基于"邪毒致变"探讨Hp相关胃病演变过程不同证候microRNAs和炎症因子基因多态性

At the foundation of different morbidity characteristic between splenogastric hygropyrexia and deficiency of spleen-QI syndrome on Hp infection、inflamm degree and the precancerous lesion of gastric cancer to atrophy accompany intestinal metaplasia and/or dysplasia in helicobacter pylori-related gastric disease(HPGD), We propose a hypothesis "evil-toxin inducing variation", planning through the study to Hp and inflammation、tumor correlated miR196a2、miR146a and IL-1B-511、IL-1-RN、IL-8-251 genes, to hinting Hp infection and the diversity of additive effect on allelic polymorphism micro-effect was the key point of malignant transformation from gastro-mucosa inflammation、anabrosis to atrophy accompany intestinal metaplasia and/or dysplasia even canceration in HPGD pathological variation，And the occurrence and invert pathogenesis characteristic from sthenia syndrome?deficiency、blood stasis condition on splenogastric hygropyrexia、incoordination between the liver and stomach、deficiency-weakness of spleen-QI and stagnation of blood stasis syndrome. At same time, on account of hypothesis "the alterability of constitution condition with the easy generate correlation in different syndromes", approaching the phaenotype characteristic of asthenia and sthenia syndromes allaxis and the corresponding constit condition in the different pathological developing stage. The result profit search disparity syndrome related risk gene polymorphism group in the pathogenesis development from trivial state of an illness to severe or from innocuousness to malignant with different syndrome related. For the early warning to aim directly at syndrome convergence liability constitution provide some extent experiment evidence.

在前期研究Hp相关胃病（HPGD）胃黏膜Hp感染、炎症程度及萎缩伴肠化生和或异型增生的胃癌前病变在脾胃湿热和脾气虚证呈现不同发病特点基础上，进一步提出"邪毒致变"假说并拟通过对Hp与炎症和肿瘤风险相关miR196a2、miR146a及IL-1B-511、IL-1-RN、IL-8-251基因的研究，提示Hp感染和各等位基因多态性微效作用累积效应的差异可能是HPGD从炎症、糜烂到萎缩伴肠化生和或异型增生甚至癌变的病理演变过程中加重和发生恶性转化的关键所在，以及脾胃湿热、肝胃不和、脾气虚弱和瘀血阻滞证及其由实至虚、瘀兼夹状态发生和转化的病机特点；同时提出"体质状态可变性与不同证候易感相关联"假说并探讨不同病理演变阶段中虚实证候转化及其所伴随体质状态的表型特征；结果将有利于寻找HPGD由轻到重、由良性到恶性病机演变中不同证候相关的风险基因多态群，为针对性证候趋同性易感体质的预警提供一定的实验依据。

幽门螺杆菌相关胃病(HPCG)涵盖慢性浅表和糜烂性胃炎、胃溃疡及胃黏膜萎缩伴肠化生、异型增生甚至胃癌之良恶性逐渐演变的病理过程；本项目提出“邪毒致变”假说，采用HE、快速尿素酶和美兰染色法对HPCG患者进行胃黏膜Hp感染和病理改变检测，一代直接测序法检测与炎症、肿瘤风险相关IL-1B-511、TNF-α-308和miR196a2、miR146a基因多态性。结果提示，Hp感染与胃黏膜炎症、萎缩、肠化生、异型增生和癌变相关，其程度呈胃癌＞溃疡＞慢性胃炎趋势；脾胃湿热、肝胃不和证者更易感染Hp且炎症程度与活动度较为明显；Hp感染的肝胃不和证患者胃黏膜更易出现单纯性萎缩，脾胃湿热和脾气虚证患者发生萎缩、肠化生、异型增生两种及以上病理改变的可能性更大，瘀血内阻证患者则胃黏膜癌变的可能性最为明显，不同证候在胃黏膜良恶性病理演变中呈现出差异改变特征趋势；IL-1B-511 T和miR-146a C以及miR-196a2 T等位基因可能是Hp感染的易感基因，与脾胃湿热和瘀血内阻证关系密切；携带TNF-α-308 A等位基因脾胃湿热、脾气虚及肝胃不和证的Hp感染者病情较重。“外邪”Hp感染与类似于“内邪”作用之IL-1β、TNF-α炎症因子可协同致病而加重HPCG的炎症反应，并可进一步导致萎缩、肠化生、异型增生甚至癌变的发生；研究初步体现了“邪毒致变”假说且对良恶性病理演变的发生提示了可能预警作用，一定程度印证了前期IL-1β、TNF-α蛋白和mRNA表达水平研究结果。进一步Hiseq高通量转录组二代测序分析则提示，Hp感染差异基因涉及蛋白质合成与代谢、炎症信号传导功能，HPCG良恶性病理演变与炎症因子IL-1β、TNF-α异常表达及相关信号通路激活有关；而脾胃湿热、肝胃不和、脾气虚和瘀血内阻证所涉及的炎症信号通路、黏膜保护以及脂质和蛋白质代谢等基因的差异，也从证候角度对疾病的易感性进行了初步诠释。