Association of interleukin-18 gene polymorphism with body mass index in women
- Hye-Lin Kim†1,
- Sung One Cho†2,
- Seon-Young Kim1,
- Sung-Hoon Kim1,
- Won-Seok Chung1,
- Seok-Hee Chung1,
- Sung-Soo Kim1,
- Seong-Gyu Ko1,
- Chang-Hyun Jeong1,
- Su-Jin Kim3,
- Seung-Heon Hong2 and
- Jae-Young Um1Email author
© Kim et al.; licensee BioMed Central Ltd. 2012
Received: 29 February 2012
Accepted: 12 April 2012
Published: 24 April 2012
Interleukin (IL)-18 is an important regulator of innate and acquired immune responses and has multiple roles in chronic inflammation and autoimmune disorders. Obesity is characterized by low- grade chronic inflammation. IL-18 has been suggested as an adipogenic cytokine that is associated with excess adiposity. The purpose of this study is to evaluate the relationship between IL-18 gene polymorphisms (−137 G/C and −607 C/A) and obesity.
All 680 subjects were genotyped for the polymorphisms of IL-18 gene promoters (at positions −137 G/C and −607 C/A) using a polymerase chain reaction (271 cases with BMI ≥25 kg/m2 and 409 controls with BMI <25 kg/m2). A chi-square test was used to compare the genotype and allele frequencies between the cases and control populations.
Analyses of the genotype distributions revealed that IL-18 –607 C/A polymorphism was associated with an increase in body mass index in obese women in the Korean population (chi(2) = 12.301, df = 2, p = 0.015).
Carriage of the A allele at position −607 in the promoter of the IL-18 gene may have a role in the development of obesity.
Obesity is increasing rapidly among women all over the world, and more women in fertile ages become overweight and obese . Among all other problems, women who are obese have higher rates of amenorrhoea and infertility . Over the past decade, research has associated obesity with inflammation; this association was first proposed in the seminal article by Hatamilsligil et al. . In this article, tumor necrosis factor-α (TNF-α) was shown to be constitutively expressed via adipose tissue, to be hyperexpressed in obesity, and to mediate insulin resistance in the major animal models of obesity. Furthermore, the neutralization of TNF-α with soluble TNF-α receptors resulted in the restoration of insulin sensitivity . Thus, obesity is now characterized by a state of low- grade inflammation that is associated with the increase of cytokine production. Adipose tissue, which is infiltrated by monocytes and macrophages in obesity, secretes numerous soluble mediators including adipokines such as adiponectin or leptin and many classical cytokines such as TNF-α, interleukin (IL)-6, and IL-1 family members [3, 4].
IL-18 has been suggested as an adipogenic cytokine  that is associated with excess adiposity . Adipocytes from obese individuals produce higher levels of IL-18 compared with lean individuals and higher circulating IL-18 levels were observed in obese individuals and those with a high body mass index (BMI), insulin resistance, hypertriglyceridemia, and metabolic syndrome [6–9]. Deficiencies of IL-18 in mice (Il18 −/− ) led to the exhibition of late- onset obesity and insulin resistance . Therefore, it has been hypothesized that the increased IL-18 concentrations have a pathophysiological role in obesity and metabolic syndromes.
Obesity has a strong genetic etiology involving numerous identified metabolic pathways and others not yet examined. IL-18 promoter polymorphisms have been associated with various inflammatory diseases, and three single nucleotide polymorphisms (SNPs) in the promoter of the IL-18 gene at the positions −656 G/T, −607 C/A and −137 G/C have been identified. The functional significance of the two SNPs of the C allele at position −607 and the G allele at position −137 is attributed to the higher transcription and protein production of IL-18 [11, 12]. In order to investigate the possible roles of the SNPs from the IL-18 gene promoter region (−137 G/C and −607 C/A) in the development of obesity, the genetic polymorphisms of obese subjects were evaluated.
