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

Ruben P A van Eijk1,2, Marinus J C Eijkemans2, Stavros Nikolakopoulos2

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

The Pharmacogenomics Journal
|October 19, 2019
PubMed

Insights

Genetic factors influence treatment response in amyotrophic lateral sclerosis (ALS). Specific gene variants like C9orf72 and UNC13A impact disease progression and mortality, while MOBP genotype interacts with creatine treatment.

Area of Science:

  • Neuroscience
  • Genetics
  • Pharmacology

Background:

  • Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease.
  • Genetic mutations contribute to diverse pathophysiological pathways in ALS.
  • Treatment responses in ALS can vary significantly among patients.

Purpose of the Study:

  • To investigate the pharmacogenetic interactions between specific genetic mutations (C9orf72, UNC13A, MOBP) and treatments (creatine, valproic acid) in ALS patients.
  • To determine if genetic information can refine treatment strategies and improve outcomes in ALS clinical trials.

Main Methods:

  • Analysis of genotypic data from 309 ALS patients across two clinical trials.
  • Assessment of the impact of C9orf72, UNC13A, and MOBP genotypes on mortality and functional decline.
  • Evaluation of pharmacogenetic interactions between creatine/valproic acid and specific genotypes.

Main Results:

  • The UNC13A genotype was significantly associated with mortality (p=0.012).
  • C9orf72 repeat-expansion carriers showed a faster decline in overall and bulbar function (p=0.051 and p=0.005, respectively).
  • A significant pharmacogenetic interaction was found between creatine and the MOBP genotype's A allele (p=0.027), indicating a dose-response relationship.

Conclusions:

  • Genetic variations significantly influence ALS progression and treatment response.
  • Incorporating genetic data into ALS research can identify patient subgroups and potential treatment biases.
  • Pharmacogenetic insights may lead to more personalized and effective therapeutic strategies for ALS.

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