.51 ± 2.02, p < 0.0167) for the S/S
genotype showed a significant difference from those of
other genotypes. However, there was no significant dif-
ference in the HAMD and PSQI scores. In the PAR group,
there were 5 patients with XL/L + XL/S + L/L, 12 patients
with L/S, and 26 patients with S/S, and the treatment re-
sponse in these subgroups was 2, 8, and 24, respectively
(a total 34 treatment responders). Similar to the AMT
group, treatment response, HAMA score (11.71 ± 4.83 vs.
4.79 ± 2.67, p < 0.0167), and GETS score (12.76 ± 3.22 vs.
5.51 ± 2.02, p < 0.0167) for the S/S genotype were signifi-
cantly improved. No significant difference in the HAMD
and PSQI scores was observed. As shown in Table 3, in
the AMT group, compared with baseline, the UES pres-
sure (mm Hg) after the 6-week treatment period was sig-
nificantly decreased in the L/S and S/S groups (83.5 ± 19.1
vs. 62.4 ± 21.5, p = 0.015; 83.5 ± 19.1 vs. 63.4 ± 21.5, p =
0.001), while there was no difference observed in the
XL/L + XL/S + L/L group (80.4 ± 31.1 vs. 80.8 ± 27.2, p =
0.380). At the end of the treatment, the UES pressure
(mm Hg) was significantly lower in both the L/S and S/S
groups compared to that in the XL/L + XL/S + L/L group
(63.4 ± 21.5 vs. 80.8 ± 27.2, p = 0.003; 63.1 ± 19.9 vs. 80.8 ±
27.2, p = 0.002). However, there was no significant differ-
ence observed in the L/S and S/S groups (63.4 ± 21.5 vs.
63.1 ± 19.9, p = 0.452). In the PAR group, compared with
baseline, the UES pressure (mm Hg) after the 6-week
treatment period was significantly decreased in the L/S
130.241.16.16 - 1/9/2018 2:18:12 PM

Serotonin Transporter Gene (SLC6A4) Digestion 2018;97:146–153 149

Polymorphism DOI: 10.1159/000484202
Göteborgs Universitet
Downloaded by:
 and S/S groups (77.6 ± 18.3 vs. 63.2 ± 16.5, p  = 0.014;

AMT, amitriptyline; PAR, paroxetine; GETS, Glasgow Edinburgh Throat Scale; HAMA, Hamilton Rating Scale of Anxiety; HAMD, Hamilton Rating Scale of Depression; PSQI,
Treatment
response
74.9 ± 25.5 vs. 46.9 ± 15.5, p = 0.001), while there was no
difference observed in the XL/L + XL/S + L/L group

16**

24**
2
8
1
2
(82.3 ± 21.4 vs. 77.6 ± 17.7, p = 0.425). At the end of the
treatment, the UES pressure (mm Hg) was significantly
5.23±2.34*

4.18±3.24*
5.46±2.43
4.71±2.78
8.85±4.01
5.42±4.92
lower in both the L/S and S/S groups compared to that in
the XL/L + XL/S + L/L group (63.2 ± 16.5 vs. 77.6 ± 17.7,
PSQI

p = 0.002; 46.9 ± 15.5 vs. 77.6 ± 17.7, p = 0.002). Moreover,
the UES pressure (mm Hg) was also significantly lower in
4.90±2.54*

5.43±3.21*
5.56±4.12
5.63±3.43
5.91±4.23
5.24±3.24

the S/S group than in the L/S group (46.9 ± 15.5 vs. 63.2 ±
HAMD

16.5, p = 0.013).

** p < 0.0167 was considered statistically significant, when S/S compared with other subgroups in GETS, UES, HAMA, treatment response.
46.9±15.5*, ** 4.71±2.78*, **
4.79±2.67* **

Discussion
6.94±4.12
6.51±2.43
9.64±4.51
8.76±3.62
HAMA

The serotonin transporter length polymorphic region

(5-HTTLPR) polymorphism located on the SLC6A4 gene
is an extensively investigated gene region. To our knowl-
63.1±19.9*
63.4±21.5*

77.6±17.7
63.2±16.5
80.8±27.2

edge, the present study is the first to investigate the asso-

UES

ciation between the SLC6A4 polymorphism and globus.

