DNA AND CELL BIOLOGY

Volume 30, Number 11, 2011

ª Mary Ann Liebert, Inc.
Pp. 913–917
DOI: 10.1089/dna.2011.1221

Association Between Promoter Variants of Interleukin-18

and Schizophrenia in a Han Chinese Population

Jinnan Liu,* Jiaming Liu,* Yi Zhou, Siyue Li, Yi Li, Xingbo Song,
Jun Wang, Lanlan Wang, and Binwu Ying

An increasing amount of evidence suggests that interleukin-18 (IL-18) plays a pivotal role in the pathophysi-
ology of schizophrenia. However, association between single nucleotide polymorphism of IL-18 and the risk of
schizophrenia has not been clarified. This study examined whether two promoter polymorphisms -137 G/C
(rs187238) and -607 C/A (rs1946518) of IL-18 were associated with schizophrenia and six clinical symptoms
(disorder of perception, thought disorder, disturbance of emotion, disorder of behavior and volition, suicide
action, and aggressive action) to provide data for screening high-risk Han Chinese individuals. Three hundred
seventy-two schizophrenic patients and 353 healthy controls from a Han Chinese population were examined to
assess their genotype and allele frequencies of the two promoter polymorphisms of IL-18. The genotype dis-
tributions in both patients and controls were within Hardy–Weinberg equilibrium. No significant differences
were observed in the genotype or the allele frequencies of the two single-nucleotide polymorphisms between
patients and controls. However, genotype frequencies of -607 C/A showed significant differences between
patients and controls in the appearance of perception disorder (w2 ¼ 6.153, p ¼ 0.046). A significant difference was
detected in -137 G/C between patients and controls in the appearance of aggressive action (w2 ¼ 3.909, p ¼ 0.048).
In conclusion, IL-18 gene promoter polymorphisms may not contribute to the susceptibility of schizophrenia in a
Han Chinese population, but two single-nucleotide polymorphisms, -137 G/C and -607 C/A, may play a role in
the development of perception disorder and aggressive action, respectively.

Introduction and in vitro production of IL-18 were changed in schizo-

phrenia, reflecting the potential association between IL-18–

I nterleukin-18 (IL-18), produced by macrophage-like

cells, is a type 1 cytokine that plays an important role in
the T-cell helper type 1 (Th1) response, primarily by its
ability to induce interferon-g production in T cells and nat-
ural killer cells (Smith, 1992; Dinarello, 1999; Kalina et al.,
2000). IL-18 participates in neuron growth, differentiation,
and apoptosis (Smith and Maes, 1995; Dinarello, 2006),
playing a role in brain development and function (Schmitz
and Chew, 2008). IL-18 takes part in pathological conditions
of the central nervous system (Alboni et al., 2010). Under-
activation in type-1 immune response is part of the patho-
physiology of schizophrenia (Müller et al., 2000; Müller and
Schwarz, 2010), causing an imbalance in the activation of the
enzyme indoleamine 2,3-dioxygenase and in tryptophan–
kynurenine metabolism (Sperner-Unterweger et al.,1999;
Grohmann et al., 2003). This mechanism results in increased
production of kynurenic acid in schizophrenia, which is as-
sociated with an imbalance in the glutamatergic neuro-
transmission, leading to N-Methyl-D-aspartate (NMDA)
antagonism. Another study showed that the circulating level
mediated inflammation and schizophrenia (Tanaka et al.,
2000). Thus, IL-18 is likely related to the pathogenesis of
schizophrenia (Freedman et al., 2001).
The IL-18 gene is located on chromosome 11q22.2–q22.3,
close to the dopamine receptor D2 locus and its promoter
region. At this area, one region with suggestive evidence of
linkage has been detected with schizophrenia (Suarez et al.,
2006). So IL-18 gene might be connected to schizophrenia.The
IL-18 gene is composed of six exons and five introns. Five
single-nucleotide polymorphic positions in the promoter re-
gion have been found: -656T/G, -607A/C, -137G/C, þ113/
GT, and þ127T/C (Giedraitis et al., 2001). Cloning and gene
expression analyses have shown that -137G/C and -607C/A
have a confirmed impact on IL-18 gene activity (Kalina et al.,
2000; Giedraitis et al., 2001). Recently, the two single nucleo-
tide polymorphism (SNP) loci have been associated with
immune-related diseases, including Crohn’s disease, diabetes,
and rheumatoid arthritis (Kretowski et al., 2002; Tamura et al.,
2002; Gracie et al., 2005; Rueda et al., 2005; Szeszko et al.,
2006). In addition, their impact on the progression of mental

Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P.R. China.
*These authors equally contributed to this work.

