What type of study is this?

This is a Prospective Study study (also classified as: Genome-Wide Interaction Analysis, Mendelian Randomization).

September 10, 2025Open Access

Helicobacter pylori, peptic ulcer disease, and colorectal cancer: a prospective study with genome-wide interaction analysis and Mendelian randomization

ZWZiqi WanChinese Academy of Medical Sciences & Peking Union Medical College JMJiarui MiSir Run Run Shaw Hospital XBXiaoyin BaiMinistry of Education of the People's Republic of China

Key Points

Seropositivity for helicobacter pylori did not significantly increase colorectal cancer incidence over 15 years, with an adjusted HR of 0.76.
No significant genetic variants were identified interacting with HP serology to modify colorectal cancer risk.
The causal relation of peptic ulcer disease on colorectal cancer was significant for East Asian ancestry with an OR of 1.47, not for European ancestry.
Results suggest that helicobacter pylori's association with colorectal cancer varies across populations, requiring further investigation.

Abstract

Helicobacter pylori (HP) is a well-established gastric carcinogen. But it shows inconsistent association with colorectal cancer (CRC) across diverse study populations. We investigated participants from the UK biobank. HP-seropositive cases and peptic ulcer diseases (PUDs) were identified. The primary outcome was CRC. We estimated the cumulative incidence using a competing risk model measured by the hazard ratios (HRs) with 95% confidence intervals (CIs) with adjustment. We did a genome-wide interaction analysis to identify genetic variants that modify HP-serology-CRC associations with exploratory gene-based and gene-set analysis. We further did a bidirectional two-sample Mendelian randomization (MR) to investigate the causal relation of gene-proxied PUD on CRC of the European ancestry and of the East Asian ancestry. We included 492,490 participants with a median follow-up of 14.7 years. HP sero-positivity did not significantly increase the incidence of CRC (adjusted HR = 0.76, 95% CI 0.53 − 1.10, p = 0.15). No SNP was identified to be significantly interacted with HP serology to modify CRC risk. The risk of CRC for PUD cases was not significantly different from non-PUD cases after adjusting (adjusted HR = 0.88, 95% CI 0.76 − 1.02, p = 0.09). The gene-proxied PUD causally increased the incidence of colon cancer of the East Asian ancestry (OR = 1.47, 95% CI = 1.00 − 2.15, p = 0.047), not of the European ancestry (OR = 1.03, 95% CI = 0.79 − 1.34, p = 0.82). Neither seropositivity for HP nor PUD showed a robust increase on the risk of CRC in a 15-year follow-up. The causal relation of PUD on CRC was significant of East Asian ancestry, not of European ancestry. • Helicobacter pylori (HP) shows inconsistent association with colorectal cancer (CRC) across diverse study populations. • Neither seropositivity for HP nor peptic ulcer diseases (PUD) showed a robust increase on the risk of CRC in a 15-year follow-up. The causal relation of PUD on CRC was significant of East Asian ancestry, not of European ancestry. • HP shows a population-dependent association with CRC.

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