We observed a significantly higher occurrence of the S/S
genotype among globus patients compared to the control
5.51±2.02*, **

5.61±2.43*, **

population from the same geographical region (Guang-

9.54±1.47
10.26±1.82
11.43±2.68
9.87±2.71

zhou, China). The relationship of the SLC6A4 polymor-

6-week
GETS

phism with other FGIDs is consistent with the results of

* p < 0.05 when compared with baseline; Bonferroni test was used for multiple comparisons.

the present study. Studies in America and Korea reported

Table 3. Association between SLC6A4 polymorphism and effect of antidepressants

that the S/S genotype was a risk factor for IBS [21, 22]. In
5 10.92±1.58 82.3±21.4 10.81±3.72 8.24±5.61 9.71±4.57
12 11.56±2.12 77.6±18.3 11.21±1.23 8.53±5.32 9.68±4.63
26 12.45±2.62 74.9±25.5 12.31±2.45 8.64±5.47 9.85±4.71
5 12.31±2.94 80.4±31.1 10.91±4.76 8.12±5.70 9.76±4.51
10 11.75±3.12 83.5±19.1 10.67±5.10 8.43±3.51 9.68±4.79
26 12.76±3.25 80.8±27.9 11.71±4.83 8.97±5.44 9.45±4.96

China and India, considering the subtypes of IBS, the S/S

genotype showed a higher significant difference in IBS
PSQI

with diarrhea than in other subtypes [7, 8]. Nevertheless,

Japanese studies showed no significant correlation be-
HAMD

tween the 5-HTTLPR genotype and FD [9]. The differ-

ences in the S/S genotype distribution in FGIDs may be
associated with the pathogenesis of this disease and re-
gional populations. As the etiology of globus remains un-
HAMA

clear, the influence of the S allele on the development of

globus needs further investigation.
p < 0.05 was considered statistically significant.

In the present study, L/S in the HUES group was sig-

nificantly higher than in the NUES group. 5-HT regulates
UES

the sensory, motor, and secretory functions of the GI tract

through interactions with different receptor subtypes. As
Baseline

described above, the S allele activity was lower than the L

GETS

Pittsburgh Sleep Quality Index.

allele activity, affecting the concentration of the serotonin

transporter, leading to lower transporter expression and
n

therefore lower uptake of 5-HT. Cui et al. [23] observed

XL/L + XL/S + L/L
XL/L + XL/S + L/L

that SERT expression was decreased in colon tissues from

visceral-sensitized rats, suggesting a potential association
of SERT with the sensitivity of the GI tract. We specu-
Genotype

lated that the visceral sensitivity may be associated with

AMT

PAR

L/S
L/S

S/S
S/S

high UES pressure, but the results of the present study did
130.241.16.16 - 1/9/2018 2:18:12 PM

