Causal relationship between infection and gastrointestinal cancers: a multivariable Mendelian randomization study

Abstract

Background: The association between infection and gastrointestinal cancers (GICs) were indicated by pervious studies, but the direct causal link between infection and GIC remains largely unknown. We performed multivariable mendelian randomization (MR) analyses in order to investigate the causal relationship between genetically predicted infection and the GIC risk.

Methods: Instrumental variables (IVs) for several common pathogens including Helicobacter pylori (H. pylori), human papillomavirus (HPV) and herpesvirus were retrieved from different genome-wide association studies (GWAS), respectively. The summary-level statistics of GIC were obtained from the European heritage. The inverse-variance weighted MR was conducted as the main approach followed by multiple sensitivity analyses. Twenty datasets of seropositivity and antigen antibody levels against infectious pathogens were utilized as IVs. Four GWAS datasets of GIC were retrieved.

Results: It is notable that no evidence demonstrated the causal relationship of H. pylori with gastric cancer (GC) in European ancestry. Several infectious agents were proposed as protective factors for GIC in European population. MR results showed that anti-Epstein-Barr virus (EBV) immunoglobulin G (IgG) seropositivity [odds ratio (OR) =0.32, 95% confidence interval (CI): 0.11-0.95] and EBV ZEBRA antibody levels (OR =0.74, 95% CI: 0.58-0.94) was negatively correlated with the risk of GC. Genetical predisposition of herpes simplex virus (HSV) infection showed a negative correlation with the risk of colon cancer. Similarly, increased levels of H. pylori GroEL antibody also exhibited as a protective factor for colorectal cancer (CRC; OR =0.80, 95% CI: 0.69-0.93).

Conclusions: The results reflected differential patterns of geographically distribution and pathogenic role of infectious pathogens among diverse population. Human and infection pathogens co-evolution shape the risk of cancers.

Keywords: Mendelian randomization (MR); gastrointestinal cancers (GICs); genetic epidemiology; infection.