Accepted Manuscript

Genetic variants of interleukin-18 are associated with reduced risk

of atrial fibrillation in a population from Northeast China

Ying-Hui Wang, Lin Fu, Bo Wang, Shu-Feng Li, Zhao Sun, Ying
Luan

PII: S0378-1119(17)30379-7
DOI: doi: 10.1016/j.gene.2017.05.034
Reference: GENE 41934
To appear in: Gene
Received date: 17 October 2016
Revised date: 25 January 2017
Accepted date: 15 May 2017

Please cite this article as: Ying-Hui Wang, Lin Fu, Bo Wang, Shu-Feng Li, Zhao Sun,
Ying Luan , Genetic variants of interleukin-18 are associated with reduced risk of atrial
fibrillation in a population from Northeast China, Gene (2017), doi: 10.1016/
j.gene.2017.05.034

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 ACCEPTED MANUSCRIPT

Genetic variants of interleukin-18 are associated with reduced risk of atrial fibrillation

in a population from Northeast China

Ying-Hui Wang1,#, Lin Fu2,#, Bo Wang3, Shu-Feng Li1, Zhao Sun1 and Ying Luan1,*

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Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University,

Harbin 150086, Heilongjiang, China

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Department of Cardiology, Heilongjiang Provincial Hospital, Harbin 150001, Heilongjiang,

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China

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Department of Cardiology, PLA 117 Hospital, Hangzhou 310003, Zhejiang, China.

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These two authors contributed equally to this work.
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*Corresponding author: Ying Luan, Department of Cardiology, The Second Affiliated
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Hospital of Harbin Medical University, 246 Xuefu Street, Nangang District, Harbin 150086,

China. Tel: +86 18645043046; Fax: +86 451 86605677; E-mail: yangl223300@gmail.com
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Running title: IL-18 SNPs and AF risk

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Abstract

Atrial fibrillation (AF) affects approximately 1-2% of general population. Chronic

inflammation plays an important role in AF development and interleukin-18 (IL-18) is a

pro-inflammatory cytokine. This study aimed to assess the association of single nucleotide

polymorphisms (SNPs) of IL-18 for with AF risk. Blood samples were taken from 243 AF

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patients and 160 non-AF individuals from a Chinese population and subjected to genotyping

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for six IL-18 SNPs using the MassArray system. Association of individual SNPs with AF risk

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was analyzed using SAS version 9.1. The results showed that the left atrial diameter was

increased and the left ventricular ejection fraction was decreased in AF patients compared to
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controls. IL-18 SNPs were associated with reduced risk of AF even after adjusting for various
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confounding factors. Specifically, rs187238 GC genotype and C allele, rs360719 AG

genotype and G allele, and rs549908 GT genotype and G allele were associated with
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decreased risk of AF. In conclusion, our findings indicate that rs187238, rs360719, and
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rs549908 in IL-18 are associated with reduced risk of AF in this cohort of patients.
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Keywords: Interleukin-18; Atrial fibrillation; Single nucleotide polymorphism

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1. Introduction

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, affects

approximately 1-2% of general population [1-3]. In recent years, the incidence of AF has

increased substantially [4]. A major pathophysiological manifestation of AF is blood

stagnation in the left atrium or left atrial appendage, which in turn leads to thrombus formation;

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and increases the risk for embolism and stroke. Indeed, AF accounts for up to 24% of all

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ischemic stroke [5]. Moreover, AF causes left atrial enlargement and increases the perimeter of

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the mitral valve, leading to heart failure. Therefore, AF is not only an independent risk factor

for heart failure, but also confers a significant risk of ischemic stroke [6, 7]. To date, the
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defined etiology and pathogenesis of AF remain unclear. Hypertension, heart or lung diseases
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such as coronary artery disease, mitral stenosis, pericarditis, congenital heart disease, lung

cancer or pneumonia, excessive alcohol consumption, and hyperthyroidism are thought to

