Leiden University Scholarly Publications

Persistent URL of this record https://hdl.handle.net/1887/3278294

Documents

In Collections

This item can be found in the following collections:

Eijk, R.P.A. van; Eijkemans, M.J.C.; Nikolakopoulos, S.; Jansen, M.D.; Westeneng, H.J.; Eijk, K.R. van; ... ; Es, M.A. van (2020)

Pharmacogenetic interactions in amyotrophic lateral sclerosis: a step closer to a cure?

Article / Letter to editor
Genetic mutations related to amyotrophic lateral sclerosis (ALS) act through distinct pathophysiological pathways, which may lead to varying treatment responses. Here we assess the genetic interaction between C9orf72, UNC13A, and MOBP with creatine and valproic acid treatment in two clinical trials. Genotypic data was available for 309 of the 338 participants (91.4%). The UNC13A genotype affected mortality (p = 0.012), whereas C9orf72 repeat-expansion carriers exhibited a faster rate of decline in overall (p = 0.051) and bulbar functioning (p = 0.005). A dose-response pharmacogenetic interaction was identified between creatine and the A allele of the MOBP genotype (p = 0.027), suggesting a qualitative interaction in a recessive model (HR 3.96, p = 0.015). Not taking genetic information into account may mask evidence of response to treatment or be an unrecognized source of bias. Incorporating genetic data could help investigators to identify critical treatment clues in patients with...Show moreGenetic mutations related to amyotrophic lateral sclerosis (ALS) act through distinct pathophysiological pathways, which may lead to varying treatment responses. Here we assess the genetic interaction between C9orf72, UNC13A, and MOBP with creatine and valproic acid treatment in two clinical trials. Genotypic data was available for 309 of the 338 participants (91.4%). The UNC13A genotype affected mortality (p = 0.012), whereas C9orf72 repeat-expansion carriers exhibited a faster rate of decline in overall (p = 0.051) and bulbar functioning (p = 0.005). A dose-response pharmacogenetic interaction was identified between creatine and the A allele of the MOBP genotype (p = 0.027), suggesting a qualitative interaction in a recessive model (HR 3.96, p = 0.015). Not taking genetic information into account may mask evidence of response to treatment or be an unrecognized source of bias. Incorporating genetic data could help investigators to identify critical treatment clues in patients with ALS.Show less
All authors
Eijk, R.P.A. van; Eijkemans, M.J.C.; Nikolakopoulos, S.; Jansen, M.D.; Westeneng, H.J.; Eijk, K.R. van; Spek, R.A.A. van der; Vugt, J.J.F.A. van; Piepers, S.; Groeneveld, G.J.; Veldink, J.H.; Berg, L.H. van den; Es, M.A. van
Date
2020-04-01
Journal
Pharmacogenomics Journal
Volume
20
Issue
2
Pages
220 - 226
DOI
doi:10.1038/s41397-019-0111-3
Link
https://www.nature.com/articles/s41397-019-0111-3