Genetic variants related to successful migraine prophylaxis with verapamil
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 pheno...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-06-01
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| Series: | Molecular Genetics & Genomic Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mgg3.1680 |
| _version_ | 1818742048377798656 |
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| author | Fred Michael Cutrer Ann M. Moyer Elizabeth J. Atkinson Liguo Wang Shulan Tian Yanhong Wu Ivan Garza Carrie E. Robertson Carey A. Huebert Brenda E. Moore Christopher J. Klein |
| author_facet | Fred Michael Cutrer Ann M. Moyer Elizabeth J. Atkinson Liguo Wang Shulan Tian Yanhong Wu Ivan Garza Carrie E. Robertson Carey A. Huebert Brenda E. Moore Christopher J. Klein |
| author_sort | Fred Michael Cutrer |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T02:06:19Z |
| format | Article |
| id | doaj.art-f36d5e69928c462996755ad83923dc7f |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-12-18T02:06:19Z |
| publishDate | 2021-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-f36d5e69928c462996755ad83923dc7f2022-12-21T21:24:35ZengWileyMolecular Genetics & Genomic Medicine2324-92692021-06-0196n/an/a10.1002/mgg3.1680Genetic variants related to successful migraine prophylaxis with verapamilFred Michael Cutrer0Ann M. Moyer1Elizabeth J. Atkinson2Liguo Wang3Shulan Tian4Yanhong Wu5Ivan Garza6Carrie E. Robertson7Carey A. Huebert8Brenda E. Moore9Christopher J. Klein10Department of Neurology Mayo Clinic Rochester MN USADepartment of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USAHealth Sciences Research Biomedical Statistics and Informatics Mayo Clinic Rochester MN USAHealth Sciences Research Biomedical Statistics and Informatics Mayo Clinic Rochester MN USAHealth Sciences Research Biomedical Statistics and Informatics Mayo Clinic Rochester MN USADepartment of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USADepartment of Neurology Mayo Clinic Rochester MN USADepartment of Neurology Mayo Clinic Rochester MN USADepartment of Neurology Mayo Clinic Rochester MN USADepartment of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USADepartment of Neurology Mayo Clinic Rochester MN USAAbstract 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.https://doi.org/10.1002/mgg3.1680genomicmigrainephospholipase‐Cprophylacticverapamil |
| spellingShingle | Fred Michael Cutrer Ann M. Moyer Elizabeth J. Atkinson Liguo Wang Shulan Tian Yanhong Wu Ivan Garza Carrie E. Robertson Carey A. Huebert Brenda E. Moore Christopher J. Klein Genetic variants related to successful migraine prophylaxis with verapamil Molecular Genetics & Genomic Medicine genomic migraine phospholipase‐C prophylactic verapamil |
| title | Genetic variants related to successful migraine prophylaxis with verapamil |
| title_full | Genetic variants related to successful migraine prophylaxis with verapamil |
| title_fullStr | Genetic variants related to successful migraine prophylaxis with verapamil |
| title_full_unstemmed | Genetic variants related to successful migraine prophylaxis with verapamil |
| title_short | Genetic variants related to successful migraine prophylaxis with verapamil |
| title_sort | genetic variants related to successful migraine prophylaxis with verapamil |
| topic | genomic migraine phospholipase‐C prophylactic verapamil |
| url | https://doi.org/10.1002/mgg3.1680 |
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