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promote the development of AF. Recent data demonstrated that atrial intimal macrophage
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activity was increased in AF patients, suggesting the presence of immune and inflammatory
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responses [8]. Inflammation and oxidative stress may promote atrial structural and/or
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electrical remodeling in a manner that promotes the development and maintenance of AF.
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Inflammation-related markers, such as C-reactive protein (CRP), interleukin-1 (IL-1), IL-6,

and tumor necrosis factor (TNF) were found to be elevated in atrial tissues [9-14]. IL-18,

known as interferon (IFN)-γ-inducing factor, is a pro-inflammatory cytokine produced mainly

by macrophages and monocytes [15]. IL-18 induces the proliferation of activated T cells and

NK cells, which mediate the secretion of several cytokines and chemokines that participate in

innate and acquired immune responses [16, 17]. Luan et al. demonstrated the upregulation of

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IL-18 levels in AF patients and proposed that IL-18 is one of the most relevant predictors of

AF, whether paroxysmal, persistent, or permanent [18].

The human IL-18 gene (IL-18) is localized at chromosome 11q22.2–q22.3 and contains six

exons [19]. Up to now, several single nucleotide polymorphisms (SNPs) have been identified

in IL-18 [20]. Two of these polymorphisms, -607C/A (rs1946518) and -137G/C (rs187238),

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have been shown to modulate IL-18 expression [21, 22]. The functional consequences of

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other IL-18 SNPs, e.g., rs549908, rs7106524, rs360719, and rs543810, remain to be

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determined. IL-18 SNPs are associate with different chronic inflammatory diseases, including

allergic rhinitis [23], bronchial asthma [24-26], and atopic dermatitis [27, 28]. However, no
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studies have examined the association of IL-18 SNPs with AF. Therefore, in this study we
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analyzed the association of IL-18 rs549908, rs7106524, rs543810, rs360719, rs187238 and

rs1946518 SNPs with AF risk using AF patients and controls as the subjects.
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2. Materials and Methods

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2.1 Study subjects

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Total 243 AF patients and 160 non-AF individuals were recruited from The Second Affiliated
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Hospital of Harbin Medical University between 2012 and 2014. AF was diagnosed based on

medical history, routine 12-lead electrocardiography (ECG), and/or ambulatory ECG

recordings according to established guidelines by the European Society of Cardiology (ESC)

for the management of AF [29]. Control subjects consisted of unrelated individuals who were

confirmed to be free of AF based on ECG or medical records. Individuals with acute coronary

syndrome, dilated cardiomyopathy, hypertrophic cardiomyopathy, viral myocarditis,

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significant valvular disease, severe left ventricular dysfunction (ejection fraction <30%),

congenital heart disease, secondary hypertension, malignant, hyperthyroidism, and liver and

kidney dysfunction were excluded. In addition, none of AF patients or controls received

beta-blockers, calcium-channel blockers, digoxin, or amiodarone before they were admitted.

This study was approved by Ethics Committee of Harbin Medical University and a written

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informed consent was obtained from all participants, in line with the Helsinki declaration,

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before inclusion in the study.

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2.2 Genomic DNA extraction and SNPs selection and genotyping
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Venous blood (5 ml) was withdrawn from AF subjects and controls in a fasting condition.
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Blood samples were collected into an ethylenediaminetetraacetic acid (EDTA) tube and

genomic DNA was extracted from 200 µl of whole peripheral blood using a Genomic DNA
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extraction kit (Thermo Scientific, Waltham, MA, USA) according to the manufacturer’s
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instructions. Genomic DNA samples were quantified using a spectrophotometer (Thermo

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Scientific) with A260/280 ratio and agarose gel electrophoresis/ethidium bromide staining
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and then stored at -20oC until use.

