Abstract
Gastric cancer (GC) is the fifth most common cancer and imposes a global cancer burden. IL-4 is a typical cytokine of Th2 cells. IL-4 genetic polymorphisms have multiple functions in many cancers. We performed a case-control study in the Chinese population, and evaluated the association between rs2243250 (590 C/T), rs2227284 (107 T/C), rs2070874 (166 T/C) and rs1801275 (576 Q/R) and gastric cancer risk. A total of 340 gastric cancer patients and 364 controls were enrolled into our study. SNP genotyping of IL-4 rs2243250, rs2227284, rs2070874 and rs1801275 was done in a 384-well plate format on the sequenom MassARRAY platform (Sequenom, San Diego, USA). We observed the CC genotype of IL-4 rs2243250 was associated with risk of gastric cancer when compared with the TT genotype (OR=2.36, 95% CI=1.49-3.75). Moreover, individuals harboring the CT+CC genotype exposed a higher risk of gastric cancer in comparison with the TT genotype (OR=1.66, 95% CI=1.17-2.35). However, there was no significant association between IL-4 rs2227284, rs2070874 and rs1801275 and gastric cancer risk. The TT+CT genotype of IL-4 rs2243250 showed a significant increased risk of gastric cancer in males (OR=2.48, 95% CI=1.67-3.68) and those without a family history of cancer (OR=1.97, 95% CI=1.44-2.70). In ever drinkers (OR=2.04, 95% CI=1.24-3.37) and H. pylori infected patients (OR=2.31, 95% CI=1.38-3.86), the TT+CT genotype of IL-4 rs2243250 had a higher risk of gastric cancer than non-drinkers (OR=1.77, 95% CI=1.20-2.61) and non-H. pylori infected ones (OR=1.76, 95% CI=1.19-2.62). The CTCA (OR=1.54, 95% CI=1.06-2.24), CTCG (OR=1.83, 95% CI=1.16-2.86) and CTTG (OR=1.89, 95% CI=1.16-3.07) haplotypes showed an increased risk in gastric cancer, while the TCTG (OR=0.22, 95% CI=0.09-0.52), TTCG (OR=0.47, 95% CI=0.32-0.69) and TTTA (OR=0.58, 95% CI=0.42-30.79) haplotypes were associated with an reduction risk of gastric cancer. In conclusion, our study indicated that the IL-4 rs2243250 CC genotype and CT+CC genotype were associated with gastric cancer risk in the Chinese population, and IL-4 haplotypes plays an important role in the development of gastric cancer.
Keywords: IL-4, polymorphism, gastric cancer, haplotype
Introduction
Gastric cancer (GC) is the fifth most common cancer and imposes a global cancer burden [1]. Although the mortality rate of gastric cancer has declined in recent years [2], many patients are diagnosed at an advanced stage with lymphatic or distant metastasis in the absence of specific symptoms, especially those with early-stage GC. Therefore, it is of great important to early detection for gastric cancer. Helicobacter pylori (H. pylori) infection is now accepted as a crucial event in the development of atrophic gastritis, and is implicated in the development of gastric carcinoma [1-3]. Gastric cancer develops incrementally beginning with chronic inflammation, and progressing through atrophic inflammation, intestinal metaplasia and dysplasia and finally frank malignancy [4]. Whereas most infected individuals are asymptomatic, chronic H. pylori infection in susceptible individuals is associated with variable degrees of mucosal damage. As a result, only a small percentage of infected individuals actually develop gastric cancer. The development of gastric cancer seems to be determined by the bacterial virulence factors, other environmental factors and genetic factors. Recently, many studies have indicated that many genetic factors play an important role in the development of gastric cancer [5].