913
914
Table 1. Basic Clinical Variables of Patients
Variables Subgroups Male (N ¼ 173)(%)
Onset, years 27.07  10.507
Age group 10–20 54 (31.21)
21–35 83 (47.98)
>36 36 (20.81)
Bold numbers indicate that p value is less than 0.05.
disease, such as Alzheimer’s disease, has been described
(Yu et al., 2009). Perhaps, they are potential susceptibility loci
for schizophrenia. These data inspired us to evaluate the as-
sociation between the IL-18 gene promoter polymorphisms
and schizophrenia, to provide new information for further
study of genetic factors involved in schizophrenia and/or its
clinical symptoms, which may be useful in screening high-
risk populations.
Material and Methods
Patients
We recruited 372 schizophrenic patients in a Han Chinese
population (mean age: 28.74  12.581; 173 men and 199
women; age of onset: 27.07  10.507 and 30.19  13.580, re-
spectively, 71 with family history and 301 without family
history) in the inpatient unit of the West China Hospital in
Chengdu, China, from October 2009 to July 2010. The basic
clinical variables of the patients are shown in Table 1. Con-
sensus diagnosis of each patient and evaluation of the clinical
symptoms were made by two psychiatrists independently in
accordance with the following criteria:
1. Met the Chinese Classification of Mental Disorders,
third version (CCMD-3) or the International Classifica-
tion of Diseases, 10th version (ICD-10)
2. Without immune system disease
3. Without other psychoses
A total of 353 healthy subjects in a Han Chinese popula-
tion (173 men and 180 women; mean age: 37.01  12.570)
were recruited from physical examinations. All of the con-
trols were interviewed to exclude any history of psychiatric
disorders. Informed consent was obtained for all individuals
tested. Our study was approved by the Ethical Committee of
West China Hospital, Sichuan University.
Genomic DNA extraction
About 3 mL peripheral vein blood from patients was
drawn into a Vacutainer tube containing the anticoagulant
ethylenediaminetetracetic acid. The QIAamp DNA Blood
mini kit (Qiagen) was used to extract genomic DNA. After
being assessed for purity, yield, concentration, and A260/
A280 ratio, DNA was diluted to 10 ng/mL. Several samples of
three genotypes were previously genotyped by sequencing
as references for the two SNPs.
IL-18 gene polymorphism type
and high-resolution melting analysis
The genotypes of samples were detected by a high-
resolution melting (HRM) method. Polymerase chain reac-
LIU ET AL.
Female (N ¼ 199)(%) T w2 p-Value
30.19  13.580 2.448 — 0.015
60 (30.15) — 3.263 0.196
82 (41.21) — — —
57 (28.64) — — —
tion (PCR) amplification for -137G/C and -607C/A variants
was carried out under the same conditions in the Light-
Cycler 480 Real-Time PCR System (Roche Diagnostics).
The -607C/A PCR primers were 50 GCCACACGGATA
CCATCATTAG 30 (forward) and 50 TGCCCTCTTACCTG
AATTTTGG 30 (reverse). The -137G/C PCR primers
were 50 TGGCAGAGGATACGAGTAC 30 (forward) and 50
GGACTAAGGAGGTGCTTTC 30 (reverse). The 20 mL PCR
contained 1.0 mL purified genomic DNA (10 ng/mL), 0.5 mL for-
ward primer (10 mmol/L), 0.5 mL reverse primer (10 mmol/L),
1.0 mL 20X EVA-GREEN, 0.5 mL dNTP (10 mM), 0.2 mL Hot Star
Taq Plus DNA polymerase, 2 mL 10X buffer, 1 mL 50 mM
MgCl2, and 13.8 mL H2O. Real-time PCR was performed under
the following conditions: an initial denaturation at 958C for 15
min; amplification for 50 cycles of 958C for 10 s, 608C for 15 s, and
extension at 728C for 25 s; and denaturation at 958C for 1 min.
Then the products were cooled to 408C for 1 min. HRM analyses
were performed by slow heating from 658C to 958C at a rate of
0.018C/s. All the data were analyzed by the LightCycler 480
Gene Scanning software v1.2 (Roche Diagnostics). Samples with
a late amplification could generate unreliable melting profiles
(Norambuena et al., 2009). Thus, samples associated with fluo-
rescence of less than 60% of the average were discarded (in-
cluding 7 samples from patients and 10 samples from control
group); we repeated the extraction of DNA or HRM reaction.
Normalization by selecting linear regions before (100% fluores-
cence) and after (0% fluorescence) the melting transition, tem-
perature shifting by selecting threshold, and automatic grouping
by calculation were analyzed step by step in software programs.
DNA sequencing
PCR products were purified using shrimp alkaline phos-
phatase. Sequencing primers for -137G/C and -607C/A were
the same as those used in PCR. Nucleotide sequencing was
detected by BigDye Terminator v3.1 Cycle Sequencing Kit
and an ABI 3130 genetic analyzer (Applied Biosystems),
using both the forward and the reverse primers.
Statistical analysis
Deviation from Hardy–Weinberg equilibrium was as-
sessed for each group. Statistical analysis was performed by
SPSS 13.0. The comparison between patients and controls in
both genotype and allele frequencies was determined using
Pearson w2 analysis as well as the relationship between the
genotype and allele frequencies and clinical symptoms. The
calculations of odds ratio and 95% confidence interval were
conducted with the risk option of Crosstabs by SPSS 13.0. In
addition, the onset ages of different sex patients were ana-
lyzed using the t-test. The level of significance for all statis-
tical tests was 0.05.
IL-18 SNPS IN CHINESE SCHIZOPHRENIA POPULATION 915