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We selected two polymorphic sites in IL-18 promoter region [-607C/A (rs1946518) and

-137G/C (rs187238)], which can affect IL-18 expression [21, 22]. Three TagSNPs [minor

allele frequency (MAF) >0.05] were genotyped in the Han Chinese (CHB) population

samples of the HapMap Project (Data Release 27 Phase II+III, Feb09, on NCBI B36

assembly, dbSNP b126), and each at 5'- and 3'- end of 5 kb extension. These SNPs were

selected using Haploview version 4.2 software (Informer Technologies, Inc.,

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http://www.informer.com/) with pairwise tagging mode and r2 > 0.80. In addition, CHB

population of 1000 genome database MAF > 0.05 functional SNP loci was searched to

identify the rs360719 SNP to be localized at IL-18 promoter region.

All SNPs were genotyped using the MassArray system (Sequenom iPLEXassay, San Diego,

CA, USA). The locus-specific PCR and detection primers (Table 1) were designed using the

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MassARRAY Assay Design 3.0 software. The sample DNA was amplified by a multiplex

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PCR, and PCR products were then used for locus-specific single-base extension reaction. The

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resulting products were desalted and transferred to a 384-element SpectroCHIP array. The

alleles were discriminated by mass spectrometry. Genotyping was performed in a blinded

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manner without knowledge of the case or control status of the sample. Genotyping was
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repeated randomly in 5% of samples.

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2.3 Statistical analysis

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All statistical analyses were performed using SAS version 9.1 (SAS Institute, Inc., Cary, NJ,
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USA). The standard independent samples t-test and the 2 test were used to compare
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continuous and categorical variables, respectively. The Hardy-Weinberg equilibrium of the

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genotype distribution of polymorphisms between case and control samples was determined

by the 2 test. Genotypes and allele frequencies were obtained by a direct count and

compared between case and control using the 2 test. The association between risk factors

and AF was assessed using logistic regression analysis, including gender, age, left ventricular

ejection fraction (LVEF), left atrium diameter (LAD), and the status of hypertension,

coronary artery disease (CAD), diabetes and tobacco smoking as the variables. Odds ratio

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(OR) with 95% confidence interval (CI) was determined. p value <0.05 was considered

significant difference.

3. Results

3.1 Characteristics of study population

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The characteristics of all participants are shown in Table 2. Compared to controls, AF patients

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exhibited increased left atrial dimension and decreased left ventricular ejection fraction.

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Nevertheless, there was no significant difference between case and control subjects in the age,

gender, and the status of hypertension, coronary heart disease, diabetes mellitus, and tobacco
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smoking.
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3.2 Association of genotypes and allele frequencies of these SNPs with the reduced AF
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risk
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The distribution of IL-18 SNPs was in accordance with the Hardy–Weinberg equilibrium
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between case and control (Table 3). Representative electrophoresis images of PCR
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products (749 bp) for genotyping were shown in Fig. 1. Representative sequencing data
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for IL-18 rs187238 and 1946518 genotypes were shown in Fig. 2 and 3.

The distribution and association of the genotypes and alleles of the six SNPs are shown in

Table 4 and Table 5. Logistic regression analyses revealed that compared to the highest

frequency of the rs187238 GG genotype, GC genotype frequency was significantly lower in

the AF group compared to controls (adjusted OR = 0.260, 95% CI: 0.115, 0.591, P= 0.0013).

Compared to the highest frequency of the rs360719 AA genotype, AG genotype was

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significantly lower in the AF group than in the control group (adjusted OR = 0.365, 95% CI:

0.175, 0.760, P= 0.0071). Compared with the highest frequency of the rs549908 TT genotype,

GT genotype was significantly lower in the AF group than in the control group (adjusted OR

= 0.400 95% CI: 0.194, 0.822, P= 0.0127). These findings indicate that individuals carrying

these SNPs are at lower risk of AF. Compared to the highest frequency of the rs187238 G

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allele, C allele was significantly lower in the AF group than in the control group (adjusted OR

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= 0.413, 95% CI: 0.211, 0.807, P= 0.0097). Compared to the highest frequency of the

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rs360719 A allele, G allele frequency was significantly lower in the AF group than in the

control group (adjusted OR = 0.473, 95% CI: 0.251, 0.894, P= 0.0211). Compared to the
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highest frequency of the rs549908 T allele, G allele frequency was also significantly lower in
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the AF group than in the control group (adjusted OR =0.506, 95% CI: 0.270, 0.948, P=

0.0333). However, there was no association of rs543810, rs1946518 and rs7106524

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genotypes with the allele distributions between the AF patients and control subjects.
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3.3 Haplotype analysis in case and control groups

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As shown in Table 6, we constructed a map of haplotype frequencies with a cutoff value of ≥

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1% using SAS software. We found that the GAATGA haplotype in four haplotypes had the

highest frequency in AF patients and control groups, indicating that the association of these

four haplotypes with atrial fibrillation was not significant.