The inflammatory microenvironment plays a role in the development of gastric cancer, because the gastric cancer is a pathogen-induced carcinoma. The interleukins (IL) mediate various effects in inflammation. IL-4 plays an important role in regulating the differentiation and activation of T and B lymphocytes and promoting the immune response to Th2 cells [6]. IL-4 has a critical role in alternatively activating macrophages (AAMs) and inhibiting the secretion of proinflammatory cytokines to promote tumor cells, such as IL-1, IL-6 and tumor necrosis factor-α [7]. Previous experimental study have indicated that the IL-4 was unregulated in gastric cancer patients [8]. The gene encoding IL-4 is located on chromosome 5 (5q31.1), and it is in conjunction with other genes for Th2 cytokines. The IL-4 gene has approximated 10Kb of base pairs, and included 4 exons [9]. The polymorphisms of rs2243250, rs2227284, rs2070874 and rs1801275 are the commonly variation of this gene, and the four SNPs have multiple functions in many cancers [10-16]. Currently, several studies reported the association between IL-4 rs2243250 and risk of gastric cancer, but the results are inconsistent. However, no study investigated the rs2227284, rs2070874 and rs180127 and risk of gastric cancer in the current study, we performed a case-control study in a Chinese population, and evaluated the association between rs2243250 (590 C/T), rs2227284 (107 T/C), rs2070874 (166 T/C) and rs1801275 (576 Q/R) and gastric cancer risk.
Materials and methods
Subjects
A hospital-based case-control study was performed in this study. A total of 340 gastric cancer patients were collected from the department of gastroenterology, the People’s Hospital of Inner Mongolia Autonomous Region between 2013 and 2015. All gastric cancer patients underwent upper gastrointestinal endoscopy, and then they were confirmed by pathological examination with pathologists. None of patients had received preoperative chemotherapy and anti-cancer treatment prior to enrollment. Gastric cancer patients who had a prior history of metastasis or recurrent tumors, malnutrition, and end-stage liver or kidney diseases were excluded from this study.
During the same time period, a total of 364 controls were recruited from the outpatient clinics of the People’s Hospital of Inner Mongolia Autonomous Region and health examination centers between 2013 and 2015. All the control subjects received digestive endoscopy examinations, and they had no history of malignant tumors and digestive diseases.
The demographic and clinical characteristics of gastric cancer patients and controls were collected from the medical records or a self-designed questionnaire. The questionnaire involved sex, age, family history of cancer, smoking habit, drinking habit, TNM stage at diagnosis, tumor size, and Lauren classification.
H. pylori specific IgG was taken to determine whether the involved subjects had H. pylori infection by ELISA (Diagnostic Automation, CA, United States) and/or a rapid urea breathe test. Positive by either of the two examinations was considered as H. pylori infection.
A face-to-face investigation was conducted in our study. The investigation was completed by trained investigators who received uniform training. All participants were informed the general purpose of our study, but not the research hypothesis, before agreeing to participate. The performance of our study was approved by the ethics committee of the People’s Hospital of Inner Mongolia Autonomous Region. All included subjects voluntary participated in our study and signed informed consents prior to enrollment.
The average age of gastric cancer patients was 54.68±8.80 years (ranged 29 to 84 years), and there were 107 (31.47%) females and 233 (68.53%) males. The average age of controls was 54.76±9.81 years (ranged 27 to 91 years), and there were 170 (46.70%) males and 194 (53.30%) females.
DNA extraction and genotyping
Each patient was asked to provide a 3-mL peripheral venous blood sample before receiving any anti-cancer treatment. These samples were kept in tubes containing 0.5 M ethylene diaminetetraacetic acid. Genomic DNA was isolated from whole blood using a TIANamp Blood DNA Kit (Tiangen, Beijing, China) according to the manufacturer’s instructions, and the DNA samples were stored in -20°C until using. SNP genotyping of was done in a 384-well plate format on the sequenom MassARRAY platform (Sequenom, San Diego, USA). Primers for polymerase chain reaction amplification and single base extension assays were designed by Sequenom Assay Design 3.1 software. The PCR reaction for genotyping IL-4 rs2243250 (590 C/T), rs2227284 (107 T/C), rs2070874 (168 T/C) and rs1801275 (576 Q/R) was performed in 5 μL, following by the SAP and iPLEX reaction. The samples are then analyzed with MALDI-TOF MS.
