Differential Expression of Cytokine-Coding Genes among Migraine Patients with and without Aura and Normal Subjects

DOI: https://doi.org/10.1007/s12031- 020- 01745- y

Abstract-Summary We compared the expression levels IL-2, IL-4, CXCL8, IL-17, IFN-γ, TGF-β and TNF-α cytokines in blood specimens of patients with migraine and those of healthy persons to identify any possible dysregulation in their expression and to propose mechanisms for this disorder.

Expression of INF-γ was suggestively higher in migraine cases than in healthy

individuals (posterior beta = 0.35, adjusted p value = 0.017).

Expression of this cytokine was lower in female subjects than in male subjects

(posterior beta = −0.712, adjusted p value = 0.012).

Expression of IL-4, TGF-β and TNF-α was also higher in cases compared with controls (posterior beta = 1.34, adjusted p value = 0.04; posterior beta = 0.849, adjusted p value = 0.036; posterior beta = 0.451, adjusted p value = 0.042, respectively).

CXCL8 expression was lower in migraine cases than in controls (posterior

beta = −0.78, adjusted p value = 0.039).

2.1 Genetics

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The current study highlights the dysregulation of cytokine-coding genes in the

blood of patients with migraine.

Extended: We compared the expression levels of cytokine-coding genes in the

blood of patients with migraine and healthy subjects.

Expression of INF-γ was lower in women than in men (posterior beta = −0.712,

adjusted p value = 0.012).

Expression of IL-4, TGF-β, IL-1β, TNF-α and CXCL8 showed similar patterns

between patients with and without aura.

Expression of IL-4, IL-17, TGF-β and TNF-α correlated significantly with the

age of study participants (p < 0.0001).

CXCL8 was lower in migraine cases compared with controls.

Introduction Migraine is a frequent disorder with a 1-year prevalence of 4–9% in males and 11–25% in females in Western countries (Manzoni and Torelli [62]).

This type of headache disorder is characterized by intermittent occurrence of headache frequently associated with other symptoms such as nausea, vomiting, photophobia and phonophobia (Yeh and others [63]).

Several genome-wide association studies (GWAS) have been executed to iden- tify the genetic cause of the disorder (Anttila and others [64]; Chasman and others [65]; Freilinger and others [66]), but the results have been inconclusive.

The secretion of pro-inflammatory cytokines by activated macrophages, microg- lia and mast cells can stimulate the release of arachidonic acid in the CNS, resulting in the induction of migraine and its associated symptoms (Conti and others [67]).

We measured the expression levels of IL-2, IL-4, CXCL8, IL-17, IFN-γ, TGF-β and TNF-α cytokines in the blood of patients with migraine compared with healthy persons to identify any possible dysregulation in their expression and to propose mechanisms for this disorder.

Materials and Methods The present study was conducted on 120 patients with migraine (20 men and 100 women, age [mean ± SD] = 37.47 ± 11.94) including 54 patients with migraine without aura and 66 with aura.

Patients were recruited consecutively during the study period. All patients were in attack-free periods during sampling. A total of 40 healthy individuals (23 women and 17 men) were enrolled as con-

trol subjects.

Control subjects had no history of migraine headache in themselves or their fam-

ily members.

All case and control subjects signed informed consent forms. To compare relative expression between cases and controls, we used the multiple Bayesian quantile regression model to reduce the uncertainty that can occur when an outcome has a non-normal distribution.

The Bayesian quantile regression model allowed for controlling the effects of

gender, age and interaction.

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2 Mechanisms

Results The level of INF-γ was meaningfully higher in migraine cases versus healthy sub- jects (posterior beta = 0.35, adjusted p value = 0.017).

The expression of IL-4, TGF-β and TNF-α was also higher in cases versus con- trols (posterior beta = 1.34, adjusted p value = 0.04; posterior beta = 0.849, adjusted p value = 0.036; posterior beta = 0.451, adjusted p value = 0.042, respectively).

The expression of IFN-γ was upregulated in patients with aura versus controls (posterior beta = 0.348, adjusted p value = 0.046), although its expression did not differ between patients without aura and controls.

Expression of IL-17 was higher in patients with aura than in controls (posterior beta = 0.65, adjusted p value = 0.025); however, its expression was similar between migraine patients without aura and controls (posterior beta = 0.244, adjusted p value = 0.149).

Discussion We compared the expression levels of cytokine-coding genes in the blood of patients with migraine and healthy subjects.

We detected higher levels of INF-γ, IL-4, TGF-β and TNF-α in migraine cases

compared with controls.

Contrary to these studies, Fidan and others found no difference in serum levels of IFN-γ and TNF-α between patients with migraine and healthy subjects either during headache attacks or in attack-free intervals (Fidan and others [68]).

The observed upregulation of IL-4  in migraineurs in the present study is in

accord with the detected higher levels of IFN-γ expression.

Consistent with our study, Bruno and others reported no difference in IL-1β lev- els between migraineurs during migraine attack and healthy controls (Bruno and others [69]).

We also assessed the diagnostic power of cytokine-coding genes in differentiat- ing patients with migraine from healthy subjects and reported the best values for IL-4 and TGF-β, respectively. Acknowledgement A machine generated summary based on the work of Taheri, Mohammad; Nicknafs, Fwad; Hesami, Omid; Javadi, Abdolreza; Arsang-Jang, Shahram; Sayad, Arezou; Ghafouri-Fard, Soudeh. 2020 in Journal of Molecular Neuroscience.

A genetic interaction of NRXN2 with GABRE, SYT1 and CASK in migraine patients: a case-control study