COX-2-8473 T>C gene variant (rs5275) is associated with depression and nausea in migraineurs by increasing inflammation through MyD88/MAP2K3/COX-2

Abstract

Abstract Migraine is a complicated neurological disorder. Cyclooxygenase-2 (COX-2) is a crucial enzyme involved in the pain response and inflammation. COX-2 modulation is necessary in migraine therapy. We hypothesized that the COX-2-8473 T > C (rs5275) gene variant might be related to migraine, depression, and nausea. In this case-control research, 100 migraineurs and 100 control cases in Bushehr province, Iran, were compared. Genomic DNA from peripheral blood was purified, and genotyping of the COX-2-8473 T > C (rs5275) polymorphism was evaluated by the PCR-RFLP technique. The SPSS software package was employed to conduct statistical tests. Then, the raw microarray data from the brain of depressed patients was used to find gene expression patterns and associated cellular pathways in depression disease. Finally, enrichment and protein-protein interaction analyses were conducted for upregulated genes. We demonstrated a positive correlation between the COX-2-8473 T > C variant and an elevated risk for progression of migraine, depression, and nausea in migraineurs. Carriers of COX-2-8473 T + genotype in controls were higher than in patients (P < 0.0001) and the frequencies of C + genotype in patients were higher than in the controls (P < 0.001). Additionally, frequencies of COX-2-8473 C + in migraineurs with depression and nausea were higher than in the controls (P ≤ 0.05). Based on the microarray data, it seems that Toll-like receptor cellular pathway may regulate COX-2 expression through MYD88 and MAP2K3 proteins in depression. COX-2-8473 TC and COX-2-8473 CC genotypes can heighten the risk of migraine, depression, and nausea considerably. Also, Toll-like receptor can regulate COX-2 expression, influencing the inflammation pathway and depression level.