150 Digestion 2018;97:146–153 Liu/Jia/Jiang/Chen/Song/Xu

DOI: 10.1159/000484202
Göteborgs Universitet
Downloaded by:
not show a significant difference in the S/S genotype be-
tween the subgroups. For the complexity of the formation
of UES pressure [24] and the mechanism of globus, this
hypothesis requires further exploration. We observed
that antidepressants decreased UES pressure. In the PAR
group, the S/S genotype showed a larger decrease in UES
pressure than in other genotypes. The mechanisms un-
derlying the ability of PAR to decrease UES pressure re-
main unknown but may partially reflect the relief of men-
tal state.
In a previous study, we observed that more than half
of patients with refractory globus had anxiety and depres-
sion. This finding supports the existence of a relationship
between psychological factors and globus [2]. Genetic
variation of the serotonin transporter (5-HTT) gene is re-
garded as a factor likely associated with susceptibility to
depressive disorders. The presence of the S allele results
in a lower transcriptional activity of the 5-HTT gene and
causes individual differences in sensitivity to daily life
stress. This relationship has been observed in both human
and animal studies [23]. Stein indicated a high relation-
ship between the presence of the S/S genotype or S allele
and a greater susceptibility to affective disorders, and
when combined with adverse environmental effects, an
increased likelihood of the development of depression
was also observed [25]. A meta-analysis showed an inter-
action between the number of stressful life events and the
number of 5HTTLPR S alleles in the risk for depression
[26]. However, another meta-analysis showed no signifi-
cant association between the polymorphism and Asian
major depressive disorder patients [27]. However, the re-
sults of the present study were not consistent with those
of the studies described above, as the frequency of the S/S
genotype in globus patients with anxiety was significant-
ly higher than in those without, and no significant differ-
ence was observed between patients with depression or
sleep disorders and those without.
The treatment efficiency of the AMT and PAR groups
is, respectively, 46.3 and 79.1% compared with the base-
line, and a distinct improvement in emotional well-being
and quality of sleep were observed in PAR and AMT
groups after the 6-week treatment. However, when these
2 groups were divided based on genotypes into sub-
groups, a significant difference was observed in the S/S
genotype in both HAMA scores and treatment responses
in the PAR and AMT groups. 5-HT is the clinical product
of the interaction of psychosocial factors and altered gut
physiology via the brain-gut axis [28].
Low-dose AMT has been identified as well tolerated
and used to treat FGIDs for many years [29]. We observed
Serotonin Transporter Gene (SLC6A4)
Polymorphism
that low-dose AMT is well tolerated and can significantly
improve patient symptoms, sleep, and quality of life.
Low-dose AMT may be an effective treatment for globus
pharyngeus [4]. A previous study suggested that AMT
could modify brain-gut axis function, upregulating brain-
gut peptides, reducing the visceral sensitivity, and regu-
lating the secretory and motor functions of the GI tract
[4]; thus, the GI symptoms and emotional well-being
could be significantly improved. In the present study, we
observed that PAR therapy is more efficacious than em-
pirical high-dose antacid treatment or even the low-dose
AMT therapy in alleviating globus symptoms and pro-
ducing global improvements for refractory globus pa-
tients [30].
A meta-analysis, including 33 studies and 5,479 sub-
jects, tested 2 phenotypes, remission and response rates,
and 3 genotype comparisons, LL vs. LS/SS, SS vs. LL/LS,
and LL vs. SS. The present study observed an association
between L allele and L/L genotype and remission when the
analysis was divided according to ethnic group: in Cauca-
sians, we observed an association between the L allele and
both responses and remission in the selective serotonin
reuptake inhibitor (SSRI) group, while no association was
observed in Asians [31]. Most of these studies included
Caucasians, and the proportion of Asians was small. Kato
investigated the different characteristics of clinical re-
sponses to PAR and fluvoxamine in 100 Japanese patients
affected by major recurrent depression. Patients with the
L allele of SERTPR showed a better response to SSRIs than
S/S genotype carriers, with a more significant response to
fluvoxamine [32]. A total of 60 patients who met the DSM-
IV criteria for major depressive disorder showed that the
plasma PAR levels at 4 weeks were significantly higher in
responders (rapid responders) than in non-responders.
However, no significant associations were observed be-
tween the L genotype (L/L, L/S) or the S genotype (S/S)
and the response rates at either 4–8 weeks [33]. Neverthe-
less, in a Korean study, 120 depressed patients and 252
normal controls were genotyped, showing that homozy-
gous S/S in the promoter region showed better responses
than all others [34]. These results were consistent with
those of the present study. In Asian populations, the re-
sults are thus conflicting, likely reflecting the small sample
sizes and some methodological aspects (i.e., rating scale
cutoff, lack of control for plasma levels, and different eth-
nicities), which does not enable us to draw a definite con-
clusion on the role of the SLC6A4 polymorphism. FGIDs
are the clinical product of the interaction of psychosocial
factors and altered gut physiology via the brain-gut axis
[35]. Antidepressant treatments have been demonstrated
130.241.16.16 - 1/9/2018 2:18:12 PM
Digestion 2018;97:146–153 151
DOI: 10.1159/000484202
Göteborgs Universitet
Downloaded by:
as reliably effective therapies for FGIDs and even for re-
fractory FGIDs [36, 37]. Moreover, antidepressants pro-
duce global improvement for treating FGIDs [38, 39].
AMT, an old-style tricyclic antidepressant, had been iden-
tified as well tolerated and used to treat FGIDs. The S allele
compared with the L allele decreased 5-HTT mRNA ex-
pression, leading to slower serotonin reuptake from the
serotonin transporter, which in turn results in high sero-
tonin concentration in the synaptic clefts. The newer gen-
eration antidepressant agent, PAR, an SSRI, improves the
serotonin concentration in the synaptic clefts. Serotonin
(5-HT) is an important neurotransmitter in both the brain
and GI tract, where it plays a key role in the regulation of
sensory and motor functions. The 5-HT receptors are lo-
cated on afferent neurons and in the enteric and auto-
nomic neurons systems and are involved in mediating
sensory and reflex responses to GI stimuli [40]. Among
the 5-HT receptor subtypes, 5-HT3, mediating visceral
sensations and gut reflexes, is the most significant to GI
function. Furthermore, there is evidence suggesting that
SSRIs, including PAR, have some activity at 5-HT3 recep-
tors and may improve the symptoms of some FGIDs [41–
43]. The underlying mechanisms of PAR for treating glo-
bus remain unclear but may partially reflect the activity of
PAR at 5-HT3 receptors. This hypothesis requires further
study to determine the mechanisms of action of antide-
pressants in general. Moreover, considering the complex-
ity of the pathogenesis of functional GI diseases and the
role genes and environmental factors play in the progress
of globus development, further studies are required.
In the present study, there were some limitations.
First, although many patients with globus symptoms and
normal examinations were treated in the clinic, the pres-
ent study included only a small sample of patients with
globus. Second, we investigated only the XL, L, and S al-
leles of SLC6A4. Other studies have examined the 5-HTT
single nucleotide polymorphisms rs25531 and STin2 in
addition to SLC6A4. If we had investigated these single
nucleotide polymorphisms, then the present study might
have yielded more important results.
In conclusion, a significant association was observed
between the S/S genotype of SLC6A4 polymorphism and
globus pharyngeus. Patients with the S/S genotype re-
sponded better to both AMT and PAR treatment than
those with other genotypes, suggesting that SLC6A4 is a
potential candidate gene involved in the pathogenesis of
globus pharyngeus.
Acknowledgments
The authors would like to thank Professor Ming-zhi Xu (from
Guangdong Mental Disorder Research Institute) for guidance on
the use of the anxiety and depression scales. The authors would
also like to thank Guangzhou Vipotion Biotechnology Co., LTD
for the genotyping SLC6A4.
Disclosure Statement
There was no funding support or potential conflicts of interest
in this work.