Statistical analysis
Categorical variables are displayed as percentages and frequencies (%). The differences between gastric cancer patients and controls in terms of demographic characteristics were analyzed by Chi-square test. Whether the IL-4 rs2243250 (590 C/T), rs2227284 (107 T/C), rs2070874 (168 T/C) and rs1801275 (576 Q/R) were deviation from the Hardy-Weinberg equilibrium were analyzed by Chi-square (χ2) test with one degree of freedom. Relationship between IL-4 rs2243250 (590 C/T), rs2227284 (107 T/C), rs2070874 (168 T/C) and rs1801275 (576 Q/R) and risk of gastric cancer were analyzed by multivariate logistic regression analysis, and the results were expressed by odds ratios (ORs) and 95% confidence intervals (CIs). The results were adjusted for potential risk factors of gastric cancer. The linkage disequilibrium and haplotype analysis were evaluated by SHEsis software [17]. The statistical analysis was performed by IBM SPSS Statistics for Windows, Version 21.0 (Armonk, NY: IBM Corp). P-value <0.05 was regarded as significant difference.
Results
Comparison with controls, gastric cancer patients were more likely to be males (χ2=17.09, P<0.001), have a family history of cancer (χ2=5.02, P=0.03), a habit of drinking habit (χ2=10.72, P=0.001) and infection of H. pylori (χ2=39.89, P<0.001) (Table 1).
Table 1.
Demographic and clinical characteristics of included subjects
| Variable | Patients N=340 | % | Controls N=364 | % | χ2 | P value | |
|---|---|---|---|---|---|---|---|
| Sex | Female | 107 | 31.47 | 170 | 46.70 | ||
| Male | 233 | 68.53 | 194 | 53.30 | 17.09 | <0.001 | |
| Age, years | Mean age | 54.68±8.80 | 54.76±9.81 | -0.12 | 0.91 | ||
| ≤50 | 92 | 27.06 | 122 | 33.52 | |||
| >50 | 248 | 72.94 | 242 | 66.48 | 3.47 | 0.06 | |
| Family history of cancer | No | 311 | 91.47 | 348 | 95.60 | ||
| Yes | 29 | 8.53 | 16 | 4.40 | 5.02 | 0.03 | |
| Smoking habit | Never | 186 | 54.71 | 217 | 59.62 | ||
| Ever | 154 | 45.29 | 147 | 40.38 | 1.73 | 0.19 | |
| Drinking habit | Never | 188 | 55.29 | 245 | 67.31 | ||
| Ever | 152 | 44.71 | 119 | 32.69 | 10.72 | 0.001 | |
| H. pylori infection | No | 97 | 28.53 | 189 | 51.92 | ||
| Yes | 243 | 71.47 | 175 | 48.08 | 39.89 | <0.001 | |
| TNM stage | I-II | 140 | 41.18 | ||||
| III-IV | 200 | 58.82 | |||||
| Tumor size, cm | <5 | 151 | 44.41 | ||||
| ≥5 | 189 | 55.59 | |||||
| Lauren classification | Intestinal | 131 | 38.53 | ||||
| Diffuse | 209 | 61.47 | |||||
We observed that the genotype distributions of IL-4 rs2243250 (P=0.07), rs2070874 (P=0.09) and rs1801275 (P=0.75) were not deviated from the Hardy-Weinberg equilibrium in the controls, while rs2227284 was (P<0.001) (Table 2; Supplementary Data).
Table 2.
