Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Oct 11:21:100518.
doi: 10.1016/j.ymgmr.2019.100518. eCollection 2019 Dec.

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

Remi Stevelink  1   2 , Faith Pangilinan  3 , Floor E Jansen  2 , Kees P J Braun  2 ; International League Against Epilepsy Consortium on Complex Epilepsies; Anne M Molloy  128 , Lawrence C Brody  3 , Bobby P C Koeleman  1
Collaborators, Affiliations

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

Remi Stevelink et al. Mol Genet Metab Rep. .

Abstract

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: GGE; GWAS; Genetics; Pharmacogenetics; Pyridoxine; SNP.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Manhattan plots for each genome-wide association analysis of the five measures of vitamin B6 metabolism. Each genome-wide association analysis was performed using an imputed SNP set and log10-transformed values. A) pyridoxal 5′-phosphate (PLP), B) pyridoxal (PL), C) pyridoxic acid (PA), D) PLP:PL ratio, E) PAr index. X-axis: Tested SNPs according to chromosomal position. Y-axis: Negative log10-transformed p-values. Red line: Genome-wide significance (p < 5 × 10−8). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 2
Fig. 2
Locusplot of the genome-wide significant locus associated with the PLP:PL ratio. This locus includes a missense variant of the gene PYROXD2 (rs2147896). Chromosomal position including gene annotations are displayed on the X-axis and negative log10-transformed P-values are displayed on the Y-axis. SNPs are plotted as circles whose colors represent the correlation (linkage disequilibrium) with the lead SNP rs942813.
Fig. 3
Fig. 3
Logistic regression to assess the difference in pyridoxine-related metabolite PRS scores between people with GGE compared to controls. Standardized beta regression coefficients ±standard error are displayed. See Supplementary Table 2 for values. None of the associations reached the significance threshold of P < .001 that is recommended for analyses with PRSice.
See this image and copyright information in PMC

References

    1. Ramachandrannair R., Parameswaran M. Prevalence of pyridoxine dependent seizures in south Indian children with early onset intractable epilepsy: a hospital based prospective study. Eur. J. Paediatr. Neurol. 2005;9:409–413. - PubMed
    1. Plecko B., Paul K., Mills P., Clayton P., Paschke E., Maier O., Hasselmann O., Schmiedel G., Kanz S., Connolly M., Wolf N., Struys E., Stockler S., Abela L., Hofer D. Pyridoxine responsiveness in novel mutations of the PNPO gene. Neurology. 2014;82:1425–1433. - PMC - PubMed
    1. Jaeger B., Abeling N.G., Salomons G.S., Struys E.A., Simas-Mendes M., Geukers V.G., Poll-The B.T. Pyridoxine responsive epilepsy caused by a novel homozygous PNPO mutation. Mol. Genet. Metab. Rep. 2016;6:60–63. - PMC - PubMed
    1. Mills P.B., Camuzeaux S.S., Footitt E.J., Mills K.A., Gissen P., Fisher L., Das K.B., Varadkar S.M., Zuberi S., McWilliam R., Stodberg T., Plecko B., Baumgartner M.R., Maier O., Calvert S., Riney K., Wolf N.I., Livingston J.H., Bala P., Morel C.F., Feillet F., Raimondi F., Del Giudice E., Chong W.K., Pitt M., Clayton P.T. Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome. Brain. 2014;137:1350–1360. - PMC - PubMed
    1. Ware T.L., Pitt J., Freeman J. Pyridoxine responsiveness in novel mutations of the PNPO gene. Neurology. 2015;84:329. - PubMed