Genome-wide association and HLA association analyses identify determinants of Helicobacter pylori infection

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Helicobacter pylori (H. pylori) infection contributes significantly to the disease burden, especially in East Asia. While host genetic factors influence susceptibility, genetic heterogeneity across populations and the lack of genome-wide scans in East Asians underscore the need for large-scale investigations. We conducted a genome-wide association study (GWAS) followed by HLA allele association analyses in a large Taiwanese cohort to identify genetic determinants of H. pylori infection risk. Genome-wide genotyping data from 106,581 unrelated Taiwan Biobank participants linked to nationwide medical records were analyzed. Classical HLA alleles were imputed to refine association signals, and in silico binding affinity predictions of selected HLA-DQ heterodimers with the H. pylori virulence factors CagA and VacA were performed to assess their potential functional relevance. We identify 78 genome-wide significant variants mapping to the HLA class II region. Three HLA class II alleles—DQA1*01:03, DRB1*08:03, and DQB1*06:01—are associated with increased infection risk (corrected p-values of 1.51 × 10−5, 3.79 × 10−4, and 6.09 × 10−3, respectively), whereas DQB1*05:02 confers a protective effect (corrected p = 0.050). Peptide-binding predictions show strong binding between HLA-DQA1*01:03-DQB1*06:01 and key H. pylori antigens, suggesting a potential molecular basis for HLA-mediated susceptibility. These findings provide insights into the genetic predisposition to H. pylori infection and suggest a role for HLA class II polymorphisms in modulating host immune responses, particularly in East Asian populations. Helicobacter pylori (H. pylori) is a common stomach bacterium that can cause stomach ulcers and cancer, especially in East Asia. However, it is still unclear why some people become infected more easily than others. We studied the genetic information of more than 100,000 Taiwanese individuals to look for inherited differences that affect the risk of infection. We found that changes in genes involved in the body’s immune system were linked to either a higher or lower risk of H. pylori infection. Our results also suggest that these genetic differences may influence how the immune system recognizes the bacterium. These results improve our understanding of why some people are more susceptible to H. pylori infection in East Asian populations. Kao et al. conduct a genome-wide association study and HLA allele analysis in more than 100,000 Taiwanese individuals to identify genetic factors associated with H. pylori infection. They identify both risk-associated and protective HLA class II alleles, providing insights into how host genetic variation may influence susceptibility to H. pylori infection.

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