| Helicobacter pylori (H. pylori) is a gram-negative, microaerophilic bacterium thatresides extracellularly in the gastric mucosa and infects more than 50% of the populationworldwide. H. pylori-induced chronic inflammation is the cause of gastritis and peptic ulcerand a risk factor for gastric cancer. H. pylori infection causes severe local inflammation inthe gastric mucosa. H.pylori infection in different populations lead to different outcomes, also incidence of H.pylori infection is not all.and it causes a broad spectrum of stomach diseases ranging from asymptomatic carrier (AsC), Chronic atrophic gastritis (CAG), Gastrointestinal ulcer (GU), Gastric cancer (GC), mucosal associated lymphoid tissue lymphoma (MALT). Persistent H.pylori infection and H.pylori -related stomach diseases have been considered as a multifactorial and polygenic disorder with bacterial, environmental and host genetic components.Host factors, especially host gene, played an important role in the pathology of H.pylori -related diseases. Almost all complex diseases are polygenic diseases,a series of genes may affect the disease process. Due to technical constraints and knowledge gaps, so far, most genetic studies of diseases start from a single gene to biological function of genes. Currently an important strategy on the genetic susceptibility of complex diseases is to choose candidate genes for case-control association study. Cancer and other complex diseases are the outcome of genetic variation and environmental factors, for the complex etiology and large numberof genes involved in these diseases, it has become the international focus of genomics research. And the early diagnosis of complex diseases can not be fully completed by a single approach, it depends on a variety of complementary diagnostic methods. With the completion of the human genome project, attention is now rapidly shifting towards the study of individual genetic variation., as of March 2010,in NCBI PubMed database, the number of articles related to SNPs is 16933, articles published in 2009 is up to 7131 (accounting for 42.11% of total), SNPs associated with cancer-related literature is 1114, accounting for 15.62% in 2009 published literature, these show the importance of SNPs research in complex disease. Search for complex disease risk factors in a complementary way is by comparing the disease group and control group without the disease to find genetic variation and the correlation between the disease. The most abundant source of genetic variation in the human genome is represented by single nucleotide polymorphisms (SNPs), which can account for heritable inter-individual differences in complex phenotypes. Identification of SNPs that contribute to susceptibility to complexs diseases, such as H.pylori-related diseases, will provide highly accurate diagnostic information that will facilitate early diagnosis, prevention, and treatment of human diseases.Interleukin-17 (IL-17) is a newly described cytokine that bridges the adaptive and innate immune systems. To date, six IL-17 family ligands (IL-17A-F) and five receptors(IL-17RA-IL-17RD and SEF) have been identified. It was also reported that both IL-17 RNA transcripts and protein were expressed at a higher level in the whole gastric mucosal and lamina propria mononuclear cell (LPMC) samples from H. pylori-infected patients than in those from uninfected subjects. Thus an important role of IL-17 in the inflammatory response to H. pylori colonization has been indicated. Our study group have systematically screened the SNPs of IL-17A and IL-17F susceptibility candidate genes by extensive literature and pre-screened have confirmed that the polymorphisms of interleukin-17 (IL-17) gene are related with susceptibility to disease process of Chronic atrophic gastritis and Gastric Cancer diseases by the case-control association study, However, many previous studies only focused on IL-17 gene polymorphism and a small number of autoimmune diseases, chronic inflammatory diseases such as ulcerative colitis, asthma, IBD and other diseases, Association study on the positive sites with chronic atrophic gastritis has not been established yet. So it is important and necessary to carry out functional studies to identify SNPs that affect transcriptional regulation. Therefore, we select IL-17 gene as candidate genes and examine the relationship between their polymorphisms and the susceptibility to H.pylori -related stomach disease of case-control research. In addition, we also investigate the significance of the relationship between the gene polymorphism and susceptibility to H.pylori -related stomach diseases from the perspective of population genetics.In our study, The clinical date and blood samples were collected and genomic DNA was isolated from peripheral blood cells using the DNA blood minikit from Promega according to the manufacturer's protocol. In a hospital-based case-control cohort composed of 230 unrelated health Controls, 151 Chronic atrophic gastritis patients (CAG),27 gastric ulcer patients(GU) and 24 gastric cancer patients (GC), three polymorphisms in the IL-17 gene were analyzed by TaqMan-MGB-PCR analysis, the presence of H.pylori infection was determined by rapid urea test ,histological examination, and serology using a commercial Ig-G ELISA kit.The main results of our study were listed as follow:1. The clinical date and blood samples of more than 432 patients with chronic H.pylori infection were collected and the classification of disease phenotype of all the samples previous collected was completed.2. The IL-17 gene polymorphisms (IL-17A (rs2275913, G-197A),IL-17F(rs763780,7488T/C),IL-17F(rs766748,6400A/G))were successfully genotyped in 230 unrelated health Controls, 151 Chronic atrophic gastritis patients and 27 gastric ulcer patients,24 gastric cancer patients.①The allele frequencies of IL-17 -7488C and -6400A were significantly higher in Chronic atrophic gastritis patients than in health Controls (P =0.026,P =0.029). Logistic regression analysis and stratification analysis with adjustment for age and sex indicated that the polymorphisms of IL-17F 7488T/C and 6400A/G were associated with susceptibility to Chronic atrophic gastritis. The individuals carrying 6400A/G AA genotype exhibited a significantly higher susceptibility to chronic atrophic gastritis, comparing with those carrying the GG or AG genotype.(Dominant model:OR =1.987, 95% CI = 1.137-3.472, P =0.016) The individuals carrying 7488T/C CCgenotype exhibited a significantly higher susceptibility to chronic atrophic gastritis, comparing with those carrying the AA or AC genotype.(Dominant model:OR = 0.603, 95% CI = 0.375-0.971, P =0.037)②The allele frequencies of IL-17 -197G and -6400A were significantly higher in Gastritis Cancer patients than in health Controls (P =0.013,P =0.023).3. In both patients and controls, the presence of H.pylori infection was determined by rapid urea test ,histological examination, and serology using a commercial Ig-G ELISA kit. In 151 cases of patients with chronic atrophic gastritis group and 27 gastric ulcer patients group,24 gastric cancer patients group has a higher rate of H. pylori infection than healthy control group(34.3%), especially gastric cancer group. H.pylori infection rates in chronic atrophic gastritis, gastric ulcers, gastric cancer group were respectively 51.7%, 55.6%, 66.7%.There was no significant difference in allele frequencies or genotype distributions of three polymorphisms in the IL-17A and IL-17F gene between the all subjective with H. pylori infection and without with H. pylori infection. (P>0.05)。Associated with H.pylori infection in all groups compared,There was no significant difference in allele frequencies or genotype distributions of IL-17A G-197A and IL-17F 7488T/C between health Controls and all gastroenteric patients (P>0.05). However, the IL-17F 6400A/G allele frequencies were higher in CAG and GC patients than those in health Controls (P =0.024, P =0.041).In conclusion, based on population genetic association study and genetic functional analysis of the cadidate genes and loci, our study emphasizes the importance of IL-17A and -17F in the pathophysiology of H.pylori -related stomach disease (CAG and GC) on the population level. The results of our research in the future play an important role, it not only provides researchers new clues to the further basic research of pathogenesis of H.pylori infection and H.pylori -related stomach diseases, but also provides the clinicians new ideas to personalized prevention and treatment strategies for patients of H.pylori infection and H.pylori -related stomach disease. |
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