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3.4 Association of IL-18 SNPs with clinicopathological features of AF patients

We then associated IL-18 SNPs with clinicopathological features of AF patients. We found

that the left atrial diameter was significantly increased in patients harboring rs187238 GC

compared to GG genotype, rs360719 AG compared to AA genotype, and rs549908 GT

compared to TT genotype (Table 7). However, there was no statistical difference in other

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characteristics, including the gender, age, hypertension, CAD, diabetes, LVEF, or tobacco

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smoking (Table 7).

4. Discussion
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Recent studies have demonstrated the association between IL-18 and cardiovascular diseases
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[30-32]. However, the association of IL-18 polymorphisms with the risk of AF remains

unclear. In this study we demonstrated that several IL-18 SNPs were associated with reduced
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risk of AF in a cohort of Chinese patients. Some of these IL-18 SNPs were shown to regulate
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IL-18 expression [21, 22]. It will be important to explore the underlying mechanism by which
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these IL-18 SNPs decrease the risk of AF.

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It is known that multiple risk factors promote the development of AF. In our study, we
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excluded the patients with acquired diseases or conditions that are known to promote AF.

Using this cohort of case and control individuals, we revealed the association of IL-18 SNPs

with reduced AF risk. As expected, we observed significant change in heart size and function

in AF patients compared to non-AF controls, consistent with previous studies [34, 35].

Interestingly, a previous study showed that there was no association of IL-18 promoter region

rs187238 and rs1946518 SNPs with the risk of AF [33] . Our current data confirmed previous

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findings on rs1946518, but not rs187238. This may be explained by different ethnic groups

between our study and previous study. In addition, the differences in study design, sample

size, sequencing method, and the adjustment of confounding variables may account for the

different results between our study and previous studies. Further large-scale multi-center and

multi-ethnic population based studies are needed to explain the different results.

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The association of three IL-18 SNPs with reduced risk of AF suggests that these SNPs

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could reduce IL-18 expression. It was reported that healthy individual carrying IL-18 promoter

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region allele 137C had a lower level of both spontaneous and lipopolysaccharides-stimulated

IL-18 production [22]. However, it remains to be determined whether these functional IL-18
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SNPs could affect IL-18 expression in peripheral blood mononuclear cells. Therefore, further
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study is needed to investigate whether these IL-18 SNPs play a functional role in the

regulation of IL-18 expression.

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Several limitations of the current study should be pointed out. First, we could not exclude
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the presence of previous asymptomatic episodes of AF in the control group because these
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individuals were recruited based on medical history and clinical tests (such as ECG) during
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the recruitment process. Second, our sample size is relatively small. Third, our subjects were
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restricted to individuals in Northeast China Heilongjiang Province. Further multiple-center

studies with large sample size are necessary to confirm the association of IL-18 SNPs with

the risk of AF.

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Acknowledgements

We thank the staff at Department of Cardiology, The Second Affiliated Hospital, Harbin

Medical University for recruiting and collecting data. This study was supported in part by a

grant from National Natural Science Foundation of China (No. 81200130).

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Conflict of interest

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The authors declared that there is no conflict of interest.

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Figure legends

Figure 1. Representative electrophoresis images of PCR products for genotyping. PCR

products were 749 bp.

Figure 2. Sequencing results of IL-18 rs187238 genotypes. The sequencing data of

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rs187238 genotypes showed that there was only a single G peak in GG genotype, a single

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C peak in CC genotype and an overlaping G and C peaks in GC genotype.

