Host Genetic Variants Associated With Helicobacter pylori Infection: A Meta-Analysis Combined With Functional Annotation.

[BACKGROUND AND AIMS] Helicobacter pylori (H. pylori) is a major risk factor for gastric cancer (GC) and multiple other chronic illnesses. Host genetic factors influence the susceptibility to H. pylori infection, as evidenced by elevated concordance in monozygotic twins and racial disparities independent of socioeconomic status. Leveraging meta-analyses and in silico functional annotation, we investigated host genetic susceptibility to H. pylori infection, and to examine how these variants may influence gastric cancer (GC) risk.

[METHODS] Meta-analyses were performed on 25 candidate genetic variants that had been investigated for the association with H. pylori infection in at least three studies, under five genetic models (allelic, dominant, recessive, homozygous, and heterozygous). Meta-analyses on genome-wide variants were conducted using the allelic model. The Bayesian False-Discovery Probability method and Venice criteria were used to assess genetic association credibility. The Genotype-Tissue Expression (GTEx) and eQTLGen databases were used for cis-expression quantitative trait locus (eQTL) analysis. Differential gene expression in H. pylori-positive (n = 61) vs. -negative (n = 17) samples, and GC (n = 414) vs. non-GC tissues (n = 210) was analyzed leveraging The Cancer Genome Atlas, GTEx, and in-house RNA-sequencing data.

[RESULTS] From a total of 103 studies for systematic review, meta-analyses based on 83 studies identified 47 variants across 18 loci associated with H. pylori susceptibility. These loci encompassed 29 cis-eQTLs affecting expression of 42 genes. Of them, seven genes at three loci-4p14 (TLR10, TLR6, KLHL5, TMEM156), 6p21.33 (HLA-DRB6, C4B), and 14q32.2 (WARS)-were consistently upregulated in H. pylori infection and GC, which may contribute to H. pylori infection-related GC development.

[CONCLUSION] Host genetic predisposition alters the odds of H. pylori infection, demonstrating the importance of host-pathogen crosstalk in infection dynamics and subsequent gastric carcinogenesis.