Genotype distributions of IL-4 rs2243250 (590 C/T), rs2227284 (107 T/C), rs2070874 (168 T/C) and rs1801275 (576 Q/R) between gastric cancer patients and controls
| Variable | Patients N=340 | % | Controls N=364 | % | χ2 value | P value | χ2 for HWE in Controls | P value |
|---|---|---|---|---|---|---|---|---|
| rs2243250 | ||||||||
| TT | 116 | 34.12 | 182 | 50.00 | ||||
| CT | 151 | 44.41 | 133 | 36.54 | ||||
| CC | 73 | 21.47 | 49 | 13.46 | 19.68 | <0.001 | 3.22 | 0.07 |
| rs2227284 | ||||||||
| TT | 227 | 66.76 | 246 | 67.58 | ||||
| TC | 75 | 22.06 | 79 | 21.70 | ||||
| CC | 38 | 11.18 | 39 | 10.71 | 0.06 | 0.97 | 47.77 | <0.001 |
| rs2070874 | ||||||||
| TT | 99 | 29.12 | 113 | 31.04 | ||||
| TC | 146 | 42.94 | 159 | 43.68 | ||||
| CC | 95 | 27.94 | 92 | 25.27 | 0.71 | 0.71 | 2.75 | 0.09 |
| rs1801275 | ||||||||
| AA | 122 | 35.88 | 145 | 39.84 | ||||
| AG | 161 | 47.35 | 155 | 42.58 | ||||
| GG | 57 | 16.76 | 64 | 17.58 | 1.68 | 0.43 | 0.10 | 0.75 |
By multivariate logistic regression analysis, we found that males (OR=2.09, 95% CI=1.50-2.91), those with a family history of cancer (OR=2.49, 95% CI=1.25-4.95), ever drinkers (OR=1.59, 95% CI=1.14-2.21) and H. pylori infected subjects (OR=2.99, 95% CI=2.15-4.17) were associated with risk of developing gastric cancer (Table 3).
Table 3.
Association of environmental factors and IL-4 rs2243250 (590 C/T), rs2227284 (107 T/C), rs2070874 (168 T/C) and rs1801275 (576 Q/R) with risk of gastric cancer
| Variables | B | S.E. | Wals | P value | Adjusted OR1 | 95% C.I. |
|---|---|---|---|---|---|---|
| Sex | ||||||
| Female | 1.0 | Reference | ||||
| Male | 0.74 | 0.17 | 19.01 | 0.00 | 2.09 | 1.50-2.91 |
| Age | 0.01 | 0.01 | 0.30 | 0.59 | 1.01 | 0.99-1.02 |
| Family history of cancer | ||||||
| No | 1.0 | Reference | ||||
| Yes | 0.91 | 0.35 | 6.73 | 0.01 | 2.49 | 1.25-4.95 |
| Drinking habit | ||||||
| Never | 1.0 | Reference | ||||
| Ever | 0.46 | 0.17 | 7.55 | 0.01 | 1.59 | 1.14-2.21 |
| Smoking habit | ||||||
| Never | 1.0 | Reference | ||||
| Ever | 0.25 | 0.17 | 2.26 | 0.13 | 1.28 | 0.93-1.77 |
| H. pylori infection | ||||||
| No | 1.0 | Reference | ||||
| Yes | 1.10 | 0.17 | 41.70 | 0.00 | 2.99 | 2.15-4.17 |
| rs2243250 | ||||||
| TT | 15.70 | 0.00 | 1.0 | Reference | ||
| CT | 0.50 | 0.18 | 7.95 | 0.01 | 1.66 | 1.17-2.35 |
| CC | 0.86 | 0.24 | 13.27 | 0.00 | 2.36 | 1.49-3.75 |
| CT+CC | 0.61 | 0.16 | 13.70 | 0.00 | 1.84 | 1.33-2.54 |
| rs2227284 | ||||||
| TT | 0.50 | 0.78 | 1.0 | Reference | ||
| TC | 0.13 | 0.20 | 0.41 | 0.52 | 1.14 | 0.77-1.69 |
| CC | 0.11 | 0.26 | 0.17 | 0.68 | 1.11 | 0.66-1.87 |
