Circulating Cytokines Mediate the Causal Relationship between Plasma Lipids and Migraine and its Subtypes: A Mediated Mendelian RandomizationStudy

INTRODUCTION: Migraine, a primary headache disorder, is the third disabling disease of neurological disorders worldwide. The pathological mechanism underlying migraine remains poorly understood. Lipid metabolism may be related to migraine pathophysiology. We aimed to investigate the causal relationship between plasma lipids and migraine or its subtypes, including migraine with aura (MA) and migraine without aura (MO), and explore whether the circulating cytokines serve as mediators in the pathway from plasma lipids to migraine. METHODS: A two-step Mendelian randomization (MR) approach was used to assess the mediating effect. The summary genetic data for 179 lipid species were obtained from were derived from a genome-wide association studies (GWAS) summary dataset encompassing 7,174 individuals. The summary genetic data for 91 circulating cytokines were obtained from genome-wide pQTL mapping data. The summary genetic data of GWAS related to migraine and its subtypes were derived from the FinnGen Release 10 database. The MR Analysis methods included the inversevariance- weighted (IVW), MR-Egger, and weighted median. RESULTS: The risk of migraine was reduced mediated by CD5 with phosphatidylinositol (18:1_18:2), sphingomyelin (d34:1), and sphingomyelin (d38:1). The risk of migraine and MA was reduced mediated by CD6 with sphingomyelin (d40:1) and sphingomyelin (d42:2). The risk of migraine and MA was increased mediated by CD6 with phosphatidylethanolamine (O- 16:1_18:2). DISCUSSION: CD5 and CD6 were found to be related to migraine. CD5 and CD6 may affect migraine by immunological dysregulation-induced neuroinflammation. Six plasma lipids are associated with two cytokines, indicating that lipid metabolism participates in neuroinflammation, and T cells may be part of it. Plasma levels of lipids were associated with the risk of migraine. The circulating cytokines may serve as mediators in the pathway from plasma lipids to migraine. CONCLUSIONS: CD5 and CD6 appeared to mediate the causal relationship between plasma lipids and migraine or MA, including four kinds of sphingomyelin, one phosphatidylinositol, and one phosphatidylethanolamine.