0.719–1.086

0.894–1.870

0.567–1.196

0.446–1.497
Results

95% CI
In this study, we investigated the distribution of IL-18

—
promoter variants -137G/C and -607C/A in 372 schizophrenic

OR, odds ratio; CI, confidence interval; family history, if any immediate family members (including the parents, siblings, or children of the patient) suffer from the same disease.
patients and 353 healthy controls in a Han Chinese population.
The average onset age of male patient was earlier than female

0.884

1.293
OR

0.823

0.817
patients (T ¼ 2.448, p ¼ 0.015; Table 1).

—
The genotypes of -137G/C and -607C/A were in Hardy–
Weinberg equilibrium in both the patient and control groups
p-Value

0.241

0.171
( p > 0.05 for all analyses). The genotype and allele frequencies of

0.307

0.513
—

—
Table 2. Allele and Genotype Frequencies of the Two Single-Nucleotide Polymorphisms in Interleukin-18

the two SNPs are shown in Table 2. In the patient group, the
frequencies of -607C/A genotypes CC, CA, and AA were
1.377

1.872

24.46%, 54.84%, and 20.70%, respectively. In the control group,

1.045

0.428
—

—
w2

—
the frequencies of genotypes CC, CA, and AA were 30.88%,
48.16%, and 20.96%, respectively. The frequencies of alleles C
(48.12)
(45.04)
(42.96)
(49.34)

and A were close in both the patient (C ¼ 51.88%, A ¼ 48.12%)

(10.56)
(9.14)
(7.65)

(8.80)
and control groups (C ¼ 54.96%, A ¼ 45.04%). Two genotypes,
A

GG and GC, were found at -137G/C locus, which showed a

358
318
61
297

similar distribution in the patient and control groups (81.72%,

68
54
15
53
Allele

18.28% vs. 84.70%, 15.30%). The frequencies of allele C were also

(51.88)
(54.96)
(57.04)
(50.66)

similar in both the patient and control groups (9.14% vs. 7.65%).
(90.86)
(92.35)
(89.44)
(91.20)

The promoter variants -607C/A and -137G/C had similar ge-

C

notype and allele frequencies in both the patients and controls.