| TC+CC | 0.11 | 0.17 | 0.37 | 0.54 | 1.11 | 0.79-1.56 |
| rs2070874 | ||||||
| TT | 0.51 | 0.77 | 1.0 | Reference | ||
| TC | 0.04 | 0.19 | 0.04 | 0.85 | 1.04 | 0.71-1.52 |
| CC | 0.15 | 0.22 | 0.48 | 0.49 | 1.16 | 0.76-1.78 |
| TC+CC | 0.08 | 0.18 | 0.22 | 0.64 | 1.09 | 0.77-1.54 |
| rs1801275 | ||||||
| AA | 3.00 | 0.22 | 1.0 | Reference | ||
| AG | 0.26 | 0.18 | 2.02 | 0.16 | 1.29 | 0.91-1.85 |
| GG | -0.08 | 0.24 | 0.10 | 0.75 | 0.93 | 0.58-1.47 |
| AG+GG | 0.17 | 0.17 | 1.01 | 0.31 | 1.18 | 0.85-1.65 |
Adjusted for age, sex, family history of cancer, smoking habit, drinking habit and H. pylori.
We observed the CC genotype of IL-4 rs2243250 was associated with risk of gastric cancer when compared with the TT genotype (OR=2.36, 95% CI=1.49-3.75). Moreover, individuals harboring the CT+CC genotype exposed a higher risk of gastric cancer in comparison with the TT genotype (OR=1.66, 95% CI=1.17-2.35) (Table 3). However, there was no significant association between IL-4 rs2227284, rs2070874 and rs1801275 and gastric cancer risk.
The interaction analyses showed that the TT+CT genotype of IL-4 rs2243250 showed a significant increased risk of gastric cancer in males (OR=2.48, 95% CI=1.67-3.68) and those without a family history of cancer (OR=1.97, 95% CI=1.44-2.70). Moreover, in ever drinkers (OR=2.04, 95% CI=1.24-3.37) and H. pylori infected patients (OR=2.31, 95% CI=1.38-3.86), the TT+CT genotype of IL-4 rs2243250 had a higher risk of gastric cancer than non-drinkers (OR=1.77, 95% CI=1.20-2.61) and non-H. pylori infected ones (OR=1.76, 95% CI=1.19-2.62) (Table 4). However, we did not find any interaction between clinical characteristics and IL-4 rs2243250 polymorphism in gastric cancer patients (Table 5).
Table 4.
Interaction between environmental factors and IL-4 rs2243250 (590 C/T) in the risk of gastric cancer
| Variables | Patients | Controls | OR | 95% CI | P value | ||
|---|---|---|---|---|---|---|---|
|
| |||||||
| CC | TT+CT | CC | TT+CT | TT+CT vs CC | |||
| Sex | |||||||
| Female | 45 | 62 | 81 | 89 | 1.25 | 0.77-2.04 | 0.36 |
| Male | 71 | 162 | 101 | 93 | 2.48 | 1.67-3.68 | <0.001 |
| Family history of cancer | |||||||
| No | 107 | 204 | 177 | 171 | 1.97 | 1.44-2.70 | <0.001 |
| Yes | 9 | 20 | 5 | 11 | 1.01 | 0.27-3.77 | 0.99 |
| Drinking habit | |||||||
| Never | 71 | 117 | 127 | 118 | 1.77 | 1.20-2.61 | 0.004 |
| Ever | 45 | 107 | 55 | 64 | 2.04 | 1.24-3.37 | 0.005 |
| H. pylori infection | |||||||
| No | 30 | 67 | 96 | 93 | 1.76 | 1.19-2.62 | 0.005 |
| Yes | 86 | 157 | 86 | 89 | 2.31 | 1.38-3.86 | 0.002 |
Table 5.
