Federico Verde1, Cinzia Tiloca2, Claudia Morelli2, Alberto Doretti2, Barbara Poletti2, Luca Maderna2, Stefano Messina2, Davide Gentilini3,4, Isabella Fogh2,5, Antonia Ratti2,6, Vincenzo Silani2,7,8, Nicola Ticozzi2,7. 1. Department of Neurology - Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, Piazzale Brescia 20, 20149, Milan, Italy. fdrc.verde@gmail.com. 2. Department of Neurology - Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, Piazzale Brescia 20, 20149, Milan, Italy. 3. Unit of Bioinformatics and Genomic Statistics, Istituto Auxologico Italiano, IRCCS, Via Zucchi 18, 20095, Cusano Milanino, Italy. 4. Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy. 5. Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK. 6. Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, via Vanvitelli 32, 20129, Milan, Italy. 7. Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, Via Francesco Sforza 35, 20122, Milan, Italy. 8. "Aldo Ravelli" Center for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, via Festa del Perdono 7, 20122, Milan, Italy.
Abstract
INTRODUCTION: Previous studies have associated single-nucleotide polymorphisms (SNPs) in the gene encoding the detoxifying enzyme paraoxonase 1 (PON1) to the risk of sporadic ALS. Here, we aimed to assess the role of the coding rs662 (Q192R) SNP as a modifier of ALS phenotype. MATERIALS AND METHODS: We genotyped a cohort of 409 patients diagnosed with ALS at our Center between 2002 and 2009 (269 males and 140 females; mean age at onset, 58.3 ± 37.5 years). RESULTS: We found PON1 to be a disease modifier gene in ALS, with the minor allele G associated both with bulbar onset (30.9% vs. 24.6%, p = 0.013) and independently with reduced survival (OR = 1.38, p = 0.012) under a dominant model. No association was found with gender or age at onset. DISCUSSION: As this SNP is known to modify the detoxifying activity of paraxonase 1 with respect to different substrates as well as other activities of the protein, we hypothesize that the identified association might reflect specific motor neuron vulnerability to certain exogenous toxic substances metabolized less efficiently by the 192R alloenzyme, or to detrimental endogenous pathophysiological processes such as oxidative stress. Further exploration of this possible metabolic susceptibility could deepen our knowledge of ALS pathomechanisms.
INTRODUCTION: Previous studies have associated single-nucleotide polymorphisms (SNPs) in the gene encoding the detoxifying enzyme paraoxonase 1 (PON1) to the risk of sporadic ALS. Here, we aimed to assess the role of the coding rs662 (Q192R) SNP as a modifier of ALS phenotype. MATERIALS AND METHODS: We genotyped a cohort of 409 patients diagnosed with ALS at our Center between 2002 and 2009 (269 males and 140 females; mean age at onset, 58.3 ± 37.5 years). RESULTS: We found PON1 to be a disease modifier gene in ALS, with the minor allele G associated both with bulbar onset (30.9% vs. 24.6%, p = 0.013) and independently with reduced survival (OR = 1.38, p = 0.012) under a dominant model. No association was found with gender or age at onset. DISCUSSION: As this SNP is known to modify the detoxifying activity of paraxonase 1 with respect to different substrates as well as other activities of the protein, we hypothesize that the identified association might reflect specific motor neuron vulnerability to certain exogenous toxic substances metabolized less efficiently by the 192R alloenzyme, or to detrimental endogenous pathophysiological processes such as oxidative stress. Further exploration of this possible metabolic susceptibility could deepen our knowledge of ALS pathomechanisms.
Entities:
Keywords:
ALS; Motor neurons; PON1; Paraoxonase; SNP; Toxicity
Authors: Jacqueline Vahey; Elizabeth J Gifford; Kellie J Sims; Blair Chesnut; Stephen H Boyle; Crystal Stafford; Julie Upchurch; Annjanette Stone; Saiju Pyarajan; Jimmy T Efird; Christina D Williams; Elizabeth R Hauser Journal: Brain Sci Date: 2021-11-25