幽门螺杆菌感染-七个多态位点的交互作用和不同胃粘膜病变的关系

Gastric cancer (GC) of the intestinal type is an end result of multifactorial and multistep process. Interplay between host susceptibility and environmental exposures including Helicobacter pylori (H. pylori) infection plays a crucial role in gastric pathogenesis. Four recent genome-wide association studies (GWAS) reported significant associations of rs4072037 at 1q22, rs9841504 at 3q13, rs13361707 at 5p13, rs2976392 and rs2294008 at 8q24, rs2274223 at 10q23 and rs13042395 at 20p13 and risk of gastric cancer in Asians. Given the importance of environmental factors and gene-environment interactions on gastric carcinogenesis, the interplay between GC risk-related loci and different strains of H. pylori infection should be further evaluated. Based on a population-based GC screening program held in Huai River Districts, we aim to conduct a case-control study of the polymorphisms and subtypes of H. pylori infection, and to evaluate their relationship with different gastric diseases in a Chinese population. We also want to determine the effect of genetic variants and H.pylori infection on gastric cancer prognosis. By using a case-control design, 500 GC, 500 severe dysplasia, 500 mild dysplasia would be chosen as cases, whereas 500 controls with normal mucosa would be frequency matched with cases by age (±5) and sex. Genetic variants would be identified by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) or TaqMan analysis. Infection status of H. pylori subtypes would be detected with Western blotting procedures. Unconditional logistic regression models and Cox regression models would be used. Gene-gene and gene-environment interactions would be explored.

胃癌发生是遗传因素与环境因素共同作用的结果。幽门螺杆菌感染是胃癌发生的明确致病因子。四项全基因组关联研究发现了7个与胃癌发病风险密切相关的遗传变异。鉴于幽门螺杆菌感染和基因-环境交互作用在胃粘膜癌变过程中的重要作用，本研究拟结合宿主不同亚型幽门螺杆菌的感染状况，探讨幽门螺杆菌亚型、7个多态位点及其交互作用和不同胃粘膜病变的关系；同时结合胃癌患者的病理、分期、治疗及生存情况，探索幽门螺杆菌感染和易感位点与胃癌预后的关系。为此，本研究以淮河流域胃癌早诊早治项目为基础，通过病例-对照研究设计，在项目实施地区选取经病理学确诊的胃癌患者、高级别上皮内瘤变者及低级别上皮内瘤变者各500例为病例组，并以年龄（±5岁）、性别频数匹配原则，选取同一地区500例正常个体为对照，在2000例样本中深入研究幽门螺杆菌亚型、细菌-易感位点交互作用与不同胃粘膜病变发生的关系，与胃癌患者预后的关系。

基因环境相互作用会增加胃癌风险。GWAS鉴定到7个易感位点，提示遗传因素在胃癌的发生发展过程中有一定的作用。同时，幽门螺杆菌感染、吸烟和饮酒也是胃癌相关的重要环境因素。为了在胃癌中探索基因-环境相互作用，研究7个易感位点与幽门螺杆菌感染、吸烟和饮酒在胃癌及肠化生和不典型增生间的潜在交互作用，我们用KASP对1273个中国人样本进行了基因分型，用幽门螺杆菌感染、吸烟和饮酒情况校正后的非条件逻辑回归模型分析了基因多态与疾病风险的关系。我们发现，PSCA rs2294008/rs2976392与幽门螺杆菌感染在胃癌风险上存在显著的相互作用。同时，PRKAA1 rs13361707与幽门螺杆菌感染存在加法相互作用，SLC52A3 rs13042395与饮酒存在相互作用。此外，3个SNP位点，MUC1 rs4072037、ZBTB20 rs9841504和PRKAA1 rs13361707与癌前病变相关。我们的数据提示，GWAS鉴定到的遗传多态位点可能与环境因素，特别是幽门螺杆菌感染和饮酒相互作用，增加胃癌风险。