Association between clinical characteristics and IL-4 rs2243250 (590 C/T) in gastric cancer patients
| Variables | Patients | OR | 95% CI | P value | |
|---|---|---|---|---|---|
|
| |||||
| CC | TT+CT | TT+CT vs CC | |||
| TNM stage | |||||
| I-II | 56 | 84 | |||
| III-IV | 60 | 140 | 1.56 | 0.99-2.45 | 0.06 |
| Tumor size, cm | |||||
| <5 | 54 | 97 | |||
| ≥5 | 62 | 127 | 1.14 | 0.73-1.79 | 0.57 |
| Lauren classification | |||||
| Intestinal | 47 | 84 | |||
| Diffuse | 69 | 140 | 1.14 | 0.72-1.80 | 0.59 |
The haplotype analysis did not show linkage disequilibrium (Figure 1). Twelve common haplotypes (frequency >0.03 in either the patients or controls has been selected) accounted for the main haplotypes in gastric cancer patients and controls (Table 6). The CTCA (OR=1.54, 95% CI=1.06-2.24), CTCG (OR=1.83, 95% CI=1.16-2.86) and CTTG (OR=1.89, 95% CI=1.16-3.07) haplotypes showed an increased risk in gastric cancer, while the TCTG (OR=0.22, 95% CI=0.09-0.52), TTCG (OR=0.47, 95% CI=0.32-0.69) and TTTA (OR=0.58, 95% CI=0.42-30.79) haplotypes were associated with an reduction risk of gastric cancer. The other six haplotypes were not associated with gastric cancer risk.
Figure 1.
The linkage disequilibrium of IL-4 rs2243250, rs2227284, rs2070874 and rs1801275.
Table 6.
Haplotype analysis of the association between IL-4 rs2243250-rs2227284-rs2070874-rs1801275 and gastric cancer risk
| Haplotype | Patients | % | Controls | % | OR (95% CI)1 | P value |
|---|---|---|---|---|---|---|
| CTCA | 70 | 10.30 | 52 | 7.10 | 1.54 (1.06-2.24) | 0.02 |
| CTCG | 53 | 7.80 | 33 | 4.50 | 1.83 (1.16-2.86) | 0.01 |
| CTTA | 70 | 10.20 | 70 | 9.70 | 1.09 (0.77-1.55) | 0.63 |
| CTTG | 46 | 6.80 | 28 | 3.80 | 1.89 (1.16-3.07) | 0.01 |
| TCCA | 27 | 4.00 | 32 | 4.40 | 0.91 (0.54-1.54) | 0.73 |
| TCCG | 24 | 3.60 | 15 | 2.00 | 1.82 (0.94-3.50) | 0.07 |
| TCTA | 35 | 5.20 | 32 | 4.40 | 1.22 (0.75-2.00) | 0.43 |
| TCTG | 6 | 0.90 | 30 | 4.10 | 0.22 (0.09-0.52) | <0.001 |
| TTCA | 96 | 14.20 | 103 | 14.20 | 1.02 (0.76-1.38) | 0.89 |
| TTCG | 41 | 6.00 | 89 | 12.20 | 0.47 (0.32-0.69) | <0.001 |
| TTTA | 72 | 10.60 | 126 | 17.30 | 0.58 (0.42-0.79) | <0.001 |
| TTTG | 81 | 12.00 | 70 | 9.60 | 1.32 (0.94-1.85) | 0.11 |
Overall P<0.001.
Discussion
In this study, we observed that the IL-4 rs2243250 was associated with gastric cancer risk. The CCTG, CTCG, CTTA, TTCA, TTCG and TTTG haplotypes were related to the risk of gastric cancer.
