Assessing the genetic association between vitamin B6 metabolism and genetic generalized epilepsy
| Autor: | Graham Neil Thomas, Remi Stevelink, Ingrid Scheffer, Andreja Avbersek, Thomas Ferraro, Costin Leu, Krishna Chinthapalli, Claudia B. Catarino, Peter Widdess-Walsh, Colin Doherty, Anthony Marson, Michele Iacomino, Martin Krenn, Aarno Palotie, Heidi Kirsch, Stefan Wolking, Gianpiero Cavalleri |
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| Přispěvatelé: | Clinicum, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, University of Helsinki, Helsinki University Hospital Area, Faculty of Medicine, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
PNPO
Genome-wide association study Neurodegenerative 3124 Neurology and psychiatry 0302 clinical medicine Endocrinology PHOSPHATE 2.1 Biological and endogenous factors GWAS Aetiology lcsh:QH301-705.5 PYRIDOXINE RESPONSIVENESS Genetics International League Against Epilepsy Consortium on Complex Epilepsies lcsh:R5-920 0303 health sciences GGE Pharmacogenetics Pyridoxine SNP 3. Good health VIRUS-X-PROTEIN lcsh:Medicine (General) medicine.drug Research Paper BIOMARKERS Locus (genetics) Single-nucleotide polymorphism Biology CELL APOPTOSIS 03 medical and health sciences medicine Molecular Biology 030304 developmental biology Genetic association Nutrition Epilepsy MUTATIONS Prevention Human Genome 3112 Neurosciences Neurosciences Brain Disorders lcsh:Biology (General) SEIZURES 3111 Biomedicine Biochemistry and Cell Biology 030217 neurology & neurosurgery |
| Zdroj: | MOLECULAR GENETICS AND METABOLISM REPORTS Molecular Genetics and Metabolism Reports, 21. Elsevier BV Molecular Genetics and Metabolism Reports Molecular Genetics and Metabolism Reports, Vol 21, Iss, Pp-(2019) |
| ISSN: | 2214-4269 |
| Popis: | Altered vitamin B6 metabolism due to pathogenic variants in the gene PNPO causes early onset epileptic encephalopathy, which can be treated with high doses of vitamin B6. We recently reported that single nucleotide polymorphisms (SNPs) that influence PNPO expression in the brain are associated with genetic generalized epilepsy (GGE). However, it is not known whether any of these GGE-associated SNPs influence vitamin B6 metabolite levels. Such an influence would suggest that vitamin B6 could play a role in GGE therapy. Here, we performed genome-wide association studies (GWAS) to assess the influence of GGE associated genetic variants on measures of vitamin B6 metabolism in blood plasma in 2232 healthy individuals. We also asked if SNPs that influence vitamin B6 were associated with GGE in 3122 affected individuals and 20,244 controls. Our GWAS of vitamin B6 metabolites reproduced a previous association and found a novel genome-wide significant locus. The SNPs in these loci were not associated with GGE. We found that 84 GGE-associated SNPs influence expression levels of PNPO in the brain as well as in blood. However, these SNPs were not associated with vitamin B6 metabolism in plasma. By leveraging polygenic risk scoring (PRS), we found suggestive evidence of higher catabolism and lower levels of the active and transport forms of vitamin B6 in GGE, although these findings require further replication. Keywords: Pyridoxine, GGE, GWAS, Genetics, SNP, Pharmacogenetics |
| Databáze: | OpenAIRE |
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