Assessing the genetic association between vitamin B6 metabolism and genetic generalized epilepsy

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...

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Bibliographic Details
Published inMolecular genetics and metabolism reports Vol. 21; p. 100518
Main Authors Stevelink, Remi, Pangilinan, Faith, Jansen, Floor E., Braun, Kees P.J., Molloy, Anne M., Brody, Lawrence C., Koeleman, Bobby P.C.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 01.12.2019
Elsevier
Subjects
Genetics
GGE
GWAS
Pharmacogenetics
Pyridoxine
Research Paper
SNP
Genetics
Pharmacogenetics
Pyridoxine
GWAS
GGE
SNP
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Summary: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.
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See supplementary information for a list of members and affiliations.
These authors contributed equally to the work.
ISSN:2214-4269
2214-4269
DOI:10.1016/j.ymgmr.2019.100518