Table_4_Comprehensive Integration of Genome-Wide Association and Gene Expression Studies Reveals Novel Gene Signatures and Potential Therapeutic Targets for Helicobacter pylori-Induced Gastric Disease.xlsx

Helicobacter pylori is a gram-negative bacterium that colonizes the human gastric mucosa and can lead to gastric inflammation, ulcers, and stomach cancer. Due to the increase in H. pylori antimicrobial resistance new methods to identify the molecular mechanisms of H. pylori-induced pathology are urgently needed. Here we utilized a computational biology approach, harnessing genome-wide association and gene expression studies to identify genes and pathways determining disease development. We mined gene expression data related to H. pylori-infection and its complications from publicly available databases to identify four human datasets as discovery datasets and used two different multi-cohort analysis pipelines to define a H. pylori-induced gene signature. An initial Helicobacter-signature was curated using the MetaIntegrator pipeline and validated in cell line model datasets. With this approach we identified cell line models that best match gene regulation in human pathology. A second analysis pipeline through NetworkAnalyst was used to refine our initial signature. This approach defined a 55-gene signature that is stably deregulated in disease conditions. The 55-gene signature was validated in datasets from human gastric adenocarcinomas and could separate tumor from normal tissue. As only a small number of H. pylori patients develop cancer, this gene-signature must interact with other host and environmental factors to initiate tumorigenesis. We tested for possible interactions between our curated gene signature and host genomic background mutations and polymorphisms by integrating genome-wide association studies (GWAS) and known oncogenes. We analyzed public databases to identify genes harboring single nucleotide polymorphisms (SNPs) associated with gastric pathologies and driver genes in gastric cancers. Using this approach, we identified 37 genes from GWA studies and 61 oncogenes, which were used with our 55-gene signature to map gene-gene interaction networks. In conclusion, our analysis defines a unique gene signature driven by H. pylori-infection at early phases and that remains relevant through different stages of pathology up to gastric cancer, a stage where H. pylori itself is rarely detectable. Furthermore, this signature elucidates many factors of host gene and pathway regulation in infection and can be used as a target for drug repurposing and testing of infection models suitability to investigate human infection.

幽门螺杆菌（Helicobacter pylori）是一种定植于人类胃黏膜的革兰氏阴性杆菌，可引发胃部炎症、溃疡乃至胃癌。随着幽门螺杆菌（H. pylori）抗菌耐药性的逐年攀升，亟需开发新方法以阐明其诱导病理发生的分子机制。本研究采用计算生物学策略，借助全基因组关联研究与基因表达研究，筛选出决定疾病发生发展的核心基因与通路。我们从公开数据库中挖掘与幽门螺杆菌感染及其并发症相关的基因表达数据，筛选出4个人类数据集作为发现队列，并采用两套不同的多队列分析流程，构建幽门螺杆菌诱导的基因特征谱。首先通过MetaIntegrator流程整理得到初始幽门螺杆菌特征谱，并在细胞系模型数据集内完成验证，借此筛选出与人类病理状态下基因调控模式最为匹配的细胞系模型。随后，借助NetworkAnalyst搭建的第二条分析流程对初始特征谱进行优化，最终得到55个基因的特征谱，该特征谱在疾病状态下呈现稳定的表达失调。我们在人类胃腺癌数据集内验证了该55基因特征谱的有效性，其可有效区分肿瘤组织与正常组织。由于仅少数幽门螺杆菌感染者会进展为胃癌，该基因特征谱必然与其他宿主及环境因素协同作用，以启动肿瘤发生过程。我们通过整合全基因组关联研究（GWAS）与已知癌基因，探究了所构建的基因特征谱与宿主基因组背景突变及多态性之间的潜在互作关系。我们对公共数据库进行分析，筛选出携带与胃部病理相关的单核苷酸多态性（SNPs）的基因，以及胃癌驱动基因。通过该策略，我们从GWAS研究中筛选得到37个相关基因，并获取61个癌基因，将其与55基因特征谱相结合，绘制了基因-基因互作网络。综上，本研究构建了一套独特的基因特征谱：该特征谱由早期幽门螺杆菌感染所驱动，并在疾病进展至胃癌的各个阶段均保持相关关联性——而在胃癌阶段，幽门螺杆菌本身已极少可被检出。此外，该特征谱阐明了感染过程中宿主基因与通路调控的诸多机制，既可作为药物重定位的潜在靶点，也可用于评估感染模型用于研究人类感染的适配性。