386
388
81
305

676
652
127
549

We then divided the cases into two subgroups according to

family history. No difference between the allele or geno-
p-Value

0.118

0.117

type of subgroups and the controls was detected ( p > 0.05).

—

0.283

0.490

From the power calculation, we estimated that the sample had a

—

power of 81.33% (-137G/C) and 96.93% (-607C/A), respectively.

Six related clinical symptoms (disorder of perception,
4.276

4.289
—

—
2

1.151

0.476
w

thought disorder, disturbance of emotion, disorder of be-

—

havior and volitional, suicide action, and aggressive action)

(20.70)
(20.96)
(19.72)
(20.93)

were analyzed in our study (Table 3). These characteristics

(0)
(0)
(0)
(0)
AA

are crucial to the clinical diagnosis of schizophrenia and

CC

easily distinguished, and all greatly influence the quality of

0
0
0
0
77
74
14
63

patients’ daily lives. We found that the genotype distribution

(18.28)
(15.30)
(21.13)
(17.61)

of -607C/A was significantly associated with disorder of

(54.84)
(48.16)
(46.48)
(56.81)

perception (w2 ¼ 6.153, p ¼ 0.046). In addition, the frequency

Genotype

GC
CA

of genotype GC of -137G/C in patients with aggressive ac-

68
54
15
53
204
170
33
171

tion was found to be significantly higher than in controls

(w2 ¼ 3.909, p ¼ 0.048).
(81.72)
(84.70)
(78.87)
(82.39)
(24.46)
(30.88)
(33.80)
(22.26)

Discussion
GG
CC

304
299
56
248

Schizophrenia is a heritable, complex mental disorder.

91
109
24
67

Studies support that genes determine predisposition to

schizophrenia to a great degree (McGuffin and Gottesman,
Patients without family history (N ¼ 301) (%)

Patients without family history (N ¼ 301) (%)

1999; Purcell et al., 2009; Stefansson et al., 2009). However, the

contribution of each specific gene is very small. Candidate
Patients with family history (N ¼ 71) (%)

Patients with family history (N ¼ 71) (%)

gene studies and genome-wide association studies have

shown inconsistent results (Gilmore 2010). A list of schizo-
phrenia candidate genes, including the IL-18 gene, was used
to draft aschizophrenia-specific network using a multidi-
mensional evidence-based approach (Sun et al., 2010).
The promoter region of the first exons of the IL-18 gene
Controls (N ¼ 353) (%)

Controls (N ¼ 353) (%)

Patients (N ¼ 372) (%)

Patients (N ¼ 372) (%)

contains five polymorphisms, among which -607C/A and

-137G/C were reported to affect the transcriptional activity
of the IL-18 gene. At position -607, a change from C to A may
IL-18 607C/A

IL-18 137G/C

disrupt a potential cAMP-responsive element-binding pro-

tein binding site. At position -137, a shift from G to C may
change the H4TF-1 nuclear factor binding site. Cloning and
gene expression analysis revealed that two SNPs of the IL-18
promoter at positions -607 and -137 may have an impact on
interferon-g production (Giedraitis et al., 2001; Khripko et al.,
916 LIU ET AL.

Table 3. Comparison Between Patients with Different Clinical Features and Controls

Clinical features

Disorder Thought Disturbance Disorder of behavior Suicide Aggressive

of perception disorder of emotion and volitional action action
Polymorphisms (N ¼ 178) (N ¼ 260) (N ¼ 97) (N ¼ 181) (N ¼ 43) (N ¼ 49)

