Association Study Of Polymorphisms In IL23R And IL17A Genes With The Susceptibility Of Gastric Cancer

Despite the incidence of gastric cancer keeps declining over past decades, it still remains one of the most common malignancies and the second cause for cancer related deaths over the world. The complex pathogenesis of gastric cancer is commonly considered as the interaction between environment exposures and genetics. Many classical epidemiology studies have established some risk factors of gastric cancer including H.pylori infection, intake of smoked and salty foods, low consumption of fruits and vegetables, smoking and obesity. Especially for the H. pylori infection, since the identification of H. pylori in 1983, many prevention trials and animal models have shown that H. pylori contributes largely to gastric cancer and has been identified as the independent risk factor for gastric cancer. Thus, H. pylori has been defined as a Group I human carcinogen by the International Agency for Research on Cancer (IARC) in 1994. Although the infection rate in global population exceeds 50%, only 1% develops gastric cancer, indicating that there exits predisposition to the similar exposure among different individuals and the genetic factor influences the outcome of H. pylori infection. Presently , the genetic susceptibility studies for gastric cancer focus on inflammatory pathway genes, DNA repair genes, proliferation and apoptosis genes and metabolism genes. Since the first promising markers of IL1B-511 and -31 polymorphisms in gastric cancer was identified, more and more evidences suggested that polymorphisms of host cytokine genes may influence the tumorigenesis of gastric cancer.IL-23/Th17 immune axis is a pivotal component of immune system. IL-23/IL-23R pathway is important for the proliferation and biological function of Th17 cells. IL-17A mainly produced by Th17 cells is a potent pro-inflammatory cytokine and responsible for the chronic inflammation by inducing multiple chemokines and cytokines to the infected site. Furthermore, studies found that IL-17A has a pro-tumor effect with the ability promoting the tumor angigenisis. Genome-wide Association Study (GWAS) has been a powerful tool for low-penetrance gene/loci in many complex diseases. Several GWAS have identified IL23R gene is a susceptible maker involved in some inflammation-related diseases such as psoriasis, inflammatory bowel disease and rheumatoid arthritis. In addition, IL17A gene has also been found associated with inflammation-related diseases including gastric cancer. Accordingly, we conducted two case-control studies aiming to investigate the association of IL23R and IL17A gene polymorphisms with gastric cancer risk in a Chinese population.PartⅠAssociation Study between IL23R Gene Polymorphisms and the Risk of Gastric Cancer[Objective] To investigate the associations of polymorphisms in IL23R with gastric cancer in a Chinese population with high gastric cancer risk[Methods] This case-control study included 1,053 histologically diagnosed incident gastric cancer patients and 1,100 cancer-free controls frequency-matched for age, sex and residential areas as the cases. We selected the potentially functional variants in IL23R (rs6682925 T > C and rs1884444 T > G) and performed the genotyping using PCR-RFLP.[Results] There was a significant difference between cases and controls in the distribution of SNP rs1884444 T > G genotypes (Ρ= 0.0006), but not in SNP rs6682925 T > C (Ρ= 0.885). When adjusted for age, sex, smoking and drinking status, multivariate logistic regression analysis showed that the rs1884444 TG, GG and combined genotype TG/GG were associated with a significantly decreased risk of gastric cancer (adjusted OR = 0.79, 95% CI = 0.66-0.96 for TG; adjusted OR = 0.60, 95% CI = 0.45-0.79 for GG; adjusted OR = 0.74, 95% CI = 0.62-0.89 for TG/GG), compared with the wild-type TT of SNP rs1884444 (T > G). However, no significant associations were found between SNP rs6682925 T > C and risk of gastric cancer in this study population (adjusted OR = 1.00, 95% CI = 0.82–1.24 for TC vs TT; adjusted OR = 1.07, 95% CI = 0.83–1.38 for CC vs TT; adjusted OR = 1.03, 95% CI = 0.84–1.25 for TC/CC vs TT).Stratified analyses for this population indicated that this significant protective effect of the SNP rs1884444 T > G variant against gastric cancer was mainly evident in intestinal-type gastric cancer (adjusted allelic OR = 0.75, 95% CI = 0.65–0.87) other than diffuse-type gastric cancer (adjusted allelic OR = 0.96, 95% CI = 0.76–1.22, P = 0.083 for heterogeneity test). However, there were no significant associations of SNP rs6682925 T > C genotypes with gastric cancer risk among different subgroups.[Conclusion] These findings indicate, for the first time, that the nonsynonymous variant rs1884444 T > G of IL-23R may contribute to gastric cancer susceptibility, especially in intestinal- type gastric cancer, in Chinese population. PartⅡAssociation Study between IL17A Gene Polymorphisms and the Risk of Gastric Cancer[Objective] To investigate the role of the polymorphisms in IL17A in the development of gastric cancer[Methods] We conducted a case-control study with 1,053 gastric cancer patients and 1,100 cancer-free controls in a Chinese population, and genotyped two polymorphisms (rs8193036 C > T and rs2275913 G > A) of the IL17A gene using the TaqMan genotyping method.[Results] There was no significant difference among the distribution of the three genotypes of IL17A rs8193036 C > T between cases and controls. Neither the distribution of the three types of rs2275913 G > A was. When adjusted for age, sex, smoking and drinking status, multivariate logistic regression analysis showed that the heterozygotes and variant homozygotes of two variant did not contribute to the gastric cancer risk when compared with their respective wild homozygotes. Additionally, dominant model revealed that the combined variant genotypes of both variants were not responsible for the risk of gastric cancer (rs8193036 TC/TT vs CC:adjusted OR = 1.05,95% CI = 0.89–1.25;rs2275913 AG/AA vs GG:adjusted OR = 1.05,95% CI = 0.87–1.27). Interestingly, we found the variant allele A of rs2275913 G > A could increased the gastric cancer risk, but the association was not significant (adjused allelic OR = 1.03,95% CI = 0.92-1.17 ).In stratified analyses, we found that rs2275913 G > A variant allele A was significantly increased the gastric cancer risk in drinker, but not in non-drinker (adjusted allelic OR = 1.37, 95% CI = 1.07–1.76 for drinker; adjusted allelic OR = 0.94, 95% CI = 0.82–1.09 for non-drinker; P = 0.01 for heterogeneity test). However, there were no significant associations of rs8193036 C > T with gastric cancer risk among different subgroups.[Conclusion] Our data indicated that IL17A rs2275913 G > A variant may be the susceptibility loci of gastric cancer in Chinese drinking population.