No major role of common SV2A variation for predisposition or levetiracetam response in epilepsy

Lynch, J.M.; Tate, S.K.; Kinirons, P.; Weale, M.E.; Cavalleri, G.L.; Depondt, C.; Murphy, K.; O’Rourke, D.; Doherty, C.P.; Shianna, K.V.; Wood, N.W.; Sander, J.W.; Delanty, N.; Goldstein, D.B.; Sisodiya, S.M.

doi:10.1016/j.eplepsyres.2008.09.003

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Volume 83, Issue 1 , Pages 44-51, January 2009

No major role of common SV2A variation for predisposition or levetiracetam response in epilepsy

J.M. Lynch
- Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK
- National Society for Epilepsy, Chalfont-St-Peter, Bucks SL9 0RJ, UK
- These authors contributed equally to this work.
S.K. Tate
- Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK
- National Society for Epilepsy, Chalfont-St-Peter, Bucks SL9 0RJ, UK
- These authors contributed equally to this work.
P. Kinirons
- The Department of Clinical Neurological Sciences and Molecular and Cellular Therapeutics, RCSI Research Institute Royal College of Surgeons in Ireland, and Division of Neurology, Beaumont Hospital, Dublin, Ireland
M.E. Weale
- Institute for Genome Sciences and Policy, Center for Population Genomics and Pharmacogenetics, Duke University, 103 Research Drive, Rm 4006 GSRB II, Box 3471 DUMC, Durham, NC 27710, USA
G.L. Cavalleri
- The Department of Clinical Neurological Sciences and Molecular and Cellular Therapeutics, RCSI Research Institute Royal College of Surgeons in Ireland, and Division of Neurology, Beaumont Hospital, Dublin, Ireland
C. Depondt
- Service de Neurologie, Hôpital Erasme, Université Libre de Bruxelles, 808 Route de Lennik, 1070 Brussels, Belgium
K. Murphy
- The Department of Clinical Neurological Sciences and Molecular and Cellular Therapeutics, RCSI Research Institute Royal College of Surgeons in Ireland, and Division of Neurology, Beaumont Hospital, Dublin, Ireland
D. O’Rourke
- The Department of Clinical Neurological Sciences and Molecular and Cellular Therapeutics, RCSI Research Institute Royal College of Surgeons in Ireland, and Division of Neurology, Beaumont Hospital, Dublin, Ireland
C.P. Doherty
- Department of Neurology, St. James’s Hospital, James Street, Dublin 8, Ireland
K.V. Shianna
- Institute for Genome Sciences and Policy, Center for Population Genomics and Pharmacogenetics, Duke University, 103 Research Drive, Rm 4006 GSRB II, Box 3471 DUMC, Durham, NC 27710, USA
N.W. Wood
- Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK
J.W. Sander
- Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK
- National Society for Epilepsy, Chalfont-St-Peter, Bucks SL9 0RJ, UK
- SEIN – Epilepsy Institutes of the Netherlands Foundation, Achterweg 5, 2103 SW Heemstede, The Netherlands
N. Delanty
- Department of Neurology, Beaumont Hospital, Dublin 9, Ireland
- Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland
D.B. Goldstein
- Institute for Genome Sciences and Policy, Center for Population Genomics and Pharmacogenetics, Duke University, 103 Research Drive, Rm 4006 GSRB II, Box 3471 DUMC, Durham, NC 27710, USA
- These authors jointly supervised this work.
- Corresponding author at: Department of Clinical and Experimental Epilepsy, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK. Tel.: +44 20 3108 0112; fax: +44 20 3108 0115.
S.M. Sisodiya
- Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK
- National Society for Epilepsy, Chalfont-St-Peter, Bucks SL9 0RJ, UK
- These authors jointly supervised this work.
- Corresponding author at: Department of Clinical and Experimental Epilepsy, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK. Tel.: +44 20 3108 0112; fax: +44 20 3108 0115.

Received 9 May 2008; received in revised form 15 August 2008; accepted 12 September 2008.

Summary

Levetiracetam (LEV), a newer antiepileptic drug (AED) useful for several epilepsy syndromes, binds to SV2A. Identifying genetic variants that influence response to LEV may allow more tailored use of LEV. Obvious candidate genes are SV2A, SV2B and SV2C, which encode the only known binding site, synaptic vesicle protein 2 (SV2), with LEV binding to the SV2A isoform. SV2A is an essential protein as homozygous SV2A knockout mice appear normal at birth but fail to grow, experience severe seizures and die by 3 weeks. We addressed characterising AED response issues in pharmacogenetics and whether variation in these genes associates with response to LEV in two independent cohorts with epilepsy. We also investigated whether variation in these three genes associated with epilepsy predisposition in two larger cohorts of patients with various epilepsy phenotypes. Common genetic variation in SV2A, encoding the actual binding site of LEV, was fully represented in this study whereas SV2B and SV2C were not fully covered. None of the polymorphisms tested in SV2A, SV2B or SV2C influence LEV response or predisposition to epilepsy. We found no association between genetic variation in SV2A, SV2B or SV2C and response to LEV or epilepsy predisposition. We suggest this study design may be used in future pharmacogenetic work examining AED or LEV efficacy. However, different study designs would be needed to examine common variation with minor effect sizes, or rare variation, influencing AED or LEV response or epilepsy predisposition.