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Susceptibility of gastric cancer according to leptin and leptin receptor gene polymorphisms in Korea

Purpose Leptin plays an important role in the control of body weight and also has a growth-factor-like function in epithelial cells. Abnormal expression of leptin and leptin receptor may be associated with cancer development and progression. We evaluated the relationship among leptin and leptin receptors polymorphisms, body mass index (BMI), serum leptin concentrations, and clinicopathologic features with gastric cancer and determined whether they could be the risk factor of gastric cancer. Methods We measured the serum leptin concentrations of 48 Korean patients with gastric cancer and 48 age- and sex-matched controls. By polymerase chain reaction-restriction fragment length polymorphism, we investigated one leptin gene promoter G-2548A genotype and four leptin receptor gene polymorphisms at codons 223, 109, 343, and 656. Results There was no significant difference between the mean leptin concentrations of the patient and control groups, while BMI was significantly lower in gastric cancer cases (22.9 ± 3.6 vs. 24.5 ± 2.8 kg/m2, P = 0.021). There was significant association between the LEPR Lys109Arg genotype and gastric cancer risk, heterozygotes for GA genotype had been proved to increased the risk of gastric cancer, and its corresponding odds ratio was 2.926 (95% confidence interval, 1.248 to 6.861). Conclusion Our results suggested that LEPR gene Lys109Arg polymorphism is associated with gastric cancer in Korean patients.


INTRODUCTION
Leptin, the product of the ob gene, is secreted by adipocytes [1]. This adipocyte-derived cytokine plays an important role in the control of satiety and energy expenditure via interaction with leptin receptor (LEPR) in the hypothalamus [2]. Generally, plasma leptin levels re-flect the size of fat stores [3]. Although initially thought to be exclusively expressed in and secreted by adipocytes, leptin expression has recently been detected in a number of additional tissues, including the placenta [4], pituitary cells [5], hepatic stellate cells [6], and gastric mucosa [7].
Leptin has been shown to act as a growth factor promoting the proliferation of cells, inhibiting the apoptosis of cells  [8,9]. Although the mechanism underlying the association between obesity and cancer was not clearly demonstrated, recent studies have shown that obesity is associated with an increasing death rate of total cancer [10][11][12][13]. Many clinical studies have investigated the relationship between serum leptin levels and the risk of cancer [11][12][13]. Epidemiological evaluations have demonstrated that the number of patients with an increased body mass index (BMI) had a significant trend of increased death rates resulting from gastric cancer [10].
The leptin (LEP) gene is located at chromosome 7q31.3 and the LEPR gene is mapped to 1p31 and has one long isoform and three short isoforms. Several single nucleotide polymorphisms in the LEP and LEPR gene have been described. Among LEP polymorphisms, a common G-2548A leptin promoter variant, which results from a G to A substitution at nucleotide -2548 upstream of the ATG start site, has been shown to be associated with either variations in serum leptin levels or the degree of obesity. A mutation in the LEPR gene leads to abnormal mRNA splicing which gives rise to abnormal signal transduction and complete leptin resistance and obesity [14,15]. Gotoda et al. [16] identified four allelic variants associated with amino acid changes (Lys109Arg, Gln223Arg, Ser343Ser, and Lys656Asn). Enhanced expression of leptin and the leptin receptor was found in cases of human gastric cancer, and leptin stimulated the proliferation of gastric epithelial cells in vitro as measured by DNA synthesis [17,18].
Herein, a relationship between leptin and gastric cancer could be suggested. However, only a few studies have addressed the association between leptin and gastric cancer [17,19,20]; to date, few studies have addressed the association between polymorphisms within the LEP and LEPR gene and gastric cancer. The present study is a case-control study of gastric cancer among pre-treatment patients. We assessed the serum leptin levels and LEP and LEPR polymorphisms in Korean gastric cancer patients to clarify the role of leptin in relation to gastric cancer.  Values are presented as number or mean ± SD. NS, not significant.   (Table 1).

