# Identifying Druggable Inflammatory Proteins Causally Contributing to Parkinson's Disease

## TL;DR

This study identifies six inflammatory proteins that influence Parkinson's disease risk, offering new therapeutic targets.

## Contribution

The study uses Mendelian randomization to identify causal inflammatory proteins linked to Parkinson's disease.

## Key findings

- Six circulating inflammatory proteins were found to be causally associated with Parkinson's disease.
- Three proteins (TNFRSF9, Flt3L, TGF-α) were protective, while three (IL-18, CD6, IL-17A) increased PD risk.
- IL-18 and IL-17A are highlighted as potential therapeutic targets for Parkinson's disease.

## Abstract

Inflammatory mechanisms are critically engaged in the pathogenesis of Parkinson's disease (PD). The objective of this research was to detect circulating inflammatory proteins that potentially elevate the susceptibility to PD.

A two‐sample Mendelian randomization (MR) analysis was performed to determine the causal effects of 91 circulating inflammatory proteins (14,824 participants) on PD (33,674 cases and 449,056 controls) by using genome‐wide association study (GWAS) summary data. The MR analysis utilized three complementary approaches: inverse variance weighted (IVW), weighted median, and MR‐Egger. Among them, IVW was the principal method. Additionally, we utilized the Drug‐Gene Interaction Database (DGIdb) to select potential therapeutic targets for proteins associated with PD.

Our MR analysis revealed that six circulating inflammatory proteins were associated with PD. Three of them conferred a protective effect against PD, including TNFRSF9 (odds ratio [OR]: 0.83, 95% confidence interval [CI]: 0.74–0.92, p = 5.09 × 10−4), Flt3L (OR: 0.89, 95% CI: 0.81–0.99, p = 0.026), and TGF‐α (OR: 0.86, 95% CI: 0.75–0.99, p = 0.04). Three additional proteins were connected with an increased risk of PD, namely, IL‐18 (OR: 1.13, 95% CI: 1.02–1.24, p = 0.016), CD6 (OR: 1.08, 95% CI: 1.01–1.16, p = 0.023), and IL‐17A (OR: 1.18, 95% CI: 1.01–1.38, p = 0.033).

Our research revealed the pathogenic contribution of several inflammatory proteins to PD development, providing new perspectives on the mechanisms and therapy of PD.

Six circulating inflammatory proteins affect Parkinson's disease risk. IL‐18 and IL‐17A are potential therapeutic targets, offering new insights for mechanisms and therapy.