Subjects were recruited consecutively from an obesity clinic at a Korean hospital; they were placed into an ongoing project that investigates candidate genes for obesity among the Korean population. The present study population included 680 individuals: 271 were chosen as cases (BMI ≥25 kg/m2) and 409 were chosen as controls (BMI <25 kg/m2). The 271 cases (BMI ≥25 kg/m2) consisted of 170 female subjects and 101 male subjects. All cases were nonsmokers and had no evidence of cancer, liver, renal, hematological disease or other metabolic disorders other than obesity. Details of the recruitment, body composition assessment, and biochemical analysis have been described previously . All participants gave informed consent prior to participating in the research, which was approved by the local ethics committee in accordance with the Helsinki Declaration. Some subjects had participated in the research reported previously .
Height (in cm) and weight (in kg) were measured in order to calculate the BMI as weight (kg)/height (m) squared. The waist circumference (measured at the narrowest point above the hip) was divided by the circumference of the hip (measured at its greatest gluteal protuberance) in order to obtain the waist-to-hip ratio (WHR).
Dual-energy X-ray absorptiometry
The fat mass was determined using dual energy X-ray absorptiometry.
Genomic DNA was extracted from peripheral blood samples using the ExgeneTM Blood SV Kit (GeneAll, Korea) as per the manufacturer’s instructions. The concentration of DNA was estimated via absorbance at 260 nm. The SNPs were noted at position −137 (G/C) and −607 (C/A) in the promoter region of the IL-18 gene, located at chromosome 11q22.2-q22.3. For the position −137-specific PCR, a common reverse primer and two sequence- specific forward primers were used to amplify the 261-bp product. A control forward primer was used to amplify the 446-bp fragment covering the polymorphic site as an internal positive amplification control. PCR was performed in a 20 μl volume containing 0.5 μM of one sequence specific primer and −137 R, 0.3 μM of −137 CTRL, 20 mM Tris–HCl (pH 8.4), 50 mM KCl, 1.5 mM MgCl2, 200 μM/dNTPs, 1 U of Taq DNA polymerase, and 200 ng genomic DNA. The cycling conditions were 2 min at 94°C, followed by 5 cycles of 20 s at 94°C and 60 s at 67°C and 25 cycles of 20 s at 94°C, 20 s at 61°C and 40 s at 72°C .
Sequence-specific primers for G/C and C/A alleles and their PCR product sizes for positions −137 and −607 in the promoter of the IL-18 gene
Product size (bp)
G/C allele at position − 137
Common reverse primer
forward primers 1
forward primers 2
Control forward primer
C/A allele at position − 607
Common reverse primer
forward primers 1
forward primers 2
Control forward primer
A χ2 test was used to compare the genotype and allele frequencies between the cases and control populations. All statistical analyses were performed using SPSS v17.00 (SPSS Inc.) statistical analysis software. Hardy-Weinberg equilibrium was tested by chi-squared test and the haplotype analyses were done using HapAnalyzer version 1.0 (http://hap.ngri.go.kr). The associations between allele frequencies of SNPs and cases were estimated by computing the odds ratios and their 95% confidence intervals with logistic regression analyses controlling for age. Genetic Power Calculator (http://pngu.mgh.harvard.edu/~purcell/gpc)  was used to compute the statistical power of our sample. A p- value of less than 0.05 was considered statistically significant.