H. pylori is an important reason for the development of gastric cancer, and long-term H. pylori accounts for about 75% of gastric cancer [18]. During the inflammation caused by H. pylori infection, many cytokines, chemokines, oxidative free radicals, and growth factors are produced in the microenvironments. These cytokines can lead to DNA damage and epigenetic modifications of DNA, which result in tumorigenesis and progression [19-21]. HP inflammation presents a Th2-mediated response. IL-4 is regarded as a typical cytokine of Th2 cells, and it plays an important role in promoting the occurrence and development of Th2 during the process of the inflammatory response. It is reported that IL-4 is produced by dendritic cells conditioned through the medium of H. pylori infected gastric epithelial cells [22]. Previous study have indicated that more IL-4 producing T cells in the peripheral blood are associated with the prognosis of gastric cancer patients [8]. Genetic polymorphisms in IL-4 may influence the individualized expression of protein, and thus influence the susceptibility to gastric cancer.
Several previous studies have reported the association between IL-4 genetic polymorphisms and gastric cancer risk, but the results are inconsistent [23-27]. Wu et al. performed a case-control study of 1045 gastric cancer patients and 1100 controls in a Chinese population, and this study indicated that individuals carrying TC/CC genotype of IL-4 rs2070874 had a 0.73 fold risk of gastric cancer when compared with the TT genotype [26]. Sugimoto et al. performed a study in a Japanese population, and they reported that rs2243250 T allele and rs2070874 C allele was significantly related to a reduced risk of non-cardia gastric cancer [25]. A recent study performed a study with 58 gastric cancer patients and 46 controls, and indicated that IL-4 rs2243250 T carriers increased the risk of gastritis when compared with the C allele carriers, and the IL-4 rs2243250 polymorphism had an interaction with H. pylori neutrophil activating protein antibodies [23]. However, Pan et al. performed a case-control study with 308 pairs of gastric cancer patients and controls, and they reported that IL-4 rs2243250 had no association with the gastric cancer risk [24]. Sun et al. performed a meta-analysis with seven studies, and reported that IL-4 polymorphism was related to a lower gastric cancer risk in Caucasians [27]. In our case-control study, we observed that IL-4 rs2243250 CC genotype and CT+CC genotype were related to an increased risk of gastric cancer, and we firstly reported that the IL-4 haplotypes were associated with gastric cancer risk. Therefore, the role of IL-4 in the development of gastric cancer requires more studies to further confirmation.
Our study found an interaction between IL-4 rs2243250 polymorphism and males, drinking habit and H. pylori infection. A previous study reported that IL-4 gene polymorphisms concur in selecting the H. pylori infecting strain and influencing the IL-4 signaling pathway [28]. Moreover, a recent study indicated that IL-4 rs2243250 polymorphism augmented the risk of gastric cancer in H. pylori positive subjects, which is in line with our results [23]. A previous study found that IL-4 diplotype had an interaction with drinking status to the risk of early stage of oral and pharyngeal carcinomas [29]. We firstly reported an interaction between IL-4 rs2243250 and drinking and males in the risk of gastric cancer, further studies are greatly warranted to confirm our results.
Two limitations should be considered in this study. First, the gastric cancer patients and controls were collected from only one hospital in China, which may not well represent the whole Chinese population, and the selection bias is unavoidable. Second, only 340 gastric cancer patients and 364 controls were enrolled into this study, and the results could be undervalued due to the limitation of sample size.
In conclusion, our study indicated that the IL-4 rs2243250 CC genotype and CT+CC genotype were associated with gastric cancer risk in a Chinese population, and IL-4 haplotypes plays an important role in the development of gastric cancer. IL-4 could be used as a potential biomarker for early detection of gastric cancer.
Acknowledgements
We thanks for funding from Inner Mongolia Autonomous Region Health and family Planning Commission (15KY259). We also thank great help from staffs in the People’s Hospital of Inner Mongolia Autonomous Region, and they help us to collect the blood samples from enrolled subjects.
Disclosure of conflict of interest
None.
Supporting Information
References
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