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

Abstract

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.

Antimicrobial resistance patterns and genetic elements associated with the antibiotic resistance of Helicobacter pylori strains from Shanghai

“…Because different phenotypes of H. pylori are considered to be associated with unique sets of genetic features [ 54 , 55 ], we conducted genome-wide gene family analysis to compare the resistant and susceptible categories to obtain unique gene pools and their functional enrichment, which has rarely been investigated in H. pylori . Putatively affected by differences in the strain number of each resistant and susceptible category, the level of the unique gene pools of the three antibiotics varied greatly.…”

Hsa_circ_0044301 Regulates Gastric Cancer Cell’s Proliferation, Migration, and Invasion by Modulating the Hsa-miR-188-5p/DAXX Axis and MAPK Pathway

“…Additionally, how and to what extent they interact, such as how circRNA-0044301 and miRNA may be unilateral or bidirectional, and the relationship between circRNA-0044301 and other key proteins of the related pathway or phosphorylated proteins of the mTOR pathway also requires further investigation. Moreover, the etiology of GC is complex, involving a multifactorial process resulting from the combination of genetic susceptibility and environmental risk factors [ 61 ]. Helicobacter pylori infection is a risk factor for GC and has been classified as a level Ι carcinogen by the World Health Organization [ 62 ].…”

Antimicrobial Resistance and Genetic Characteristics that Might be Related to Antibiotic Resistance of 112 Helicobacter Pylori Shanghai Isolates

“…Because different phenotypes of H. pylori are considered to be associated with unique sets of genetic features [53,54], we conducted the genome-wide gene family analysis to compare resistant and susceptible categories to obtain unique-gene pools and their functional enrichment, which is rarely investigated in H. pylori. Putatively affected by differences in the strain number of each resistant and susceptible category, the content of the unique-gene pools of the three antibiotics varied greatly.…”