Clinical characteristics of subjects according to BMI
Characteristics of obese subjects according to BMI
25 ~ 26.9
28.9 ± 11.2
31.3 ± 10.54
33.1 ± 12.9
64.7 ± 4.7
71.3 ± 6.2
84.5 ± 12.9
158.3 ± 5.9
159.0 ± 5.9
160.8 ± 5.6
Total cholesterol (mg/dL)
184.3 ± 46.0
184.2 ± 36.6
189.0 ± 40.4
117.0 ± 112.4
136.3 ± 112.8
Fat mass (kg)
23.3 ± 2.3
26.6 ± 2.9
36.4 ± 8.1
36.1 ± 2.7
37.0 ± 5.0
41.9 ± 4.3
0.89 ± 0.03
0.92 ± 0.03
0.99 ± .07
Allele and haplotype frequencies in obese cases and controls
Genotype frequencies of IL-18 gene promoter polymorphism of 271 cases and 409 controls
Cases (BMI ≥25), n (%)
Controls (BMI <25), n (%)
Position −137 genotype
Position −607 genotype
Haplotype frequencies of IL-18 gene promoter polymorphism in case alleles and control alleles
Cases (BMI ≥25), n (%)
Controls (BMI <25), n (%)
Relationship between IL-18 polymorphism and BMI seen in obese women
Frequencies of IL-18 gene promoter polymorphism according to BMI in female cases with BMI ≥25 kg/m 2 (n = 170)
25 ~26.9, n (%)
27 ~ 29.9, n (%)
≥ 30, n (%)
18 (30.0) *,†
This study determined whether the promoter polymorphisms of IL-18 gene were associated with obesity and anthropometric parameters in obese women. Obesity is a complex metabolic disorder with a strong genetic component . There are many candidate genes for obesity and its related phenotypes . Most of these genes are candidates for obesity because their mutations cause rare genetic syndromes that affect the adipocyte differentiation . However, the association between inflammatory cytokine genes and obesity has been studied less frequently when compared with other candidate genes. Thus, the association between the polymorphism of IL-18, a member of the IL-1 family, and obesity without metabolic disease was a primary focus of this study.
In this study, an association between the polymorphism in the IL-18 gene and BMI in women was found. The frequency of haplotype I, which has the C allele at position −607 and the G allele at position −137, was higher in the subjects with BMI ≥25 kg/m2 than in the control subjects with BMI <25 kg/m2, although the statistical significance was marginal. In addition, there was an apparent association between the −607 C/A polymorphism in IL-18 and obesity in women.
The functional significance of the two SNPs of the C allele at position −607 and the G allele at position −137 is attributed to the higher transcription and protein production of IL-18 [11, 12]. From the results presented here, it was observed that the frequency of haplotype I (the C allele at position −607 and the G allele at position −137) in the cases with BMI ≥25 kg/m2 was higher than that in the controls with BMI <25 kg/m2. Therefore, it can be inferred that the mechanism by which the IL-18 gene polymorphism might influence obesity is related to different IL-18 synthesis, secretion, and activity. Indeed, several studies have shown elevated circulating IL-18 concentrations in subjects with obesity and insulin resistance [6, 18–20]. In addition, serum IL-18 was increased in obese women, and it declined as body weight was lost .
The human IL-18 gene is located on chromosome 11q22.2-q23.3. Three SNPs in the promoter of the IL-18 gene at positions −656 G/T, −607 C/A and −137 G/C have been identified. These promoter SNPs have been implicated as susceptibility loci for various diseases, including asthma , pulmonary tuberculosis , inflammatory bowel disease , Parkinson’s disease , polycystic ovary syndrome , type I diabetes , and allergic disorders .
It now appears that obesity is associated with a low- grade inflammation of the white adipose tissue resulting from the chronic activation of the innate immune system as the IL-1 family. Until recently, there were four members of the IL-1 family: IL-1α, IL-1β, IL-1 receptor antagonist (IL-1ra), and IL-18 . Previous studies have described an association between the IL-1 family gene polymorphism and obesity. Manica-Cattani et al.  and Lee et al.  reported that IL-1β polymorphism (+3953 C/T) is linked to the development of obesity. Song et al.  also suggested that IL-1α polymorphism (−889 C/T) is associated with obesity in women. In addition, Strandberg et al. [32, 33] demonstrated that the IL-1 system gene polymorphisms are associated with fat mass in men. The present study is the first approach in exploring the role of the IL-18 gene promoter polymorphism in the etiology of obesity in the Korean population. In addition, obesity is increasing rapidly among women all over the world. Obese women have a higher risk than nonobese women of infertility and pregnancy. The loss of as little as 5% of body weight is accompanied by an increase in ovulation rates and reduces biochemical abnormalities . Therefore, the present study might allow targeted therapies to be developed to improve reproductive health in obese women.
In the present study, two polymorphisms in the promoter regions of the IL-18 gene were identified. An association between the −607 C/A polymorphism and BMI were demonstrated in women. The results suggest that the −607 C/A polymorphism of the IL-18 gene may have a role in the development of obesity.
This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (No. 2011–0006220).
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