Variants in KCNJ11 and BAD do not predict response to ketogenic dietary therapies for epilepsy.

Natasha E Schoeler, Costin Leu, Jon White, Vincent Plagnol, Sian Ellard, Mar Matarin, Gary Yellen, Elizabeth A Thiele, Mark Mackay, Jacinta M McMahon, Ingrid E Scheffer, Josemir W Sander, J Helen Cross, Sanjay M Sisodiya

Journal: Epilepsy research 2016;118():22-8

PMID: 26590798

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Abstract

In the absence of specific metabolic disorders, predictors of response to ketogenic dietary therapies (KDT) are unknown. We aimed to determine whether variants in established candidate genes KCNJ11 and BAD influence response to KDT. We sequenced KCNJ11 and BAD in individuals without previously-known glucose transporter type 1 deficiency syndrome or other metabolic disorders, who received KDT for epilepsy. Hospital records were used to obtain demographic and clinical data. Two response phenotypes were used: ≥ 50% seizure reduction and seizure-freedom at 3-month follow-up. Case/control association tests were conducted with KCNJ11 and BAD variants with minor allele frequency (MAF)>0.01, using PLINK. Response to KDT in individuals with variants with MAF<0.01 was evaluated. 303 Individuals had KCNJ11 and 246 individuals had BAD sequencing data and diet response data. Six SNPs in KCNJ11 and two in BAD had MAF>0.01. Eight variants in KCNJ11 and seven in BAD (of which three were previously-unreported) had MAF<0.01. No significant results were obtained from association analyses, with either KDT response phenotype. P-values were similar when accounting for ethnicity using a stratified Cochran-Mantel-Haenszel test. There did not seem to be a consistent effect of rare variants on response to KDT, although the cohort size was too small to assess significance. Common variants in KCNJ11 and BAD do not predict response to KDT for epilepsy. We can exclude, with 80% power, association from variants with a MAF of >0.05 and effect size >3. A larger sample size is needed to detect associations from rare variants or those with smaller effect sizes.

Address: NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom; UCL Institute of Child Health, London, United Kingdom. Electronic address: [email protected].; NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom.; Department of Genetics Environment and Evolution, UCL Genetics Institute, London, United Kingdom.; Department of Statistical Genetics, University College London, London, United Kingdom.; Molecular Genetics, University of Exeter Medical School, Exeter, United Kingdom.; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.; Royal Children's Hospital, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia.; Epilepsy Research Centre, The University of Melbourne, Austin Health, Melbourne, Australia.; Royal Children's Hospital, Melbourne, Australia; Departments of Medicine and Paediatrics, The University of Melbourne, Melbourne, Australia; Florey Institute of Neurosciences and Mental Health, Austin Health, Melbourne, Australia.; NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom; Epilepsy Society, Chalfont St Peter, United Kingdom; Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands.; UCL Institute of Child Health, London, United Kingdom; Great Ormond Street Hospital for Children, London, United Kingdom; Young Epilepsy, Lingfield, United Kingdom.; NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom; Epilepsy Society, Chalfont St Peter, United Kingdom.

DOI: 10.1016/j.eplepsyres.2015.10.003