CALCA and TRPV1 genes polymorphisms are related to a good outcome in female chronic migraine patients treated with OnabotulinumtoxinA

DOI: https://doi.org/10.1186/s10194- 019- 0989- 9

Abstract-Summary Some variables have been proposed as predictors of efficacy of OnabotulinumtoxinA in chronic migraine patients, but data available are inconclusive.

We aimed to analyse the influence of single nucleotide polymorphisms in the response to OnabotulinumtoxinA.  We included 156 female patients treated with OnabotulinumtoxinA accordingly to PREEMPT paradigm in three headache units. OnabotulinumtoxinA was offered to patients that had not responded to topira-

mate and at least one other preventative.

Patients with a reduction of at least 50% in the number of migraine days after

two OnabotulinumtoxinA procedures were considered as responders.

Response to treatment with OnabotulinumtoxinA was achieved in 120 patients

(76,9%).

Two polymorphisms showed differences: CALCA rs3781719, where allele C represents 26.9% in responders and 40.9% in non-responders (p = 0.007, OR = 3.11 (1.33–7.26)); and TRPV1 rs222749, where allele A represents 4.17% in responders and 12.5% in non-responders (p = 0.013, OR = 3.29 (1.28–8.43)).

Polymorphic variations of CALCA and TRPV1 genes might play a role as prog- nostic markers of efficacy of OnabotulinumtoxinA in chronic migraine female patients in our population.

Extended: We aimed to analyse single nucleotide polymorphisms (SNPs) previ- ously related with a possible susceptibility to migraine, and to determine their value as prognostic markers of efficacy, in a population of CM patients treated with OnabotA.

Response to treatment with OnabotA was evaluated 3 months after the second procedure and was defined as a reduction of at least 50% in the number of monthly migraine days.

Future studies should explore this possible association in detail.

Background The pathophysiology of migraine attacks is based on the activation of the trigemi- novascular system and the liberation of vasoactive neuropeptides which cause men- ingeal inflammation and produce pain, such as the calcitonin gene related peptide (CGRP) [122].

In a real-life clinical practice OnabotA pericranial injections effectively reduced

headache and migraine days [123–129].

Molecular mechanism of action of OnabotA consists on cleaving SNAP-25 and, so, impairing intracellular vesicular fusion and down regulating release of pain related neuropeptides, such as glutamate, substance p or CGRP [130, 131].

2.1 Genetics

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They have been mainly related with the mechanism of action of OnabotA (as plasma levels of CGRP) [132] and with parameters that might imply a loss of pos- sibility of dechronification of migraine as age, time from onset of migraine or chronic migraine [133], or structural or functional changes in pain related brain structures [134].

We aimed to analyse single nucleotide polymorphisms (SNPs) previously related with a possible susceptibility to migraine, and to determine their value as prognostic markers of efficacy, in a population of CM patients treated with OnabotA.

Methods All patients included were eligible for treatment with OnabotA in accordance with the PREEMPT protocol.

License of OnabotA in Spain indicates its use “for patients who have not ade-

quately responded or are intolerant to prophylactic drugs for migraine”.

We analysed 25 SNPs from each patient; they were selected for their relevance regarding migraine pathophysiology and their association with migraine according to previously published genome-wide association studies (GWAS).

We evaluated the highest possible variance (0.164) and the smallest possible dif- ference in the proportions (0.15), with a type 1 error of 5% and a statistical power of 90%, with a possible attrition rate of 15%, with a minimum estimated sample size of 147 patients.

We firstly analysed if clinical and demographic variables related with the response to OnabotA. We also searched for any differences between the groups in relation to any of the 25 SNPs for allelic, genotypic frequencies and dominance/ recesivity hypothesis of the allelic variants.

Results Regarding the strength of association, the following values of Odds Ratio were obtained with confidence intervals of 95%: allele C related with a greater risk of non-response than allele T: [OR = 1.88 (1.06–3.32)] and, in relation to genetic mod- els, the dominant model had a value of OR  =  3.11 (1.33–7.26); the codominant model had a value of OR = 1.6 (0.85–3.00) and the recessive model had a value of OR = 1.2 (0.31–4.71).

The SNP rs222749 located on the gene TRPV1 also showed significant differ-

ences between the two groups.

Regarding the strength of association, the following values of Odds Ratio were obtained with confidence intervals of 95%: allele A related with a greater risk of non-response than allele G [OR = 3.29 (1.28–8.43)] and, in relation to genetic mod- els, the dominant model had a value of OR = 2.47 (0.81–7.48); the codominant model had a value of OR = 2.40 (0.80–7.24) and the recessive model had a value of OR = 10.82 (1.09–107.45).

Discussion To the best of our knowledge, no previous study has addressed the relationship between the variants and genes included in this study and response to OnabotA. The relationship between an SNP and a particular phenotype is more consistent when

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2 Mechanisms

sample size is large, when the gene is located in a related area of genetic linkage (for example in the case of migraine in an area related to pain response) or if the rela- tionship has been demonstrated in animal models [135].

The SNP rs3781719 c.-767 T > C of the CALCA gene showed significant differ- ences between the group of responders and the group of non-responders to OnabotA. All of the analyses were statistically significant, particularly the hypoth- esis of dominance of the allele C (p = 0.007), whose presence, not only as homozy- gous but also as heterozygous, impedes the response to OnabotA. The CALCA gene encodes for the peptide CGRP, whose involvement in migraine has been studied widely [136].

Conclusions In this study, and for the first time, two genetic polymorphisms have been associated with the response to therapy with OnabotA in Chronic Migraine patients.

Acknowledgement A machine generated summary based on the work of Moreno-Mayordomo, R.; Ruiz, M.; Pascual, J.; Gallego de la Sacristana, M.; Vidriales, I.; Sobrado, M.; Cernuda- Morollon, E.; Gago-Veiga, A.  B.; Garcia-Azorin, D.; Telleria, J.  J.; Guerrero, A. L. 2019 in The Journal of Headache and Pain.

A genetic risk score is differentially associated with migraine with and without aura