TNF Treatment Fails to Prevent or Delay Parkinson Disease in Clinical Trial


Genetically-indexed inhibition of TNF-TNFR1 signaling was predicted to reduce the risk of Crohn’s disease and ulcerative colitis, and increased the risk of multiple sclerosis.

Xioying Kang, MPH, BSc

Xioying Kang, MPH, BSc

This article was originally published in NeurologyLive.

A recent study failed to show tumor necrosis factor receptor 1 (TNF-TNFR1) signaling inhibition can prevent or delay the risk or age at onset of Parkinson disease (PD).

Lead author Xioying Kang, MPH, BSc, department of medical epidemiology and biostatistics, Karolinka Institut, and colleagues found that TNF-TNFR1 signaling inhibition was not estimated to affect PD risk (odds ratio [OR] per 10% lower circulating C-reactive protein [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).

To the authors’ knowledge, this was the first Mendelian randomization (MR) study to address whether exposure to TNF inhibitors affect PD.

"Human genetics provides valuable guidance for therapeutic programs because the chances of successful drug development are substantially improved when genetic evidence links a drug’s target to an indication for therapeutic use,” Kang et al wrote. “Hence, our findings should be considered as part of discourse on the repurposing potential of TNF inhibitors for PD prevention and treatment, particularly if/when selective inhibitors of TNF-TNFR1 signaling become available.”

A total of 23 single nucleotide polymorphisms (SNPs) in the vicinity of the gene TNFRSF1a, which encodes TNFR1, the principal effector of pro-inflammatory signaling following TNF agonism were present in the CRP data (genome-wide association studies [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.

Researchers found, however, that genetically-indexed inhibition of TNF-TNFR1 signaling was predicted to reduce the risk of Crohn’s disease (OR, 0.75; 95% CI, 0.65–0.86) and ulcerative colitis (OR, 0.84; 95% CI, 0.74–0.97), and increased the risk of multiple sclerosis (MS; OR, 1.57; 95% CI, 1.36–1.81), as the authors noted was expected.

In secondary analyses, the more liberal linkage disequilibrium (LD) clumping yielded 4 correlated SNPs associated with CRP at false discovery rate-corrected (<.05), 1 of which was not associated with either white blood cell count (WBC; P = .07) or mean platelet volume (MPV; P = .95) and was therefore removed.

The other 3 variants were associated with all 3 inflammatory markers for secondary MR models.

Using adapted inverse variance weighting (IVW) methodology to account for correlations between the variants, MR estimates based on the 3 SNPs remained consistent with the main results that neither PD risk nor age at onset were predicted to be affected by TNF-TNFR1 blockade.

Kang and colleagues also found that there were no associations of the genotypes of implicated functional variant (rs1800693) with PD risk (OR, 1.00 per TNF-inhibiting allele; 95% CI, 0.98–1.02) or age at onset (0.05 years of increase per TNF-inhibiting allele; 95% CI, –0.13 to 0.24), despite strong associations of this SNP with other inflammatory traits.

The study, “Tumor Necrosis Factor Inhibition and Parkinson Disease: A Mendelian Randomization Study,” was published online in Neurology.

Related Videos
Addressing HS Risks at the Genetic Level, with Kai Li, BSc
Maternal Hidradenitits Suppurativa Linked to Neonatal Mortality, Pediatric Hospitalization Risk
Reviewing 2023 with FDA Commissioner Robert M. Califf, MD
A Year of RSV Highs and Lows, with Tina Tan, MD
Gestational Low-Dose Aspirin Does Not Increase Risk of IBD Flares in Women
Karen Shen, PhD: How COVID-19 Impacted Nursing Homes Staff Turnover Rates
Karen Shen, PhD: High Turnover Rates in Nursing Homes
Riha Bhatt, MD: Mimickers and Concurrent Diseases in Pediatric IBD
Elizabeth Spencer, MD: Precision Medicine in Pediatric IBD
Anita Clayton, MD: Zuranolone for Postpartum Depression
© 2024 MJH Life Sciences

All rights reserved.