The host genetic variation predisposes Helicobacter pylori-infected patients to gastric precancerous lesions as intestinal metaplasia

• Main Authors: Hui-Wen Hung, 洪惠雯
• Other Authors: Bor-Shyang Sheu
• Format: Others
• Language: zh-TW
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/77956311890599152216

碩士 === 國立成功大學 === 微生物及免疫學研究所 === 95 === Background and objectives: Gastric adenocarcinoma is usually linked with a precancerous lesion such as intestinal metaplasia (IM). Recent evidences demonstrated the host genetic polymorphisms and Helicobacter pylori (H. pylori) genotypes have been linked to the development of gastric cancer. The prevalence of the triple-positive (cagA, vacA s1 and babA-positive) H. pylori infection is nearly 100 % in Taiwan, therefore overwhere should be the most suitable site to determine whether there could be any host genetic predispositions to have gastric precancerous lesions as IM. In Taiwan, the IL-10 promoter single nucleotide polymorphism (SNP), instead of IL-1β SNP, is associated with an increased gastric cancer (GC) risk. The aim of first part in this study was to determine whether IL-10 polymorphism could be a risk factor simultaneously related with an increased risk to have IM after H. pylori infection. As cyclooxygenase-2 (COX-2) overexpression shall be also significantly correlated with the presence of IM after H. pylori infection, we also test whether COX-2 host genetic polymorphism could have different risk to get IM after H. pylori infection. Moreover, as matrix metallpproteinase-9 (MMP-9) and its inhibitors, known as tissue metalloproteinase inhibitor-1 (TIMP-1) and TIMP-2, can be important during the gastric cancer invasion. This study also deliberated if imbalance of MMPs and TIMPs contributed by the host genetic polymorphisms would be associated the presence or any progression of IM after H. pylroi infection. Methods: A total of 352 dyspeptic patients, including 52 without and 300 with H. pylori infection, were sequentially included after panendoscopy. The gastric specimen about the presence of IM was recorded, and the host white blood cell DNA was collected for the analysis to the host genomic polymorphisms about the IL-10, COX-2, MMP-9, MMP-2, TIMP-1, and TIMP-2 using the SSOP, RFLP or other methods. Results: This study revealed the presence of H. pylori infection and an old age were significant risk factor to correlate with the presence of IM (P < 0.001). People with age above 40 years old will have a 2-fold risk to have IM, whereas age above 50 years old become increased up to near 3 folds (P < 0.001). Our study included 352 patients, including 52 without and 300 with H. pylori infection, and all of them had complete linkage disequilibrium between IL-10-592 and IL-10-819. The carriage of a low IL-10 secreting haplotype (defined as A, T, and A allele over the -1082, -819, and -592 loci, respectively) had a higher prevalence of H. pylori than those with other IL-10 haplotypes (P < 0.05, relative risk: 6.8). However, there was no association between IL-10 haplotype GCC and the presence of IM (P＞0.05). Moreover, our data only observed a borderline significant correlation between COX-2 genetic polymorphism and the presence of IM in the H. pylori-infected patients (P＝0.049). The combination haplotype MMP-9-1562 C→T / TIMP-2-418 G→C /MMP-2-735 T→C had not an increased rate of IM in the gastric corpus in H. pylori-infected patients (p＞0.05). Nevertheless, when subjects were stratified by age as less than 40 years old, the combination haplotype of the MMP-9-1562 C→T / TIMP-2-418 G→C /MMP-2-735 T→C become significantly associated with the presence of IM over the gastric corpus (p＜0.001). Only in female, the genotype as TIMP-1 372 T-carrier has a significantly higher rate to have IM than the genotype as CC (p<0.05). Conclusion: This study disclosed an increased age and H. pylori infection should be important factor to have the presence of IM in stomach. The host factors, as the combination haplotype of the TIMP-2, MMP-2, and MMP-9 in the patients’ age less than 40 years old and the genotype of TIMP1-372 as T-carrier in female, instead of the IL-10 polymorphyisms, should have increased the risk of getting IM after H. pylori infection in Taiwanese.