TY - JOUR
T1 - Pharmacogenetic interactions in amyotrophic lateral sclerosis
T2 - a step closer to a cure?
AU - van Eijk, Ruben P A
AU - Eijkemans, Marinus J C
AU - Nikolakopoulos, Stavros
AU - Jansen, Marc D
AU - Westeneng, Henk-Jan
AU - van Eijk, Kristel R
AU - van der Spek, Rick A A
AU - van Vugt, Joke J F A
AU - Piepers, Sanne
AU - Groeneveld, Geert-Jan
AU - Veldink, Jan H
AU - van den Berg, Leonard H
AU - van Es, Michael A
N1 - Funding Information:
Acknowledgements The Netherlands ALS Foundation funded this study (grant: Project TryMe).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/4
Y1 - 2020/4
N2 - 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 ALS.
AB - 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 ALS.
UR - https://www.scopus.com/pages/publications/85074606568
U2 - 10.1038/s41397-019-0111-3
DO - 10.1038/s41397-019-0111-3
M3 - Article
C2 - 31624333
SN - 1470-269X
VL - 20
SP - 220
EP - 226
JO - The Pharmacogenomics Journal
JF - The Pharmacogenomics Journal
IS - 2
ER -