Statistical analysis
The data was statistically analyzed using SPSS ver. 11.5 (SPSS Inc., Chicago, IL, USA). The comparisons of the patient group and the control group for serum leptin levels and genotypes were performed with a non-parametric Mann-Whitney test. The relationship between genotypes and gastric cancer was also examined by odds ratios (ORs) with 95% confidence intervals (CIs). P-values less than 0.05 were considered statistically significant.

DISCUSSION
In this study, the evaluation of the relationship of the LEPR Lys109Arg polymorphisms and gastric cancer risk showed that cases carrying LEPR 109Arg allele were at a modestly increased risk of gastric cancer (OR, 9.926; 95% CI, 1.248 to 6.861). Several studies have demonstrated that specific genotypes in the LEPR gene were associated with an increased risk for breast cancer. However, there are few previous studies that address the relationship between LEPR polymorphisms and gastric cancer risk. Our study is the first trial to analyze the LEP and LEPR polymorphisms in patients with gastric cancer. We selected cases that had not been treated in any manner that might affect leptin levels.
Circulating concentrations of leptin are highly correlated with body fat mass [22]. In our study, however, there was no significant difference observed regarding the mean serum leptin concentrations between the patient group and control group, while BMI was significantly lower in gastric cancer cases than the controls. Another mechanism suspected is that a sequence variation in gene coding leptin may affect the expression of leptin [23]. However, there have been conflicting reports about the potential effect of the G2548A LEP variant on leptin expression [23,24]. In the Tunisian population, no association was found between this LEP polymorphism and plasma leptin concentrations [23]. On the other hand, in men from a French cohort, the AA genotype was associated with increased plasma leptin levels [24]. Although not mentioned above, no association was found between LEP polymorphism and serum leptin concentrations. The issue regarding leptin level and gastric cancer requires debate and additional study with a larger number of cases to clarify this relationship.
Gastric leptin plays a role in serum leptin levels, regulating intestinal nutrient absorption, delaying gastric emptying, and signaling short-term satiety via vagal afferent nerves [25]. H. pylori induced inflammatory response affects many gastric cell types, including those responsible for leptin production [26]. Eradication of H. pylori has been reported to increase nutrition and weight, suggesting that H. pylori could play a role in the regulation of leptin expression [27]. In our study, cases with positive H. pylori on gastric mucosa showed lower concentrations of leptin than those with negative H. pylori. This result suggested that gastric H. pylori colonization reduces circulating levels of leptin by inhibiting their gastric production.
The frequencies of LEPR polymorphisms, except that of Ser343Ser, were different from those previously reported.
In our study, the frequencies of Lys109Arg and Gln223Arg wild-types were zero, whereas in other studies, 53 to 97%, 23 to 66% of the subjects showed wild-type sequences at codons 109 and 223, respectively [16,28]. Most studies regarding LEPR polymorphisms were performed in Caucasian patients. The genotype frequencies for Lys109Arg and Gln223Arg in the Korean and Japanese population were similar to those in our study, although both studies were performed in breast cancer patients [29,30]. Therefore, further studies are needed to clarify racial differences in the genotype frequencies of LEPR polymorphisms between Asians and Caucasians.
In this study, there was no association between genotypes and serum leptin levels. A trend was observed for cancer patients who were hetorozygotic for Lys656Asn to have lower mean leptin concentrations compared to those with the wild-type. There have been a few previous studies that addressed a relationship between LEPR polymorphism and serum concentrations of leptin. Woo et al. [29] reported that being heterozygotic for Lys656Asn was significantly associated with lower leptin levels in premenopausal subjects and being homozygotic for Gln223 Arg and Lys109Arg was significantly associated with higher leptin levels in post-menopausal patients and in controls, respectively. Our result corresponds with the Woo et al. [29] report, although that report was performed in breast cancer patients.
Our study has several limitations.

CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.