Worldwide Phylogenetic and Clinical Risk Association of the Helicobacter pylori Outer Membrane Gene hopQ

Helicobacter pylori (Hp) infection is the primary risk factor for gastric cancer, yet the consequences of the infection vary by bacterial and host factors. The outer membrane protein HopQ plays a key role in Hp adhesion, but its genetic diversity and clinical implications are unclear. HopQ-CEACAM interaction facilitates the translocation of the cytotoxin-associated gene A (CagA).

We analyzed hopQ sequences from 1038 Hp strains, mainly from the Helicobacter pylori Genome Project, integrating phylogenetic, genotypic, and disease association analyses. Logistic regression models assessed the association between hopQ genotypes and disease, accounting for cagA status and Hp ancestry.

hopQ genotypes have a strong population structure. The hpAfrica1 and hpNorthAsia (including hspIndigenousAmerica) populations exhibited distinct hopQ patterns, suggesting ancestry-specific pathogenicity. hopQ genotypes were classified as hopQI and hopQII; hopQI was further divided into high-risk and low-risk variants. Ancestry-adjusted analyses showed that hopQI high-risk was associated (odds ratio = 3.1; p < 0.0001) with advanced disease (intestinal metaplasia and gastric cancer combined vs. non-atrophic gastritis), independently of cagA. In contrast, hopQII and hopQI low-risk variants correlated with a reduced risk.

The hopQ diversity is a key determinant of Hp pathogenicity. hopQI high-risk is a predictor of advanced disease, whereas hopQII and hopQI low-risk may be protective. Understanding hopQ variability could improve risk stratification and the targeted therapies for gastric cancer.