Homocysteine as a biomarker in arthritis and depression: Evidence from NHANES and gene expression studies

Rheumatoid arthritis (RA) and major depressive disorder (MDD) are interconnected conditions with a growing incidence, yet the mechanism that links them remains uncertain. This research focused on identifying the overlapping genes and pathogenic processes of RA and MDD via bioinformatics and National Health and Nutrition Examination Survey (NHANES) validation.

The Gene Expression Omnibus (GEO) database provided RA and MDD-related data from datasets GSE715573 and GSE76826. To identify common differentially expressed genes (co-DEGs) between RA and MDD, a differential analysis was carried out with |logFC| > 0.5 and p < 0.05 as the screening thresholds. GEO 2R was used to screen the differential genes applied to construct volcano diagrams; Genome Ontology and Kyoto Encyclopedia of Genes and Genomes, and Database for Annotation, Visualization, and Integration Discovery were used to explore the functions and regulatory pathways of co-DEGs. In addition, we examined data from the NHANES between 2005 and 2006 to verify the link between Hcy and depression symptoms in arthritis patients.

Differential gene expression analysis identified 142 downregulated and 102 upregulated genes in RA peripheral blood, 935 upregulated genes, and 409 downregulated genes in MDD peripheral blood. Ten common genes (VNN1, CKAP4, CLEC4D, F5, CBS, TNFRSF25, NELL2, RNASE2, TXN, and SRPK1) were identified, and abnormal biosynthesis and catabolism process of cysteine was found as a comorbid link between RA and MDD. Population-level NHANES analysis confirmed higher serum Hcy associated with more severe depression symptoms in arthritis patients.

This investigation reveals the overlapping genetic signatures that explain the common manifestations and the association between RA and MDD. The two diseases share DEGs of CBS, VNN1, and TXN, which indicates that the abnormal metabolic pathway of homocysteine is a common pathogenic pathway in RA and MDD. NHANES proved an association between Hcy and depression in arthritis participants, indicating that Hcy may be an important biomarker for intervention to delay or ultimately prevent comorbidities, and highlights the importance of dietary interventions such as supplementing folate. The knowledge may help develop novel therapies and a potential strategy to prevent or delay the coexistence of depression and arthritis, especially RA.