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Figure 3. Sequencing results of IL-18 rs1946518 genotypes. The sequencing data of
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rs1946518 genotypes showed that there was only a single A peak in AA genotype, a
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single C peak in CC genotype and an overlaping A and C peaks in AC genotype.

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Table 1 Primers used for genotyping and sequencing of IL-18 SNPs

SNP ID Primer PCR product Extension sequence

size (bp) primer

rs549908 5'-ACGTTGGATGATGTTTATTGTAGAAAACCT-3' 5'-CAAGCTTGCCAAA

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5'-ACGTTGGATGGGTCAATGAAGAGAACTTGG-3' GTAATC-3'

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rs7106524 5'-ACGTTGGATGGAACTCACCACAGATTTGGC-3' 5'-ccccgTGGTGCATGCC
110

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5'-ACGTTGGATGATTACCTGGGTGTGTTGGTG-3' TGTAGAACTA-3'

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rs543810 5'-ACGTTGGATGTTCAGCTCTTTCCGTCCTTG-3' 5'-TGGAGGCAATTTTG
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5'-ACGTTGGATGTATGAACAGGCAAATGGAGG-3' GAC-3'
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rs360719 5'-ACGTTGGATGGTGCTGCTTCTGATCACTAC-3' 5'-tttctTCCAATTGGGCC
100
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5'-ACGTTGGATGCACCTTCCAACTGTAGAGTC-3' AATTAAC-3'

rs187238 5'-ACGTTGGATGACAGAGCCCCAACTTTTACG-3' 5'-tacTGTAATATCACTA

100
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5'-ACGTTGGATGGCAGAGGATACGAGTACTTC-3' TTTTCATGAAAT-3'
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rs1946518 5'-ACGTTGGATGCTGTATCAGATGCAAGCCAC-3' 5'-ggTGCAGAAAGTGT

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5'-ACGTTGGATGCTCCCCAAGCTTACTTTCTG-3' AAAAATTATTA-3'
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Table 2 Characteristics of AF patients and non-AF controls

Characteristics AF (n=243) Controls (n=160) p value

Gender (% male) 58.44 58.13 0.95

Age (years) 62.60 ± 11.38 61.49 ± 9.99 0.31

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HT (n, %) 119 (48.97) 82 (37.50) 0.65

CAD (n, %) 151 (62.14) 100 (80.00) 0.94

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DM (n, %) 45 (18.52) 28 (11.25) 0.79

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LVEF (%) 59.35 ± 8.94 NU 62.90 ± 6.16 <0.05

LAD (mm) 42.33 ± 9.14 31.11 ± 5.38 <0.05

Tobacco smoking (n, %) 92 (37.86) 57 (35.63) 0.64

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Note: AF, atrial fibrillation; LAD, left atrium diameter; LVEF, left ventricular ejection fraction; HT,
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hypertension; DM, diabetes mellitus; CAD, coronary artery disease. Continuous variables were analyzed by
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t-test and categorical variables were analyzed by 2 test.

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Table 3 Hardy-Weinberg Equilibrium analysis of IL-18 SNPs in AF patients and

controls

SNPs Group N GG GC CC 2 p value

rs187238 AF Real 187 34 5 4.68 0.096

Prospective 184.14 39.12 2.14

PT
Control Real 100 30 3 0.17 0.91

RI
Prospective 99.44 31.13 2.43

SC
rs360719 AF Real 200 37 4 2.08 0.35

Prospective 198.10 40.80 2.10

NU
Control Real 121 34 3 0.11 0.94
MA

Prospective 120.53 34.94 2.53

rs543810 AF Real 103 94 38 4.20 0.12

D

Prospective 95.74 108.51 30.75

E
PT

Control Real 69 69 18 0.014 0.99

Prospective 120.53 34.94 2.53

CE

rs549908 AF Real 200 38 4 1.83 0.39

AC

Prospective 198.19 41.63 2.18

Control Real 121 35 3 0.064 0.96

Prospective 120.64 35.71 2.65

rs1946518 AF Real 72 110 55 1.06 0.58

Prospective 68.05 117.89 51.06

Control Real 46 78 35 0.032 0.98

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Prospective 45.44 79.12 34.44

rs7106524 AF Real 67 106 63 2.42 0.29

Prospective 61.02 117.97 57.01

Control Real 40 76 37 0.006 0.99

Prospective 39.76 76.47 36.77

PT
The data were analyzed by 2 test.

