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Liver X Receptor Genes Variants Modulate ALS Phenotype

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Abstract

Amyotrophic lateral sclerosis (ALS) is one of the most severe motor neuron (MN) disorders in adults. Phenotype of ALS patients is highly variable and may be influenced by modulators of energy metabolism. Recent works have implicated the liver X receptors α and β (LXRs), either in the propagation process of ALS or in the maintenance of MN survival. LXRs are nuclear receptors activated by oxysterols, modulating cholesterol levels, a suspected modulator of ALS severity. In a cohort of 438 ALS patients and 330 healthy controls, the influence of LXR genes on ALS risk and phenotype was studied using single nucleotide polymorphisms (SNPs). The two LXRα SNPs rs2279238 and rs7120118 were shown to be associated with age at onset in ALS patients. Consistently, homozygotes were twice more correlated than were heterozygotes to delayed onset. The onset was thus delayed by 3.9 years for rs2279238 C/T carriers and 7.8 years for T/T carriers. Similar results were obtained for rs7120118 (+2.1 years and +6.7 years for T/C and C/C genotypes, respectively). The LXRβ SNP rs2695121 was also shown to be associated with a 30% increase of ALS duration (p = 0.0055, FDR = 0.044). The tested genotypes were not associated with ALS risk. These findings add further evidence to the suspected implication of LXR genes in the disease process of ALS and might open new perspectives in ALS therapeutics.

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Acknowledgments

We thank the participants, patients, and controls who agreed to participate in this study and all the technicians of the Department of Biochemistry and Molecular Biology of Nîmes University Hospital and Emmanuelle Huet for their excellent technical assistance. This work was supported by grants from Groupement de Coopération Sanitaire Montpellier-Nîmes (GCS-MERRI).

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Authors and Affiliations

  1. Laboratoire de Biochimie et Biologie Moléculaire, CHU Nîmes et Université de Montpellier, Nîmes, France

    Kevin Mouzat, Jovana Kantar, Anne Polge & Serge Lumbroso

  2. INSERM UMR1051, Institut des Neurosciences de Montpellier, Hôpital Saint Eloi, Montpellier, France

    Kevin Mouzat, Raul Juntas-Morales, Nicolas Pageot, Cedric Raoul, Serge Lumbroso & William Camu

  3. IMAG, UMR 5149, DIM, CHRU de Montpellier, Montpellier, France

    Nicolas Molinari

  4. Centre SLA, Service de Neurologie et Neurophysiologie Clinique, CHRU de Tours, UMR INSERM U930, Tours, France

    Philippe Corcia

  5. Centre SLA, Service de Neurologie, CHU Limoges, Limoges, France

    Philippe Couratier

  6. Centre SLA, Service de Neurologie A, CHU Clermont-Ferrand, Clermont-Ferrand, France

    Pierre Clavelou

  7. ALS Center, Département de Neurologie, CHU Gui de Chauliac, Montpellier, France

    Raul Juntas-Morales, Nicolas Pageot & William Camu

  8. Génétique Reproduction et Développement, Clermont Université Clermont Université, Clermont-Ferrand, France; CNRS, UMR 6293, GReD, Aubière, France; INSERM, UMR 1103, GReD, Aubière, France

    Jean -Marc A. Lobaccaro

  9. Centre de Recherche en Nutrition Humaine d’Auvergne, Clermont-Ferrand, France

    Jean -Marc A. Lobaccaro

Authors
  1. Kevin Mouzat
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  2. Nicolas Molinari
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  3. Jovana Kantar
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  4. Anne Polge
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  5. Philippe Corcia
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  6. Philippe Couratier
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  7. Pierre Clavelou
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  8. Raul Juntas-Morales
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  9. Nicolas Pageot
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  10. Jean -Marc A. Lobaccaro
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  11. Cedric Raoul
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  12. Serge Lumbroso
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  13. William Camu
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Corresponding author

Correspondence to Kevin Mouzat.

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This DNA banking was approved by the Pitié-Salpêtrière Ethics Committee, and all patients and controls gave their informed consent.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Mouzat, K., Molinari, N., Kantar, J. et al. Liver X Receptor Genes Variants Modulate ALS Phenotype. Mol Neurobiol 55, 1959–1965 (2018). https://doi.org/10.1007/s12035-017-0453-2

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  • DOI: https://doi.org/10.1007/s12035-017-0453-2

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