Liver X Receptor Genes Variants Modulate ALS Phenotype |
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Authors: | Kevin Mouzat Nicolas Molinari Jovana Kantar Anne Polge Philippe Corcia Philippe Couratier Pierre Clavelou Raul Juntas-Morales Nicolas Pageot Jean -Marc A Lobaccaro Cedric Raoul Serge Lumbroso William Camu |
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Institution: | 1.Laboratoire de Biochimie et Biologie Moléculaire,CHU N?mes et Université de Montpellier,N?mes,France;2.INSERM UMR1051,Institut des Neurosciences de Montpellier, H?pital Saint Eloi,Montpellier,France;3.IMAG, UMR 5149, DIM, CHRU de Montpellier,Montpellier,France;4.Centre SLA, Service de Neurologie et Neurophysiologie Clinique, CHRU de Tours, UMR INSERM U930,Tours,France;5.Centre SLA, Service de Neurologie, CHU Limoges,Limoges,France;6.Centre SLA, Service de Neurologie A, CHU Clermont-Ferrand,Clermont-Ferrand,France;7.ALS Center, Département de Neurologie, CHU Gui de Chauliac,Montpellier,France;8.Génétique Reproduction et Développement,Clermont Université Clermont Université, Clermont-Ferrand, France; CNRS, UMR 6293, GReD, Aubière, France; INSERM, UMR 1103, GReD,Aubière,France;9.Centre de Recherche en Nutrition Humaine d’Auvergne,Clermont-Ferrand,France |
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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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