Proteome-wide Mendelian randomization identifies therapeutic targets for ankylosing spondylitis

Wenlong Zhao; Peng Fang; Chengteng Lai; Xiaoyu Xu; Yang Wang; Hao Liu; Hui Jiang; Xiaozhou Liu; Jun Liu

doi:10.3389/fimmu.2024.1366736

Proteome-wide Mendelian randomization identifies therapeutic targets for ankylosing spondylitis

Front Immunol. 2024 Mar 19:15:1366736. doi: 10.3389/fimmu.2024.1366736. eCollection 2024.

Authors

Wenlong Zhao^#^{1

2}, Peng Fang^#³, Chengteng Lai^#³, Xiaoyu Xu⁴, Yang Wang³, Hao Liu³, Hui Jiang³, Xiaozhou Liu³, Jun Liu¹

Affiliations

¹ Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
² Department of Orthopedics, The Affiliated Jinling Hospital of Nanjing Medical University, Nanjing, China.
³ Department of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
⁴ Department of Biology, Wake Forest University, North Carolina, NC, United States.

^# Contributed equally.

Abstract

Background: Ankylosing Spondylitis (AS) is a chronic inflammatory disorder which can lead to considerable pain and disability. Mendelian randomization (MR) has been extensively applied for repurposing licensed drugs and uncovering new therapeutic targets. Our objective is to pinpoint innovative therapeutic protein targets for AS and assess the potential adverse effects of druggable proteins.

Methods: We conducted a comprehensive proteome-wide MR study to assess the causal relationships between plasma proteins and the risk of AS. The plasma proteins were sourced from the UK Biobank Pharma Proteomics Project (UKB-PPP) database, encompassing GWAS data for 2,940 plasma proteins. Additionally, GWAS data for AS were extracted from the R9 version of the Finnish database, including 2,860 patients and 270,964 controls. The colocalization analysis was executed to identify shared causal variants between plasma proteins and AS. Finally, we examined the potential adverse effects of druggable proteins for AS therapy by conducting a phenome-wide association study (PheWAS) utilizing the extensive Finnish database in version R9, encompassing 2,272 phenotypes categorized into 46 groups.

Results: The findings revealed a positive genetic association between the predicted plasma levels of six proteins and an elevated risk of AS, while two proteins exhibited an inverse association with AS risk (P _fdr < 0.05). Among these eight plasma proteins, colocalization analysis identified AIF1, TNF, FKBPL, AGER, ALDH5A1, and ACOT13 as shared variation with AS(PPH3+PPH4>0.8), suggesting that they represent potential direct targets for AS intervention. Further phenotype-wide association studies have shown some potential side effects of these six targets (P _fdr < 0.05).

Conclusion: Our investigation examined the causal connections between six plasma proteins and AS, providing a comprehensive understanding of potential therapeutic targets.

Keywords: Mendelian randomization; ankylosing spondylitis; drug target; phenome-wide association study; plasma proteins.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Blood Proteins
Cell Cycle Proteins
Humans
Mendelian Randomization Analysis
Proteome*
Spondylitis, Ankylosing* / drug therapy
Spondylitis, Ankylosing* / genetics
Tacrolimus Binding Proteins

Substances

Proteome
Cell Cycle Proteins
Blood Proteins
FKBPL protein, human
Tacrolimus Binding Proteins

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Health Commission Medical Research Project of Jiangsu Province (M2021051) and National Natural Science Foundation of China (No. 82172486).