Introduction: Helicobacter pylori is able to persist within the gastric niche of half the population, however it only initiates gastric carcinogenesis in a small portion of infected individuals. Toll-like receptor 4 (TLR4) is proposedly involved in responsiveness to H. pylori, and the carriage of commonly-occurring TLR4 polymorphisms may influence clinical outcomes in patients. While this has been largely explored in low-risk Caucasian populations, these effects remain poorly understood in high-risk cohorts. This study therefore serves to identify genetic signatures for improved therapeutic measures.
Methods: The relationship between the novel TLR4 rs11536889 (G>C) polymorphism, H. pylori infection and gastric carcinogenesis was evaluated in a multi-ethnic (Australian Caucasian, Colombian, Han Chinese and Iranian) case-control study comprising 315 GC cases, 372 gastric precancerous lesion cases and 1043 controls. Local host transcriptomics of gastric tissue and systemic inflammation were interrogated and correlated with carriage of rs11536889. Inflammation and bacterial clearance were further examined in H. pylori-challenged CRISPR/Cas9-edited gastric epithelial (AGS) and macrophage (THP-1) cell lines.
Results: Carriage of rs11536889 correlated with downregulated tumour suppressor expression (TCL1A, IFI16L and CXCL10) in gastric tissue of high-risk patients. Likewise, rs11536889 also modulated the secretion of inflammatory antagonists (IL-1Ra) and chemoattractants (IL-8 and GM-CSF) in gastric epithelial cells infected with H. pylori. Further, both high-risk patients and macrophages harbouring rs11536889 showed widespread abnormal systemic inflammatory signatures, most notably marked by the consistent reduction in anti-inflammatory cytokine (IL-1Ra and IL-18) production. In parallel, rs11536689-carrying macrophages showed enhanced phagocytosis of H. pylori. Overall, in our population-based case-control study, carriage of rs11536889 conferred reduced susceptibility to H. pylori infection, while independently increased the risk of gastric cancer in high-risk populations.
Conclusion: Our genetic study of TLR4 rs11536889 in high-risk individuals reveals this polymorphism to be crucial in both mediating H. pylori clearance and the instauration of tumour-promoting inflammation during gastric carcinogenesis.