IL-18 -607C/A
Controls (N ¼ 353)
CC (N ¼ 109) 43 63 23 43 10 11
CA (N ¼ 170) 106 145 58 96 24 29
AA (N ¼ 74) 29 52 16 42 9 9
w2 6.153 4.113 4.125 2.980 1.200 2.221
p 0.046 0.128 0.127 0.225 0.549 0.329
Power 0.7549 0.9525 0.8485 0.9115 0.9744 0.9441
calculation
C (N ¼ 388) 192 271 104 182 44 51
A (N ¼ 318) 164 249 90 180 42 47
w2 0.100 0.973 0.112 2.107 0.445 0.295
p 0.751 0.324 0.738 0.147 0.505 0.587
OR 1.042 1.121 1.056 1.207 1.165 1.124
95% CI 0.807–1.346 0.893–1.407 0.768–1.452 0.936–1.555 0.744–1.823 0.736–1.717
IL-18 -137G/C
Controls (N ¼ 353)
GG (N ¼ 299) 151 212 81 143 35 36
GC (N ¼ 54) 27 48 16 38 8 13
CC (N ¼ 0) 0 0 0 0 0 0
w2 0.002 1.081 0.083 2.723 0.317 3.909
p 0.969 0.299 0.773 0.099 0.573 0.048
Power 0.9726 0.8186 0.9495 0.6179 0.9049 0.4960
calculation
G (N ¼ 652) 329 472 178 324 78 85
C (N ¼ 54) 27 48 16 38 8 13
w2 0.001 0.983 0.076 2.467 0.291 3.554
p 0.970 0.322 0.783 0.116 0.590 0.059
OR 0.991 1.228 1.085 1.416 1.238 1.847
95% CI 0.613–1.602 0.818–1.844 0.606–1.942 0.916–2.190 0.568–2.698 0.968–3.524

Bold numbers indicate that p value is less than 0.05.

2008). In the present study, our results demonstrated no sig-
nificant association in a Han Chinese population in genotype
or allele frequencies of -137G/C and -607C/A and schizo-
phrenia risk even after grouping by family history. We further
estimated that our samples have power of 81.33% to detect
-137G/C and 96.93% to detect -607C/A. Thus, the likelihood
of a type II error with our sample size appears to be low.
Other schizophrenia candidate genes influencing the produc-
tion level of IL-18 might play a more important role than the
IL-18 gene in the pathogenesis of schizophrenia, or other SNPs
in IL-18 gene might be associated with schizophrenia. Further
studies to explore the above hypotheses may provide strate-
gies for approaching the genetic heterogeneity of this disease.
In 1999, Takeuchi et al. reported that overexpression of IL-
18 was found in patients with some mental disorders, such
as depression and panic disorder. In our study, further
analysis of the relationship between the two IL-18 gene pro-
moter polymorphisms and the existence of schizophrenia-
associated clinical features showed that -607C/A genotypes
might be related to the emergence of perception disorder
and the GC genotype of -137G/C might contribute to the risk
of aggressive action. No association was confirmed between
these two SNPs and the appearance of thought disorder,
disturbance of emotion, suicide action, and disorder of be-
havior and volitional. This finding indicated that IL-18 might
be associated with some specific clinical manifestation of
schizophrenia, not connected with the risk of schizophrenia.
This research explored the role of IL-18 promoter polymor-
phism in the risk of schizophrenia and its relation to
schizophrenia-associated clinical symptoms. The genotypes
of samples were confirmed by HRM method. All three ge-
notypes of -607C/A were detected, whereas only two ge-
notypes of -137G/C were detected: GG and GC. This may
be due to the low CC genotype frequency of -137G/C in the
Chinese population (Liu et al., 2007). In our research, we
studied only two promoter variants, and the sample size and
the number of patients in each of the six subgroups with
different clinical symptoms were moderate. In addition, the
interaction between IL-18 SNPs and its protein level in pa-
tients with certain clinical features remains to be evaluated.
In conclusion, IL-18 gene promoter polymorphisms may
not contribute to the susceptibility of schizophrenia in the
Han Chinese population. However, two SNPs, -137G/C and
-607C/A, may play a role in the development of perception
disorder and aggressive action, respectively.
Acknowledgments
The authors thank Dr. Haiyan Chen (Rush University
Medical Center) for critical review and editorial assistance
IL-18 SNPS IN CHINESE SCHIZOPHRENIA POPULATION 917

during manuscript preparation. This study was supported Purcell, S.M., Wray, N.R., Stone, J.L., Visscher, P.M., O’Dono-
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