References
  1 Tang B, Jia L, Liu J, Gu X, Ye HX, Song JS, Su
F, Ji XB, Xie JH, Zhang XH: Clinical-psycho-
logical characteristics of refractory globus pa-
tients in China. Dig Liver Dis 2016; 48: 381–
384.
  2 Liu J, Jia L, Lei XG, Jiang SM, Wang SB, Xu M:
The clinical-psychological features of func-
tional dyspepsia patients with weight loss: a
multi-center study from China. Digestion
2015;91:197–201.
  3 You LQ, Liu J, Jia L, Jiang SM, Wang GQ: Ef-
fect of low-dose amitriptyline on Globus Pha-
ryngeus and its side effects. World J Gastro-
enterol 2013;19:7455–6740.
  4 Huang W, Jiang SM, Jia L, You LQ, Huang
YX, Gong YM, Wang GQ: Effect of amitrip-
tyline on gastrointestinal function and brain-
gut peptides: a double-blind trial. World J
Gastroenterol 2013;19:4214–4220.
  5 Khan WI, Ghia JE: Gut hormones: emerging
role in immune activation and inflammation.
Clin Exp Immunol 2010;161:19–27.
  6 Kim DY, Camilleri M: Serotonin: a mediator
of the brain-gut connection. Am J Gastroen-
terol 2000;95:2698–2709.
  7 Kumar S, Ranjan P, Mittal B, Ghoshal UC: Se-
rotonin transporter gene (SLC6A4) polymor-
phism in patients with irritable bowel syn-
drome and healthy controls. J Gastrointestin
Liver Dis 2012;21:31–38.
  8 Yuan J, Kang C, Wang M, Wang Q, Li P, Liu
H, Hou Y, Su P, Yang F, Wei Y, Yang J: As-
sociation study of serotonin transporter SL-
C6A4 gene with Chinese Han irritable bowel
syndrome. PLoS One 2014;9:e84414.
  9 Toyoshima F, Oshima T, Nakajima S, Sakurai
J, Tanaka J, Tomita T, Hori K, Matsumoto T,
Miwa H: Serotonin transporter gene poly-
morphism may be associated with functional
dyspepsia in a Japanese population. BMC
Med Genet 2011;12:88.
10 Lesch KP, Bengel D, Heils A, Sabol SZ, Green-
berg BD, Petri S, Benjamin J, Müller CR,
Hamer DH, Murphy DL: Association of anx-
iety-related traits with a polymorphism in the
serotonin transporter gene regulatory region.
Science. 1996;274:1527–1531.
11 Ogilvie AD, Battersby S, Bubb VJ, Fink G,
Harmar AJ, Goodwim GM, Smith CA: Poly-
morphism in serotonin transporter gene as-
sociated with susceptibility to major depres-
sion. Lancet 1996;347:731–733.
12 Lin PY, Tsai G: Association between sero-
tonin transporter gene promoter polymor-
phism and suicide: results of a meta-analysis.
Biol Psychiatry 2004;55:1023–1030.
13 Kremer I, Bachner-Melman R, Reshef A,
Broude L, Nemanov L, Gritsenko I, Heresco-
Levy U, Elizur Y, Ebstein RP: Association of
the serotonin transporter gene with smoking
behavior. Am J Psychiatry 2005;162:924–930.
14 Ho PS, Shih MC, Ma KH, Huang WS, Ho KK,
Yen CH, Lu RB, Huang SY: Availability of the
serotonin transporter in patients with alcohol
dependence. World J Biol Psychiatry 2011;12:
134–142.
130.241.16.16 - 1/9/2018 2:18:12 PM

