Exploring potential drug targets for SLE through Mendelian randomization and network pharmacology
Yanan Xu, Zelin Wang, Tiewen Jia, Shufen Liang
Abstract
Background
Systemic lupus erythematosus (SLE) is a complex and incurable autoimmune disease, so several drug remission for SLE symptoms have been developed and used at present. However, treatment varies by patient and disease activity, and existing medications for SLE were far from satisfactory. Novel drug targets to be found for SLE therapy are still needed.
Introduction
Systemic lupus erythematosus (SLE) is a chronic immune system disorder with abnormalities of immune cells, manifesting as the dysregulated immune system, characterized by overactivated B and T cells attacking normal cells and tissues, which affects multiple organs and systems [1]. According to published epidemiological surveys, the incidence and prevalence of SLE are high in North America (241 per 100,000 people) [2].
Method
2.1. SLE and proteins of CSF and plasma data source
In this study, CSF pQTL was selected from Yang’s study, which recruited 713 proteins from Washington University School of Medicine in St. Louis [13]. Plasma pQTL was obtained from Cheng’s study containing 1699 proteins from summary of 5 GWAS [5]. 4907 proteins and 18084 pQTL from the deCODE database which recruited 35,559 Icelanders from 24 August 2000 until 11 January 2019, were used for replication verification [14].
Results
3.1. MR analysis
The causal relationship of CSF and plasma proteins on SLE were assessed using two-sample MR analysis. At Bonferroni correction (p<0.05/888), the result revealed that four potential causal proteins were finally obtained for SLE (Table 1 and S2 Fig). Intercellular adhesion molecule 1 (sICAM-1)(P = 4.62×10−5, OR = 0.49(0.35, 0.69)), Low affinity immunoglobulin gamma Fc region receptor II-b (FCG2B) (P = 7.63×10−11, OR = 0.57(0.48, 0.67)), and Protein phosphatase 3 catalytic subunit alpha (PPP3CA); Calcineurin subunit B type 1 (PPP3R1)(P = 5.47×10−7, OR = 0.66(0.57, 0.78)), Intercellular adhesion molecule 1 (ICAM1)(P = 4.62×10−5, OR = 0.90(0.86, 0.95)).
Discussion
In this study, we used CSF and plasma proteins for MR analysis and co-localization analysis to find proteins causally associated with SLE. We used cis-pQTL as IV because it directly affects transcription and translation, and reduces horizontal pleiotropy [21]. Preliminary analyses of the proteins provided four causal proteins. At the same time, we found one identical protein, ICAM1, in CSF and plasma. Because the results of MR analysis may be affected by reverse causality, we corroborated each other by Steiger filtering and reverse causality detection to minimize the error. The results showed that the proteins analyzed by MR did not have reverse causality.
Discussion
In this study, we used CSF and plasma proteins for MR analysis and co-localization analysis to find proteins causally associated with SLE. We used cis-pQTL as IV because it directly affects transcription and translation, and reduces horizontal pleiotropy [21]. Preliminary analyses of the proteins provided four causal proteins. At the same time, we found one identical protein, ICAM1, in CSF and plasma. Because the results of MR analysis may be affected by reverse causality, we corroborated each other by Steiger filtering and reverse causality detection to minimize the error. The results showed that the proteins analyzed by MR did not have reverse causality.
Citation: Xu Y, Wang Z, Jia T, Liang S (2025) Exploring potential drug targets for SLE through Mendelian randomization and network pharmacology. PLoS ONE 20(1): e0316481. https://doi.org/10.1371/journal.pone.0316481
Editor: Wesam Gouda, Prime Hospital LLC, UNITED ARAB EMIRATES
Received: July 22, 2024; Accepted: December 11, 2024; Published: January 17, 2025
Copyright: © 2025 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Protein pQTL data from original literature(5, 13, 14). SLE data from the IEU Open GWAS (https://gwas.mrcieu.ac.uk/; Accession numbers: ebi-a-GCST003156 and ebi-a-GCST90011866).
Funding: The author(s) received no specific funding for this work.
Competing interests: No competing interests to declare.
Abbreviations: SLE, Systemic lupus erythematosus; MR, Mendelian randomization; pQTL, protein quantitative trait loci; GWAS, published genome-wide association studies; CSF, cerebrospinal fluid; PPI, Protein-protein interaction; LD, linkage disequilibrium; NSAIDs, nonsteroidal anti-inflammatory drugs; sICAM-1, Intercellular adhesion molecule 1; FCG2B, Fc region receptor II-b; PPP3CA, Protein phosphatase 3 catalytic subunit alpha; PPP3R1, Calcineurin subunit B type 1; ACE, Angiotensin-converting enzyme; SIRT1, Silent information regulator 2 related enzyme 1; APP, amyloid precursor protein
