Searching for Predictors of Migraine Chronification: a Pilot Study of 1911A>G Polymorphism of TRPV1 Gene in Episodic Versus Chronic Migraine

DOI: https://doi.org/10.1007/s12031- 020- 01683- 9

Abstract-Summary We evaluated frequency distribution of AA, AG, and GG variants of SNP 1911A>G in the TRPV1 gene in patients with episodic and chronic migraine compared with healthy individuals.

The study included 46 patients diagnosed with migraine (27 episodic and 19

chronic) and 50 healthy individuals as a control group.

The genotype frequency distribution in episodic migraine was comparable with that in controls (AA 33%, AG 56%, GG 11% and AA 34%, AG 46%, GG 20%, respectively).

In chronic migraine, the distribution differed significantly (p < 0.05) (AA 68%,

AG 32%, GG 0%).

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2 Mechanisms

This are first indications for a distinctive genotype frequency distribution of TRPV1 1911A>G in chronic migraine patients compared with episodic migraine patients and controls.

Our data confirm a different predisposition to chronic pain in migraine and give a prerequisite for a new look at the nature of chronification of migraine, proposing that the absence of GG genotype may be considered as possible risk biomarker of episodic migraine evolution to chronic form.

Introduction Recent studies suggest that the non-synonymous TRPV1 single-nucleotide poly- morphism (SNP) 1911A>G (rs8065080), resulting to amino acid substitution Ile585Val, co-determines functional activity of these receptors (Forstenpointner and others [105]; Okamoto and others [106]).

Carreno and others [107] already showed some evidence for association of the 2841C>T (rs222741) SNP of TRPV1 gene with migraine, but it was different from 1911A>G SNP and that study was performed in overall migraine group in Spanish population, without subdivision on certain disease forms.

The aim of the current study was to investigate the genotype frequency distribu- tion of TRPV1 1911A>G SNP in chronic and episodic migraine and compare those with healthy controls to clarify whether genotype frequencies are associated with any of these migraine subtypes.

Our results give first evidence that the genotype distribution of TRPV1 SNP

1911A>G is different between CM compared with the EM and healthy groups.

Material and Methods Patients meeting the following criteria were included in the study: previously diag- nosed episodic or chronic migraine as defined in ICHD and age from 18 to 55 years. Total genomic DNA was extracted from samples from each participant by an

isolation kit (Litech, Russia) according to the manufacturer’s instructions.

Measurement of DNA concentration in samples was performed using a

NanoDrop2000 (Thermo Fisher Scientific Inc., USA).

The total volume of AS-PCR reaction solution was 10 μL, including 1.0 μL buf- fer solution 10X TaqPol, dNTP mix (25 mM) 0.4 μL, MgCl2 (25 mM) 0.5 μL, for- ward primer (100 μМ) 0.1 μL, reverse primer (100 μМ) 0.1 μL, TaqPol polymerase, 5 U/μL (Eurogen, Russia) 0.2 μL, 0.5 μL of 10–100  ng of DNA extract, and nuclease- free water to adjust the volume.

Results We checked the accordance of TRPV1 1911A>G genotyping results in the studied healthy control group with the European population data from the 1000 Genomes Project (Ensembl 98, [108]).

We compared the genotype frequencies in male and female data from 1000 Genomes Project (Ensembl 98, [108]) and their distributions did not differ signifi- cantly (p = 0.342).

The genotype distribution of CM patients differed significantly from the control

(p = 0.015) and from the EM (p = 0.042) groups.

2.1 Genetics

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Discussion Distribution of genotypes in CM patients was markedly different: the AA genotype nearly doubly increased, whereas the GG variant was completely absent.

The latter finding of the complete absence of the GG variant in CM was the most surprising, what could be interpreted that this genotype is associated with adaptive protective mechanism against migraine chronification, as far as the prevailing view suggests that CM is a progression of EM (Buse and others [109]).

Found highly heterogeneous reaction of migraine patients to stimulation of TRPV1 receptors by capsaicin (Kamshilin and others [110]) also may be explained by different TRPV1 1911A>G polymorphism in EM and CM patients’ cohorts.

We may assume that there is different genetic determinism of episodic and chronic forms of migraine based on differences in TRPV1 1911A>G genotype distribution.

Conclusion The main finding is that TRPV1 1911A>G SNP is differently associated with CM and EM, what assumes different genetic predisposition to these migraine forms.

Potentially, detection of GG variant of TRPV1 1911A>G polymorphism can serve as a marker of protection against progression of EM to CM (migraine chroni- fication) and could be a step to personalized treatments of migraine patients.

Acknowledgement A machine generated summary based on the work of Yakubova, Aliya; Davidyuk, Yuriy; Tohka, Jussi; Khayrutdinova, Olga; Kudryavtsev, Igor; Nurkhametova, Dilyara; Kamshilin, Alexei; Giniatullin, Rashid; Rizvanov, Albert. 2020 in Journal of Molecular Neuroscience.

Implications for the migraine SNP rs1835740 in a Swedish cluster headache population