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. 2021 Jun;9(6):e1680.
doi: 10.1002/mgg3.1680. Epub 2021 Apr 7.

Genetic variants related to successful migraine prophylaxis with verapamil

Fred Michael Cutrer  1 , Ann M Moyer  2   3 , Elizabeth J Atkinson  4 , Liguo Wang  4 , Shulan Tian  4 , Yanhong Wu  2 , Ivan Garza  1 , Carrie E Robertson  1 , Carey A Huebert  1 , Brenda E Moore  2 , Christopher J Klein  1   2   3
Affiliations

Genetic variants related to successful migraine prophylaxis with verapamil

Fred Michael Cutrer et al. Mol Genet Genomic Med. 2021 Jun.

Abstract

Background: Currently, there is no biologically based rationale for drug selection in migraine prophylactic treatment.

Methods: To investigate the genetic variation underlying treatment response to verapamil prophylaxis, we selected 225 patients from a longitudinally established, deeply phenotyped migraine database (N = 5983), and collected uninterrupted quantitated verapamil treatment response data and DNA for these 225 cases. We recorded the number of headache days in the four weeks preceding treatment with verapamil and for four weeks, following completion of a treatment period with verapamil lasting at least five weeks. Whole-exome sequencing (WES) was applied to a discovery cohort consisting of 21 definitive responders and 14 definitive non-responders, and the identified single nucleotide polymorphisms (SNPs) showing significant association were genotyped in a separate confirmation cohort (185 verapamil treated patients). Statistical analysis of the WES data from the discovery cohort identified 524 SNPs associated with verapamil responsiveness (p < 0.01); among them, 39 SNPs were validated in the confirmatory cohort (n = 185) which included the full range of response to verapamil from highly responsive to not responsive.

Results: Fourteen SNPs were confirmed by both percentage and arithmetic statistical approaches. Pathway and protein network analysis implicated myo-inositol biosynthetic and phospholipase-C second messenger pathways in verapamil responsiveness, emphasizing the earlier pathogenic understanding of migraine. No association was found between genetic variation in verapamil metabolic enzymes and treatment response.

Conclusion: Our findings demonstrate that genetic analysis in well-characterized subpopulations can yield important pharmacogenetic information pertaining to the mechanism of anti-migraine prophylactic medications.

Keywords: genomic; migraine; phospholipase-C; prophylactic; verapamil.

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Conflict of interest statement

F. Michael Cutrer reports royalties for UptoDate as author, honorarium for Advisory Board for Biohaven, no conflicts for this study. Ann M. Moyer reports no disclosures. Elizabeth Atkinson reports no disclosures. Liguo Wang reports no disclosures. Shulan Tian reports no disclosures. Yanhong Wu reports no disclosures. Ivan Garza reports royalties from UpToDate as an author no conflicts for this study. Carrie E. Robertson reports honoraria from UpToDate as an author. Advisory board for Alder, Amgen, and Eli‐Lilly no conflicts for this study. Carey Huebert reports no disclosures. Brenda E. Moore reports no disclosures. Christopher J. Klein has received educational honorarium from Akcea therapeutics no conflicts for this study.

Figures

FIGURE 1
FIGURE 1
Of 5983 migraine patients evaluated at Mayo clinic from 2004 to 2016, pre‐ and post‐verapamil treatment data were obtained using the protocol shown in 380 patients, 225 of whom provided DNA samples
FIGURE 2
FIGURE 2
Distribution of the extreme responders and non‐responders to verapamil treatment studied in the WES phase shows a clear separation of the two groups. Subjects are plotted using the % change in the number of headache days pre‐treatment to the number of headache days post‐treatment versus % change in headache severity (0–10 visual analog scale) pre‐treatment to post‐treatment
FIGURE 3
FIGURE 3
Schematic summary of the study procedures: Whole‐exome sequencing was carried out in 21 definite responders and 14 definite non‐responders to verapamil and 524 SNPs were found to have a significant association with treatment response with p‐value < 0.01. The 524 identified SNP’s were then genotyped using Sequenom custom panel approach in much larger, separate cohort of 185 patients. After genotyping 39 SNP’s attained significance of p < 0.05 and of those 13 reached of p‐value <0.01. Ingenuity pathway analysis was then performed using SNP’s with p < 0.05 and Ingenuity Protein network analysis was carried out using the SNP’s with p < 0.01. To assess whether the observed treatment response to verapamil might be related to variation in the genes involved in verapamil metabolism or cellular transport, all the definite responders and non‐responders from the combined WES and larger Sequenom MassARRAY genotyped cohorts (37 definite responders and 99 definite non‐responders) were genotyped for variants in CYP2C8, CYP3A4 and CYP3A5 as well as in the transporter gene ABCB1 (c.3435T>C, count C; rs2032582 c.2677G>T/A, count A; c.2677G>T/A, count T) with QuantStudio OpenArray
FIGURE 4
FIGURE 4
Distribution of change in pre‐ to post‐verapamil treatment data in a separate cohort of 185 different subjects in whom we genotyped the 524 SNP’s identified using WES in the discovery phase. Subjects are plotted using the % change in the number of headache days pre‐treatment to the number of headache days post‐treatment versus % change in headache severity (0–10 visual analog scale) pre‐treatment to post‐treatment
See this image and copyright information in PMC

References

    1. .Mega, J. L. , Simon, T. , Collet, J.‐P. , Anderson, J. L. , Antman, E. M. , Bliden, K. , Cannon, C. P. , Danchin, N. , Giusti, B. , Gurbel, P. , Horne, B. D. , Hulot, J.‐S. , Kastrati, A. , Montalescot, G. , Neumann, F.‐J. , Shen, L. , Sibbing, D. , Steg, P. G. , … Sabatine, M. S. (2010). Reduced‐function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: A meta‐analysis. JAMA, 304, 1821–1830. - PMC - PubMed
    1. Backman, J. D. , O’Connell, J. R. , Tanner, K. , Peer, C. J. , Figg, W. D. , Spencer, S. D. , Mitchell, B. D. , Shuldiner, A. R. , Yerges‐Armstrong, L. M. , Horenstein, R. B. , & Lewis, J. P. (2017). Genome‐wide analysis of clopidogrel active metabolite levels identifies novel variants that influence antiplatelet response. Pharmacogenetics and Genomics, 27(4), 159–163. - PMC - PubMed
    1. Baun, M. , Pedersen, M. H. , Olesen, J. , & Jansen‐Olesen, I. (2012). Dural mast cell degranulation is a putative mechanism for headache induced by PACAP‐38. Cephalalgia, 32(4), 337–345. - PubMed
    1. Chiappelli, J. , Rowland, L. M. , Wijtenburg, S. A. , Muellerklein, F. , Tagamets, M. , McMahon, R. P. , Gaston, F. , Kochunov, P. , & Hong, L. E. (2015). Evaluation of myo‐inosital as a potential biomarker for depression in schizophrenia. Neuropsychopharmacology, 40, 2157–2164. - PMC - PubMed
    1. DePetrillo, P. B. , Abernethy, D. R. , Wainer, I. W. , & Andrawis, N. S. (1994). Verapamil decreases lymphocyte protein kinase C activity in humans. Clinical Pharmacology and Therapeutics, 55(1), 44–49. - PubMed

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