Causal associations of circulating Helicobacter pylori antibodies with stroke and the mediating role of inflammation.

Abstract

Observational studies have shown that Helicobacter pylori (H. pylori) infection and H. pylori antibodies are associated with an increased risk of stroke. However, which and how H. pylori antibodies serve as the causal determinant of the development of stroke remains largely unknown. Genome-wide association studies (GWAS) on seven different antibodies of H. pylori-specific proteins, stroke, and stroke subtypes were included in this study. Mendelian randomization (MR) and multivariable MR (MVMR) analysis were performed to assess the causal associations between H. pylori antibodies and the development of stroke and to determine the potential mechanisms underlying the associations. Genetically predicted serum H. pylori vacuolating cytotoxin-A (VacA) antibody level was associated with an increased risk of all-cause stroke (odds ratio [OR] = 1.04, 95% CI 1.01-1.07, P = 0.017) and cardioembolic stroke (CES, OR = 1.11, 95% CI 1.04-1.18, P = 0.001). The results of multivariable MR (MVMR) showed that C-reactive protein (CRP), but not monocyte chemoattractant protein-1 and peptic ulcer, mediated the causal effects of VacA-positive H. pylori infection on all-cause stroke and CES. No strong causal associations were found between other H. pylori antibodies and stroke and its subtypes. Our results demonstrate that H. pylori VacA antibody is the only causal determinant associated with the risk of stroke in the spectrum of H. pylori-related antibodies, in which CRP may mediate the association. This study suggests that inhibition of the CRP signaling pathway may reduce the risk of stroke in patients with VacA-positive H. pylori infection.