title: Variants in KCNJ11 and BAD do not predict response to ketogenic dietary therapies for epilepsy.
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.
authors.affiliation: 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: n.schoeler.10@ucl.ac.uk.
authors.forename: Natasha E
authors.initials: NE
authors.lastname: Schoeler
authors.affiliation: NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Costin
authors.initials: C
authors.lastname: Leu
authors.affiliation: Department of Genetics Environment and Evolution, UCL Genetics Institute, London, United Kingdom.
authors.forename: Jon
authors.initials: J
authors.lastname: White
authors.affiliation: Department of Statistical Genetics, University College London, London, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Molecular Genetics, University of Exeter Medical School, Exeter, United Kingdom.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Mar
authors.initials: M
authors.lastname: Matarin
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Yellen
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Thiele
authors.affiliation: Royal Children's Hospital, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Mackay
authors.affiliation: Epilepsy Research Centre, The University of Melbourne, Austin Health, Melbourne, Australia.
authors.forename: Jacinta M
authors.initials: JM
authors.lastname: McMahon
authors.affiliation: 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.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: 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.
authors.forename: Josemir W
authors.initials: JW
authors.lastname: Sander
authors.affiliation: UCL Institute of Child Health, London, United Kingdom; Great Ormond Street Hospital for Children, London, United Kingdom; Young Epilepsy, Lingfield, United Kingdom.
authors.forename: J Helen
authors.initials: JH
authors.lastname: Cross
authors.affiliation: 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.
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Sisodiya
mesh_terms: D000704:Analysis of Variance; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D055423:Diet, Ketogenic / Q000379:methods*; D004569:Electroencephalography; D004827:Epilepsy / Q000178:diet therapy* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D006113:United Kingdom; D051025:bcl-Associated Death Protein / Q000235:genetics*; D000099161:Kcnj11 Channel
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D051025:bcl-Associated Death Protein; D000099161:Kcnj11 Channel; C494819:BAD protein, human
keywords: BAD; Epilepsy; Genetic biomarker; KCNJ11; Ketogenic diet; Seizures