152 Digestion 2018;97:146–153 Liu/Jia/Jiang/Chen/Song/Xu

DOI: 10.1159/000484202
Göteborgs Universitet
Downloaded by:
15 Galmiche JP, Clouse RE, Bálint A, Cook IJ,
Kahrilas PJ, Paterson WG, Smout AJ: Func-
tional esophageal disorders. Gastroenterolo-
gy 2006;130:1459–1465.
16 Kahrilas PJ, Ghosh SK, Pandolfino JE: Esoph-
ageal motility disorders in terms of pressure
topography: the Chicago classification. J Clin
Gastroenterol 2008;42:627–635.
17 Deary IJ, Wilson JA, Harris MB, MacDougall
G: Globus pharyngis: development of a symp-
tom assessment scale. J Psychosom Res 1995;
39:203–213.
18 Buysse DJ, Reynolds CF, Monk TH, Berman
SR, Kupfer DJ: The pittsburgh sleep quality
index: a new instrument for psychiatric prac-
tice and research. Psychiatry Res 1989; 28:
193–213.
19 Matza LS, Morlock R, Sexton C, Malley K,
Feltner D: Identifying HAM-A cutoffs for
mild, moderate, and severe generalized anxi-
ety disorder. Int J Methods Psychiatr Res
2010;19:223–232.
20 Calotă DR, Niţescu C, Marinescu S, Cristescu
C, Boiangiu I, Florescu IP, Lascăr I: Correla-
tions between morphological appearance and
psychosocial difficulties in patients with ex-
tensive burns who received allotransplant. J
Morphol Embryol 2012;53(3 suppl):703–711.
21 Yeo A, Boyd P, Lumsden S, Saunders T,
Handley A, Stubbins M, Knaggs A, Asquith S,
Taylor I, Bahari B, Crocker N, Rallan R,
Varsani S, Montgomery D, Alpers DH, Dukes
GE, Purvis I, Hicks GA: Association between
a functional polymorphism in the serotonin
transporter gene and diarrhoea predominant
irritable bowel syndrome in women. Gut
2004;53:1452–1458.
22 Park JM, Choi MG, Park JA, Oh JH, Cho YK,
Lee IS, Kim SW, Choi KY, Chung IS: Sero-
tonin transporter gene polymorphism and ir-
ritable bowel syndrome. Neurogastroenterol
Motil 2006;18:995–1000.
23 Cui XF, Zhou WM, Yang Y, Zhou J, Li XL, Lin
L, Zhang HJ: Epidermal growth factor upreg-
ulates serotonin transporter and its associa-
tion with visceral hypersensitivity in irritable
bowel syndrome. World J Gastroenterol 2014;
20:13521–13529.
24 Kawaguchi S, Takeuchi T, Inoue Y, Takahashi
Y, Ozaki H, Ota K, Harada S, Edogawa S, Ko-
jima Y, Yamashita H, Fukuchi T, Ashida K,
Higuchi K: Exploratory research on latent
Serotonin Transporter Gene (SLC6A4)
Polymorphism
esophageal motility disorders in dysphagia
patients. Digestion 2017;95:269–274.
25 Skalkidou A, Hellgren C, Comasco E, Sylvén
S, Sundström Poromaa I: Biological aspects of
postpartum depression. Womens Health
(Lond) 2012;8:659–672.
26 Stein MB, Campbell-Sills L, Gelernter J: Ge-
netic variation in 5HTTLPR is associated with
emotional resilience. Am J Med Genet B Neu-
ropsychiatr Genet 2009;150B:900–906.
27 Karg K, Burmeister M, Shedden K, Sen S: The
serotonin transporter promoter variant
(5-HTTLPR), stress, and depression meta-
analysis revisited: evidence of genetic mod-
eration. Arch Gen Psychiatry 2011; 68: 444–
454.
28 Kiyohara C, Yoshimasu K: Association be-
tween major depressive disorder and a func-
tional polymorphism of the 5-hydroxytrypta-
mine (serotonin) transporter gene: a meta-
analysis. Psychiatr Genet 2010;20:49–58.
29 Grover M, Camilleri M: Effects on gastroin-
testinal functions and symptoms of seroto-
nergic psychoactive agents used in functional
