Mendelian randomization analysis identifies potential drug targets for spinal osteoarthritis

Abstract

BACKGROUND: Spinal osteoarthritis is a common degenerative spinal disease that severely affects quality of life of patients, but its exact molecular mechanism remains unclear. OBJECTIVE: To identify plasma proteins related to spinal osteoarthritis through Mendelian randomization analysis and provide a reference for finding new potential therapeutic targets in this disease field. METHODS: Protein data were obtained from the deCODE Genetics database (A total of 35 559 Icelandic individuals were included, and genetic association information of 4 907 plasma proteins was detected, https://www.decode.com/summarydata/). Spinal osteoarthritis data were obtained from the Osteoarthritis Genetics Consortium (A total of 826 690 samples are available for free download via https://msk.hugeamp.org/downloads.html). All data are open source and comply with ethical requirements. Wald ratio or inverse variance weighting was used to assess the causal relationship between 4 907 plasma proteins and spinal osteoarthritis, with Bonferroni correction applied to the P-values. In addition, Steiger directional test was performed to exclude reverse causality; colocalization analysis to exclude linkage disequilibrium; phenotype scanning to exclude horizontal pleiotropy; and external validation to exclude chance findings. Finally, the online analysis tool Enrichr was used to screen small-molecule compounds targeting causal proteins, and molecular docking was performed for the top-ranked compounds to predict their binding modes and energies, thereby identifying the most stable and possible binding modes. RESULTS AND CONCLUSION: Among 4 907 proteins, 1 878 significant protein quantitative trait loci for 1 553 proteins were screened. After Mendelian randomization analysis, four proteins were identified to have strong causal relationships with spinal osteoarthritis: monocyte CD14, interleukin-12 subunit beta (IL12B), hepatocyte growth factor-like protein (MST1), and Semaphorin-4A (SEMA4A). IL12B was negatively correlated with spinal osteoarthritis, while the others were positively correlated. Drug prediction results showed that tesmilifene targeting CD14, montelukast targeting IL12B, naphthylamine targeting MST1, and colchicine targeting SEMA4A all exhibited good binding abilities in molecular docking, with the lowest binding energies all below -6.0 kJ/mol. Comprehensive analysis indicates that these four plasma proteins may serve as potential biomarkers or drug targets for clinical screening, prevention, and intervention of spinal osteoarthritis, and also provide theoretical basis and reference value for related research in the Chinese population.

1. Introduction

Osteoarthritis can affect multiple joints, with the knee having the highest incidence, followed by the cervical spine, hand, ankle, and hip joints [1-2]. Among these, spinal osteoarthritis is a degenerative joint disease occurring in various segments of the spine, mainly including degeneration of the facet joint cartilage, osteophyte formation of the articular processes, and chronic degenerative changes of adjacent structures. It often manifests as chronic low back pain and limited mobility, severely affecting patients' quality of life and work capacity [3-4]. Although considerable research has been conducted on osteoarthritis, its pathogenesis remains unclear, and there is currently no effective treatment to delay disease progression [5-6]. Therefore, in-depth exploration of the pathogenesis of osteoarthritis and identification of potential intervention targets are crucial for both experimental research and clinical treatment.

Proteins in the body are direct executors of cellular functions and play key roles in maintaining health and disease states [7]. Plasma proteins are mainly composed of proteins secreted or released by cells into the blood circulation, which play roles in signal transduction and regulation of biological functions between different tissues [8]. Dysregulation of plasma protein expression is a common feature of many diseases [9-10]. Circulating proteins play important roles in disease development, making them key candidate molecules for exploring therapeutic targets for osteoarthritis. In addition, plasma sample collection is relatively simple and non-invasive, and is rich in genetic information, making it a preferred material for screening population molecular markers.

Genome-wide association studies (GWAS) are important tools for revealing the interaction between genetic and environmental factors in disease occurrence [11]. Using GWAS to investigate circulating protein levels has identified a large number of protein quantitative trait loci (pQTL) [12]. Meanwhile, Mendelian randomization uses single nucleotide polymorphisms (SNPs) as instrumental variables to assess the potential causal effect of exposure on outcome. Mendelian randomization analysis can effectively control confounding bias and more objectively infer causality [13-15]. This method is currently widely used to identify drug targets and repurpose existing drugs [16].