RI
SC
NU
MA
E D
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Table 4 IL-18 genotype distributions in AF patients and controls

SNPs Genotype AF (n=243) Controls (n=160) p value Adjusted OR

N (%) N (%) (95﹪CI)

rs187238 GG 187 (82.74) 100 (75.19) reference

GC 34 (15.04) 30 (22.56) 0.0013 0.260 (0.115, 0.591)

PT
CC 5 (2.21) 3 (2.26) 0.86 1.202 (0.144, 10.044)

RI
rs360719 AA 200 (82.99) 121 (76.58) reference

SC
AG 37 (15.35) 34 (21.52) 0.0071 0.365 (0.175, 0.760)

GG 4 (1.66) 3 (1.90) 0.97 1.033 (0.110,9.699)

NU
rs543810 AA 103 (43.83) 69 (44.23) reference
MA

AG 94 (40.00) 69 (44.23) 0.64 0.871 (0.484, 1.568)

GG 38 (16.17) 18 (11.54) 0.83 1.090 (0.474, 2.506)

D

rs549908 TT 200 (82.64) 121 (76.10) reference

E
PT

GT 38 (15.70) 35 (22.01) 0.012 0.400 (0.194, 0.822)

GG 4 (1.65) 3 (1.89) 0.96 1.044 (0.111, 9.783)

CE

rs1946518 CC 72 (30.38) 46 (28.93) reference

AC

AC 110 (46.41) 78 (49.06) 0.67 0.873 (0.465, 1.639)

AA 55 (23.21) 35 (22.01) 0.32 0.680 (0.317, 1.458)

rs7106524 AA 67 (28.39) 40 (26.14) reference

GA 106 (44.92) 76 (49.67) 0.23 0.671 (0.347, 1.301)

GG 63 (26.69) 37 (24.18) 0.44 0.742 (0.347, 1.589)

The data were assessed by logistic regression analysis.

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Table 5 IL-18 SNP allele distributions in AF patients and controls

SNPs Allele AF (n=243) Controls (n=160) p value Adjusted OR (95﹪CI)

N (%) N (%)

rs187238 G 408 (90.27) 230 (86.47) reference

PT
C 44 (9.73) 36 (13.53) 0.0097 0.413 (0.211, 0.807)

rs360719 A 437 (90.66) 276 (87.34) reference

RI
G 45 (9.34) 40 (12.66) 0.021 0.473 (0.251, 0.894)

SC
rs543810 A 300 (63.83) 207 (66.35) reference
NU
G 170 (36.17) 105 (33.65) 0.98 0.997 (0.668, 1.489)

rs549908 T 438 (90.50) 277 (87.11) reference

MA

G 46 (9.50) 41 (12.89) 0.033 0.506 (0.270, 0.948)

D

rs1946518 G 254 (53.59) 170 (53.46) reference

E

T 220 (46.41) 148 (46.54) 0.32 0.823 (0.560, 1.209)

PT

rs7106524 A 240 (50.85) 156 (50.98) reference

CE

G 232 (49.15) 150 (49.02) 0.40 0.848 (0.575, 1.251)

The data were assessed by logistic regression analysis.

