Xin Wang ¹ Deming Jiang ² Xiao Zhang ^1* Ran Wang ^1* Fengyi Yang ^1* Chunrong Xie ^1*

• ¹ Department of Neurology, Beijing Huairou Hospital of Traditional Chinese Medicine, Department 3 of Encephalopathy, Beijing Huairou Hospital of Traditional Chinese Medicine, Beijing, China
• ² Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China

Background: Increasing evidence suggests an association between Helicobacter pylori (HP) infection and Parkinson’s disease (PD) and its clinical manifestations, but the causal relationship remain largely unknown. Objective: To investigate the causal relationship between HP infection and PD risk, PD symptoms, and secondary parkinsonism, we conducted two-sample Mendelian randomization (MR). Methods: We obtained summary data from genome-wide association studies for seven different antibodies specific to HP proteins and five PD-related phenotypes. The inverse-variance weighted (IVW), weighted median, weighted mode, and MR-Egger methods were used to assess the causal relationships. Sensitivity analyses were performed to examine the stability of the MR results and reverse MR analysis was conducted to evaluate the presence of reverse causality. Results: Genetically predicted HP antibodies were not causally associated with an increased risk of PD. However, HP cytotoxin-associated gene-A (CagA) and outer membrane protein (OMP) antibody level were causally associated with PD motor subtype (tremor to postural instability/gait difficulty score ratio; β = -0.16 and 0.46, P = 0.002 and 0.048, respectively). HP vacuolating cytotoxin-A (VacA) antibody level was causally associated with an increased risk of PD dementia [odds ratio (OR) = 1.93, P = 0.040]. Additionally, HP OMP antibody level was identified as a risk factor for drug-induced secondary parkinsonism (OR = 2.08, P = 0.033). These results were stable, showed no evidence of heterogeneity or directional pleiotropy, and no evidence of a reverse causal relationship. Conclusions: Our findings indicate that HP infection does not increase the risk of PD, but contributes to PD motor and cognitive symptoms. Different types of HP antibodies affect different symptoms of PD. Eradication of HP infection may help modulate and improve symptoms in PD patients.