Changes in the gene expression profile during spontaneous migraine attacks

Abstract

Migraine attacks are delimited, allowing investigation of changes during and outside attack. Gene expression fluctuates according to environmental and endogenous events and therefore, we hypothesized that changes in RNA expression during and outside a spontaneous migraine attack exist which are specific to migraine. Twenty-seven migraine patients were assessed during a spontaneous migraine attack, including headache characteristics and treatment effect. Blood samples were taken during attack, two hours after treatment, on a headache-free day and after a cold pressor test. RNA-Sequencing, genotyping, and steroid profiling were performed. RNA-Sequences were analyzed at gene level (differential expression analysis) and at network level, and genomic and transcriptomic data were integrated. We found 29 differentially expressed genes between 'attack' and 'after treatment', after subtracting non-migraine specific genes, that were functioning in fatty acid oxidation, signaling pathways and immune-related pathways. Network analysis revealed mechanisms affected by changes in gene interactions, e.g. 'ion transmembrane transport'. Integration of genomic and transcriptomic data revealed pathways related to sumatriptan treatment, i.e. '5HT1 type receptor mediated signaling pathway'. In conclusion, we uniquely investigated intra-individual changes in gene expression during a migraine attack. We revealed both genes and pathways potentially involved in the pathophysiology of migraine and/or migraine treatment.

Figure 1

Study design with on the x-axis the time and on the y-axis the degree of headache. Blood sampling (marked by red arrows) was performed during migraine attack (A), two hours after treatment (B), one month later outside attack at a headache-free day (C) and after performing a cold-pressor test (D).

Figure 2

Workflow of differential gene regulatory network analysis, where the different time points are represented by (A) during attack, (B) after treatment, (C) headache-free, (D) after cold-pressor test.

Figure 3

Difference in headache during the two hours after treatment with sumatriptan.

Figure 4

Expression of the four differentially expressed genes, detected both in the paired-sample design (i.e. A vs B) and in the temporal model (i.e. with timepoint of sampling as covariate). On the y-axis the gene expression in transcripts per million (log2) and on the x-axis the three time points (i.e. A = during attack, B = after treatment, C = headache-free).