RT Journal Article
T1 Tumor Necrosis Factor Inhibition and Parkinson Disease: A Mendelian Randomization Study.
A1 Kang, Xiaoying
A1 Ploner, Alexander
A1 Pedersen, Nancy L
A1 Bandres-Ciga, Sara
A1 Noyce, Alastair J
A1 Wirdefeldt, Karin
A1 Williams, Dylan M
AB 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 2-sample Mendelian randomization study using genome-wide association studies (GWAS) summary statistics. 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 Parkinson's 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). TNF-TNFR1 signaling inhibition was not estimated to affect PD risk (odds ratio [OR] per 10% lower circulating CRP = 0.99; 95% confidence interval [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 Mendelian randomization estimators. Our findings do not imply that TNF-TNFR1 signaling inhibition will prevent or delay PD onset. This study provides Class II evidence that TNF-TNFR1 signaling inhibition is not associated with the risk or age at onset of PD.
PB Wolters Kluwer Health
YR 2020
FD 2020-12-11
LK http://hdl.handle.net/10668/17200
UL http://hdl.handle.net/10668/17200
LA en
NO Kang X, Ploner A, Pedersen NL, Bandres-Ciga S, Noyce AJ, Wirdefeldt K, et al. Tumor Necrosis Factor Inhibition and Parkinson Disease: A Mendelian Randomization Study. Neurology. 2021 Mar 23;96(12):e1672-e1679.
NO Study funded by the Swedish Research Council (grant 2017-02175). Dylan M. Williams is funded by the United Kingdom’s Medical Research Council (MC_UU_00019/2)
DS RISalud
RD Apr 7, 2025