Gamma-aminobutyric acid (GABA) receptors GABRA4, GABRE, and GABRQ gene polymorphisms and risk for migraine

DOI: https://doi.org/10.1007/s00702- 017- 1834- 4

Abstract-Summary A TaqMan-based qPCR assay designed to detect the most common SNPs in the GABRA4 (rs2229940), GABRE (rs1139916), and GABRQ (rs3810651) was per- formed in 197 migraine patients and 394 age- and gender-matched controls.

The possible influence of gender, age at onset of migraine, positive family his- tory of migraine, presence or absence of aura, and triggering of migraine by ethanol on the frequency of the genotypes was also studied.

2.1 Genetics

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The frequency of GABRE rs1139916AA genotype was significantly lower in the migraine group only in the female gender, but the differences did not reach statisti- cal significance after correction for multiple comparisons.

The mean ± SD age at onset of migraine was significantly lower in patients with

GABRQ rs3810651AA as compared with the other two genotypes.

Triggering of migraine by ethanol was significantly less frequent in patients with GABRA4 rs2229940GG and more frequent in patients with GABRQ 3810651TT genotype, but the differences lost statistical significance after correction for multi- ple comparisons.

Introduction Gamma-amino-butyric acid (GABA), which is the most widespread inhibitory neu- rotransmitter in the brain, has been implicated in the pathogenesis of migraine (both in the cortical spreading depression, responsible for the aura, and in the activation of the trigeminovascular system, responsible for the pain), being its role in the pathogenesis of migraine suggested by many pharmacological, biochemical, exper- imental and neurophysiological data (revised by García-Martín and others [57]).

Despite GABR genes not being included among the 38 susceptibility loci for migraine, as described in recent GWAS studies (Gormley and others [58]), the pos- sible role of GABA in the pathophysiology of this disease makes reasonable to assess the possible association between polymorphisms in GABR genes and the risk for migraine.

We investigated the possible association between the most common nonsynony- mous single nucleotide polymorphisms (SNPs) of the GABRA4 (GABRA4-L26M, Leu26Met, rs2229940), GABRE (GABRE-S102A, Ser102Ala, rs1139916), and GABRQ (GABRQ-I478F, Ile478Phe, rs3810651) genes with the risk of developing migraine in Caucasian Spanish individuals.

Patients and Methods The determination of the sample size was performed from variant allele frequencies observed in control individuals using a genetic model, which analyzed the frequency for carriers of the disease gene with a RR value = 1.5 (p = 0.05), as it is usually recommended for pharmacogenomic studies (Daly and Day [59], Pértegas Díaz and Pita Fernández [60]).

The statistical power in this study group, calculated for one-tailed and two-tailed associations of the minor allele frequencies was, respectively, 94.4% and 90.0% for GABRA4 rs2229940, 90.7% and 84.3% for GABRE rs1139916, and 89.6% and 82.7% for GABRQ rs3810651.

A secondary analysis using the Chi-square test or the Fisher’s exact test, when appropriate, was performed to compare the genotype and allelic frequencies between subgroups of migraine patients according with the age at onset of migraine (≤15 vs. ≥16 years), positivity or negativity of family history of migraine, presence or absence of aura, and triggering of migraine attacks by ethanol.

Results The frequencies of rs2229940 genotype variants were at the Hardy–Weinberg (HW) equilibrium both in migraine patients and control groups.

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2 Mechanisms

With regard to the SNPs rs1139916 and rs3810651, because these are located at chromosome X, HW equilibrium analyses were performed in women only, and both SNPs were at HW equilibrium both, in patients and control women.

Discussion The possible association between GABRE rs1139916 and GABRQ rs3810651 SNPs with migraine risk has been previously reported by Quintas and others [61].

This group found increased risk for migraine in carriers of the GABRQ rs3810651AT genotype, with an OR (95% CI) = 4.07 (1.71–9.73), and a significant gene-gene interaction between GABRE rs1139916 and GABRQ rs3810651 SNPs in the risk for migraine in the female gender.

An analysis of the pooled data regarding GABRQ rs3810651 SNP in women obtained in the present study with those reported by Quintas and others [61], involv- ing 289 migraine patients and 489 controls, showed a marginal association for the minor allele frequency difference (OR 1.23; 95% CI 1.00–1.52; p = 0.048) and for the minor allele positivity (OR 1.44; 95% CI 1.06–1.96; p = 0.020).

Acknowledgement A machine generated summary based on the work of García-Martín, Elena; Esguevillas, Gara; Serrador, Mercedes; Alonso-Navarro, Hortensia; Navacerrada, Francisco; Amo, Gemma; García-Albea, Esteban; Agúndez, José A. G.; Jiménez- Jiménez, Félix Javier. 2018 in Journal of Neural Transmission.

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