Integrative analyses of mendelian randomization and bioinformatics reveal casual relationship and genetic links between COVID-19 and knee osteoarthritis

Abstract

Background: Clinical and epidemiological analyses have found an association between coronavirus disease 2019 (COVID-19) and knee osteoarthritis (KOA). Infection with COVID-19 may increase the risk of developing KOA.

Objectives: This study aimed to investigate the potential causal relationship between COVID-19 and KOA using Mendelian randomization (MR) and to explore the underlying mechanisms through a systematic bioinformatics approach.

Methods: Our investigation focused on exploring the potential causal relationship between COVID-19, acute upper respiratory tract infection (URTI) and KOA utilizing a bidirectional MR approach. Additionally, we conducted differential gene expression analysis using public datasets related to these three conditions. Subsequent analyses, including transcriptional regulation analysis, immune cell infiltration analysis, single-cell analysis, and druggability evaluation, were performed to explore potential mechanisms and prioritize therapeutic targets.

Results: The results indicate that COVID-19 has a one-way impact on KOA, while URTI does not play a causal role in this association. Ribosomal dysfunction may serve as an intermediate factor connecting COVID-19 with KOA. Specifically, COVID-19 has the potential to influence the metabolic processes of the extracellular matrix, potentially impacting the joint homeostasis. A specific group of genes (COL10A1, BGN, COL3A1, COMP, ACAN, THBS2, COL5A1, COL16A1, COL5A2) has been identified as a shared transcriptomic signature in response to KOA with COVID-19. Imatinib, Adiponectin, Myricetin, Tranexamic acid, and Chenodeoxycholic acid are potential drugs for the treatment of KOA patients with COVID-19.

Conclusions: This study uniquely combines Mendelian randomization and bioinformatics tools to explore the possibility of a causal relationship and genetic association between COVID-19 and KOA. These findings are expected to provide novel perspectives on the underlying biological mechanisms that link COVID-19 and KOA.

Keywords: Acute upper respiratory tract infection (URTI); Bioinformatics analysis; COVID-19; Knee osteoarthritis (KOA); Mendelian randomization (MR).

Fig. 1

Work flow

Fig. 2

Potential causal associations of COVID-19, URTI and KOA in MR analyses

Fig. 3

Identification of common DEGs. A-B Venn diagram identifies coupregulated and codownregulated DEGs of KOA, COVID-19, and URTI. C GO enrichment analysis of 91 DEGs

Fig. 4

A Venn diagrams identify the intersection of genes between WGCNA module genes and common DEGs. B Visualization of the protein‒protein interaction (PPI) network of the 17 genes. Red indicates upregulated DEGs and blue downregulated genes in COVID-19 and KOA

Fig. 5

Analysis of immune infiltration associated with COVID-19 and KOA. A-B Box plot showing the distribution of immune cells in the COVID-19 and KOA samples, A for COVID-19 and B for KOA. The round dots indicate the outliners. C-D The correlation between the nine core genes and immune cells, C for COVID-19 and D for KOA. The symbol * (A-D) represents p-value < 0.05, **p-value < 0.01, ***p-value < 0.001, **** p-value < 0.0001

Fig. 6

A TF networks of core genes, the yellow line denotes promotion and the grey line inhibition. Only the nodes with degrees exceeding 10 are presented by their names. B mRNA‒miRNA networks of hub genes, with red indicating mRNA and blue miRNA. C Expression profiles of the nine core genes in different cellular subtypes of cartilage tissue. D Potential therapeutics for KOA patients with COVID-19