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

The Pharmacogenomics Journal volume 20, pages 220–226 (2020)Cite this article

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Abstract

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.

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Acknowledgements

The Netherlands ALS Foundation funded this study (grant: Project TryMe).

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Authors and Affiliations

  1. Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands

    Ruben P. A. van Eijk, Marc D. Jansen, Henk-Jan Westeneng, Kristel R. van Eijk, Rick A. A. van der Spek, Joke J. F. A. van Vugt, Jan H. Veldink, Leonard H. van den Berg & Michael A. van Es

  2. Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

    Ruben P. A. van Eijk, Marinus J. C. Eijkemans & Stavros Nikolakopoulos

  3. Department of Neurology, Meander Medical Center, Amersfoort, The Netherlands

    Sanne Piepers

  4. Centre for Human Drug Research, Leiden, The Netherlands

    Geert-Jan Groeneveld

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  1. Ruben P. A. van Eijk
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Correspondence to Michael A. van Es.

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Conflict of interest

RPAvE, SN, MDJ, H-JW, KRvE, RAAvdS, JJFAvV, SP, G-JG, JHV, MJCE report no disclosures. MAvE received grants from the Netherlands Organization for Health Research and Development (Veni scheme), The Thierry Latran foundation and the Netherlands ALS foundation (Stichting ALS Nederland), the EU Joint Programme—Neurodegenerative Disease Research (JPND). LHvdB reports grants from Netherlands ALS Foundation, the Netherlands Organization for Health Research and Development (Vici scheme), the Netherlands Organization for Health Research and Development (SOPHIA, STRENGTH, ALS-CarE project), funded through the EU Joint Programme—Neurodegenerative Disease Research, JPND), served on the Scientific Advisory Board of Biogen, Cytokinetics, Prinses Beatrix SpierFonds, and the Latran Foundation.

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van Eijk, R.P.A., Eijkemans, M.J.C., Nikolakopoulos, S. et al. Pharmacogenetic interactions in amyotrophic lateral sclerosis: a step closer to a cure?. Pharmacogenomics J 20, 220–226 (2020). https://doi.org/10.1038/s41397-019-0111-3

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