Background
Obesity is increasing rapidly among women all over the world, and more women in fertile ages become overweight and obese [
1]. Among all other problems, women who are obese have higher rates of amenorrhoea and infertility [
1]. Over the past decade, research has associated obesity with inflammation; this association was first proposed in the seminal article by Hatamilsligil et al. [
2]. 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 [
2]. 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 [
5] that is associated with excess adiposity [
6]. 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 [
10]. 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.
Discussion
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 [
16]. There are many candidate genes for obesity and its related phenotypes [
16]. Most of these genes are candidates for obesity because their mutations cause rare genetic syndromes that affect the adipocyte differentiation [
17]. 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/m
2 was higher than that in the controls with BMI <25 kg/m
2. 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 [
21].
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 [
22], pulmonary tuberculosis [
23], inflammatory bowel disease [
24], Parkinson’s disease [
25], polycystic ovary syndrome [
26], type I diabetes [
27], and allergic disorders [
28].
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 [
29]. Previous studies have described an association between the
IL-1 family gene polymorphism and obesity. Manica-Cattani et al. [
30] and Lee et al. [
16] reported that
IL-1β polymorphism (+3953 C/T) is linked to the development of obesity. Song et al. [
31] 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 [
34]. Therefore, the present study might allow targeted therapies to be developed to improve reproductive health in obese women.
Competing interests
The authors have declared that no conflict of interest exists.
Authors’ contributions
Conceived and designed the experiments: JYU and SHH. Performed the experiments: HLK, SOC, SYK, and SJK. Analyzed and interpreted the data: JYU, SHK, WSC, SHC, SSK, CHJ, and SGK. Contributed Wrote the paper: HLK, SOC, and JYU. All authors read and authorized the final manuscript.