AC

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Table 6 IL-18 haplotype frequencies in AF patients and controls

Haplotype Frequency AF Control p value

CGAGTG 0.10246 0.09465 0.11452 0.36

GAATGA 0.50192 0.50190 0.50244 0.98

PT
GAATGG 0.02825 0.03165 0.02268 0.45

RI
GAGTTG 0.34995 0.36119 0.33248 0.40

SC
The data were analyzed by 2 test.
NU
MA
E D
PT
CE
AC

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Table 7 Association of rs187238, rs360719 and rs549908 with characteristics of AF

patients

rs187238

Characteristics GG GC CC p valuea

Genotypes frequencies (n, %) 187 (82.74) 34 (15.04) 5 (2.21)

PT
Gender (M/F) 103/84 24/10 3/2 0.24

RI
Age (years) 62.81 ± 11.13 61.97 ± 12.17 59.00 ± 14.14 0.71

SC
Hypertension (n, %) 92 (49.20) 19 (55.88) 1 (20.00) 0.31

CAD (n, %) 113 (60.43) 21 (61.76) 5 (100.00) 0.19

NU
Diabetes (n, %) 34 (18.18) 8 (23.53) 1 (20.00) 0.76
MA

LVEF (%) 59.77 ± 8.28 57.22 ± 9.31 57.42 ± 16.25 0.26

LAD (mm) 41.65 ± 9.28 46.25 ± 7.84a 43.60 ± 10.43 0.029

D

Tobacco smoking (n, %) 66 (35.29) 16 (47.06) 2 (40.00) 0.42

E
PT

a
compared to the GG genotype.

rs360719
CE

Characteristics AA AG GG p valuea
AC

Genotypes frequencies (n, %) 200 (82.99) 37 (15.35) 4 (1.66)

Gender (M/F) 113/87 26/11 2/2 0.27

Age (years) 62.78 ± 11.20 61.65 ± 12.06 61.00 ± 15.49 0.82

Hypertension (n, %) 97 (48.50) 20 (54.05) 1 (25.00) 0.51

CAD (n, %) 122 (61.00) 23 (62.16) 4 (100.00) 0.28

Diabetes (n, %) 35 (17.50) 9 (24.32) 1 (25.00) 0.58

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LVEF (%) 59.91 ± 8.45 56.70 ± 10.05 56.28 ± 18.53 0.11

LAD (mm) 41.51 ± 9.22 46.12 ± 7.84a 45.00 ± 11.49 0.017

Tobacco smoking (n, %) 73 (36.50) 17 (45.95) 1 (25.00) 0.48

a
compared to the AA genotype.

rs549908

PT
Characteristics TT GT GG p valuea

RI
Genotypes frequencies (n, %) 200 (82.64) 38 (15.70) 4 (1.65)

SC
Gender (M/F) 114/86 26/12 2/2 0.39

Age (years) 62.65 ± 11.18 62.05 ± 12.15 61.00 ± 15.49 0.92

NU
Hypertension (n, %) 96 (48.00) 21 (55.26) 1 (25.00) 0.45
MA

CAD (n, %) 122 (61.00) 24 (63.16) 4 (100.00) 0.27

Diabetes (n, %) 35 (17.50) 9 (23.68) 1 (25.00) 0.63

D

LVEF (%) 59.91 ± 8.46 56.82 ± 9.94 56.28 ± 18.53 0.12

E
PT

LAD (mm) 41.58 ± 9.17 45.65 ± 8.22a 45.00 ± 11.49 0.038

Tobacco smoking (n, %) 74 (37.00) 17 (44.74) 1 (25.00) 0.57

CE

a
compared to the TT genotype.
AC

Continuous variables were analyzed by t-test and categorical variables were analyzed by 2 test.

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MA

Fig. 1
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Fig. 2
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Fig. 3
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Abbreviation list

IL-18, interleukin-18; AF, atrial fibrillation; LAD, left atrium diameter; LVEF, left ventricular

ejection fraction; HT, hypertension; DM, diabetes mellitus; CAD, coronary artery disease.

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Highlights

 Genotyping for six IL-18 SNPs in 43 AF patients and 160 non-AF Chinese

 Left atrial diameter increased and left ventricular ejection fraction decreased in AF

PT
patients

RI
 rs187238, rs360719, and rs549908 in IL-18 are associated with reduced risk of AF

SC
NU
MA
E D
PT
CE
AC

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