gastrointestinal diseases. J Gastroenterol
2013;48:177–181.
30 Breen M, Camilleri M, Burton D, Zinsmeister
AR: Performance characteristics of the mea-
surement of gastric volume using single pho-
ton emission computed tomography. Neuro-
gastroenterol Motil 2011;23:308–315.
31 Chen DY, Jia L, Gu X, Jiang SM, Xie HL, Xu
J: Comparison of paroxetine and amitripty-
line in the treatment of refractory globus
pharyngeus. Dig Liver Dis 2016; 48: 1012–
1017.
32 Tack J, Broekaert D, Fischler B, Van Ouden-
hove L, Gevers AM, Janssens J: A controlled
crossover study of the selective serotonin
reuptake inhibitor citalopram in irritable
bowel syndrome. Gut 2006;55:1095–1103.
33 Kato M, Fukuda T, Wakeno M, Fukuda K,
Okugawa G, Ikenaga Y, Yamashita M, Takeki-
ta Y, Nobuhara K, Azuma J, Kinoshita T: Ef-
fects of the serotonin type 2A, 3A and 3B re-
ceptor and the serotonin transporter genes on
paroxetine and fluvoxamine efficacy and ad-
verse drug reactions in depressed Japanese
patients. Neuropsychobiology 2006; 53: 186–
195.
34 Yoshimura R, Umene-Nakano W, Suzuki A,
Ueda N, Miyamoto K, Ikenouchi-Sugita A,
Digestion 2018;97:146–153
DOI: 10.1159/000484202
Hori H, Otani K, Nakamura J: Rapid response
to paroxetine is associated with plasma parox-
etine levels at 4 but not 8 weeks of treatment,
and is independent of serotonin transporter
promoter polymorphism in Japanese de-
pressed patients. Hum Psychopharmacol
2009;24:489–494.
35 Kim DK, Lim SW, Lee S, Sohn SE, Kim S,
Hahn CG, Carroll BJ: Serotonin transporter
gene polymorphism and antidepressant re-
sponse. Neuroreport 2000;11:215–219.
36 Grover M, Camilleri M: Effects on gastroin-
testinal functions and symptoms of seroto-
nergic psychoactive agents used in functional
gastrointestinal diseases. J Gastroenterol
2013;48:177–181.
37 Otaka M, Jin M, Odashima M, Matsuhashi T,
Wada I, Horikawa Y, Komatsu K, Ohba R,
Oyake J, Hatakeyama N, Watanabe S: New
strategy of therapy for functional dyspepsia
using famotidine, mosapride and amitripty-
line. Aliment Pharmacol Ther 2005; 21(suppl
2):42–46.
38 Creed F, Fernandes L, Guthrie E, Palmer S,
Ratcliffe J, Read N, Rigby C, Thompson D,
Tomenson B; North of England IBS Research
Group: The cost-effectiveness of psychother-
apy and paroxetine for severe irritable bowel
syndrome. Gastroenterology 2003; 124: 303–
317.
39 Breen M, Camilleri M, Burton D, Zinsmeis-
ter AR: Performance characteristics of the
measurement of gastric volume using sin-
gle photon emission computed tomogra-
phy. Neurogastroenterol Motil 2011; 23:
308–315.
40 Tack J, Broekaert D, Corsetti M, Fischler B,
Janssens J: Influence of acute serotonin reup-
take inhibition on colonic sensorimotor func-
tion in man. Aliment Pharmacol Ther 2006;
23:265–274.
41 Read NW, Gwee KA: The importance of 5-hy-
droxytryptamine receptors in the gut. Phar-
macol Ther 1994;62:159–173.
42 Clouse RE: Antidepressants for functional
gastrointestinal syndromes. Dig Dis Sci 1994;
39:2352–2363.
43 Lucchelli A, Santagostino-Barbone MG, Bar-
bieri A, Candura SM, Tonini M: The interac-
tion of antidepressant drugs with central and
peripheral (enteric) 5-HT3 and 5-HT4 recep-
tors. Br J Pharmacol 1995;114:1017–1025.
130.241.16.16 - 1/9/2018 2:18:12 PM
153
Göteborgs Universitet
Downloaded by: