Tumor Necrosis Factor Inhibition and Parkinson Disease: A Mendelian Randomization Study.

Objective To evaluate the effects of long-term tumor necrosis factor (TNF) inhibition on the risk and age at onset of Parkinson disease (PD), we performed a two-sample Mendelian randomization study using genome-wide association studies (GWAS) summary statistics. Methods Genetic variants in the vicinity of TNFRSF1A, the gene encoding TNF receptor 1 (TNFR1), were identified as predictive of pharmacologic blockade of TNFR1 signaling by anti-TNF therapy, based on genetic associations with lower circulating C-reactive protein (CRP; GWAS N = 204,402). The effects of TNF-TNFR1 inhibition were estimated for PD risk (Ncases/controls = 37,688/981,372) and age at PD onset (N = 28,568) using GWAS data from the International Parkinson9s Disease Genomics Consortium and 23andMe, Inc. To validate variants as proxies of long-term anti-TNF treatment, we also assessed whether variant associations reflected anticipated effects of TNFR1 inhibition on Crohn disease, ulcerative colitis and multiple sclerosis risk (N = 38,589-45,975). Results TNF-TNFR1 signaling inhibition was not estimated to affect PD risk (odds ratio/OR per 10% lower circulating CRP = 0.99; 95% CI: 0.91–1.08) or age at onset (0.13 years later onset; 95% CI: −0.66 to 0.92). In contrast, genetically-indexed TNF-TNFR1 signaling blockade predicted reduced risk of Crohn disease (OR = 0.75; 95% CI: 0.65–0.86) and ulcerative colitis (OR = 0.84; 95% CI: 0.74–0.97) and increased multiple sclerosis risk (OR = 1.57; 95% CI: 1.36–1.81). Findings were consistent across models using different genetic instruments and MR estimators. Conclusions Our findings do not imply that TNF-TNFR1 signaling inhibition will prevent or delay PD onset. Classification of evidence This study provides Class II evidence that TNF-TNFR1 signaling inhibition is not associated with the risk or age at onset of PD.