RAR-related orphan receptor A: One gene with multiple functions related to migraine

Abstract

Aims: RAR-related orphan receptor (RORA) involves in regulation of several biological processes including inflammation and circadian rhythm that probably are involved in migraine pathophysiology. In the current study, the association between RORA rs11639084 and rs4774388 variants and susceptibility to migraine were investigated in a sample of Iranian migraine patients for the first time.

Methods: In a case-control study including 400 participants, 200 migraineurs and 200 healthy controls, genotyping of RORA rs4774388 and rs11639084 polymorphisms was performed using tetra-primer amplification refractory mutation system-polymerase chain reaction (TP-ARMS-PCR).

Results: The distribution of rs4774388 C/T and T/T genotypes differed significantly between the studied groups. Moreover, an association was observed between rs4774388 and migraine under the recessive mode of inheritance (P = 0.002; OR = 1.89.; CI = 1.25-2.87). The distribution of rs11639084 alleles and genotypes was not significantly different between migraineurs and healthy controls.

Conclusion: Current results suggest RORA, as a molecular link, may explain inflammation and circadian rhythm dysfunction in migraine. Further studies in different ethnicities are required to confirm the function of RORA in migraine development.

Keywords: RORA; genetic association study; migraine; rs11639084; rs4774388.

Figure 1

A, A representative 2% agarose gel electrophoresis for the identification of the RORA rs4774388 genotypes. Lanes 1, 2, 4, and 6: CC genotype; Lanes 3 and 5: TT genotype; Lane 7:100 bp DNA ladder. B, A representative 2% agarose gel electrophoresis for the identification of the RORA rs11639084 genotypes. Lane 1:100 bp DNA ladder; Lanes 2, 4, 5 and 6: TT genotype; Lane 3: CC genotype; lane 7: TC genotype

Figure 2

Electropherograms showing rs4774388 genotypes: A, CT; B, CC; C, TT. Arrows indicate the polymorphism locations

Figure 3

Electropherograms showing rs11639084 genotypes: A, CC; B, TC; C, TT. Arrows indicate the polymorphism locations

Figure 4

Schematic representation of the possible roles for RORA in migraine pathogenesis. RORA may contribute to migraine susceptibility as well as some symptoms with different mechanisms as follows: (i) affecting the expression of IL‐17 in Th17 and mast cells suggesting a pro‐inflammatory role; (ii) regulation of inflammation, neurodegeneration, and circadian rhythms via the mediation of melatonin effect; and (iii) affecting the circadian rhythms through the regulatory role of BMAL1 and REV‐ERB on its expression