Host Genetic Determinants Associated With Helicobacter pylori Eradication Treatment Failure: A Systematic Review and Meta-analysis

Abstract

Background & aims: Helicobacter pylori infects approximately 50% of individuals worldwide. Successful H pylori eradication is associated with reduced risk of gastric cancer and peptic ulcer disease, among other conditions. We hypothesized that host genetic determinants, especially those affecting gastric pH, might contribute to eradication therapy failure, particularly when treatment adherence and antibiotic susceptibility are confirmed. We aimed to conduct a meta-analysis of host genetic variants associated with H pylori eradication failure.

Methods: We searched the literature for studies comparing posttreatment H pylori eradication failure vs success (outcome) according to host genetic polymorphisms (exposure). Reference groups were defined according to genotypes (or corresponding phenotypes) hypothesized to be associated with successful eradication. We pooled estimates using a random-effects model and performed comprehensive sensitivity analyses.

Results: We analyzed 57 studies from 11 countries; the vast majority analyzed CYP2C19 polymorphisms. Among individuals prescribed eradication regimens with proton pump inhibitors predominantly CYP2C19 metabolized, enhanced vs poor metabolizer phenotypes were associated with a 2.52-fold significantly higher likelihood of eradication failure and 4.44-fold significantly higher likelihood when treatment adherence and H pylori clarithromycin susceptibility (if relevant) were confirmed. There was no association between CYP2C19 variants and eradication failure if proton pump inhibitors less metabolized by or that bypass CYP2C19 metabolism were used. IL1B polymorphisms that are vs are not associated with less gastric acid suppression were associated with 1.72-fold significantly higher likelihood of eradication failure. There was no association between MDR1 polymorphisms and H pylori eradication failure. The certainty of evidence was moderate.

Conclusion: Based on meta-analysis, we identified host genetic polymorphisms significantly associated with H pylori eradication failure; host genetics might underlie eradication failure among treatment-adherent individuals with confirmed H pylori antibiotic susceptibility.

Keywords: Antibiotic Resistance; Genome-Wide Association Studies; Pharmacogenetics; Precision Medicine; Stomach Neoplasm.

Figure 1.

PRISMA diagram of study inclusion

Figure 2A–2C. (CYP2C19: PPI type).

Meta-analysis of studies analyzing the association between enhanced metabolizer CYP2C19 phenotypes (i.e. URM/RM/EM, variant group) vs. PM only phenotype (wild-type/reference) and H. pylori eradication failure, when including only studies/study arms using OMZ, PPZ, LNZ (Figure 2A; low heterogeneity, I² 21.7%, P=0.15) and EMZ (Figure 2B; low heterogeneity, I² 0%, P=0.87) or RAL (Figure 2C; low heterogeneity, I² 9.8%, P=0.34)

Figure 3A–3B. (CYP2C19: PPI type, clarithromycin susceptibility).

Meta-analysis of studies analyzing the association between enhanced metabolizer CYP2C19 phenotypes (i.e. URM/RM/EM, variant group) vs. PM only phenotype (wild-type/reference) and H. pylori eradication failure, when including studies where clarithromycin susceptibility was confirmed, or resistance rates were confirmed ≤15% if clarithromycin-based regimens were used. Figure 3A: studies/study arms using OMZ, PPZ, LNZ (low heterogeneity, I² 20.4%, P=0.27); Figure 3B: studies/study arms using EMZ or RAL (low heterogeneity, I² 17.3%, P=0.29).

Figure 4 (IL-1B).

Meta-analysis of studies analyzing the association between IL-1B polymorphisms and H. pylori eradication treatment failure. Compared to the TC or TT genotype (higher IL-1B expression, more potent acid suppression), the CC genotype was associated with a 1.72-fold significantly higher likelihood of eradication failure (moderate, statistically significant heterogeneity I² 51.5%, P=0.05). Note, this analysis excludes the two studies by Matsuo et al. and Ishida et al., and includes only the IL-1B-31 genetic polymorphism from the Hong et al. study to avoid potential duplicates (see text for full details and supplemental material for additional IL-1B analyses)