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PON1 is a disease modifier gene in amyotrophic lateral sclerosis: association of the Q192R polymorphism with bulbar onset and reduced survival.

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Title: PON1 is a disease modifier gene in amyotrophic lateral sclerosis: association of the Q192R polymorphism with bulbar onset and reduced survival.
Authors: Verde, Federico (AUTHOR), Tiloca, Cinzia (AUTHOR), Morelli, Claudia (AUTHOR), Doretti, Alberto (AUTHOR), Poletti, Barbara (AUTHOR), Maderna, Luca (AUTHOR), Messina, Stefano (AUTHOR), Gentilini, Davide (AUTHOR), Fogh, Isabella (AUTHOR), Ratti, Antonia (AUTHOR), Silani, Vincenzo (AUTHOR), Ticozzi, Nicola (AUTHOR)
Source: Neurological Sciences. Jul2019, Vol. 40 Issue 7, p1469-1473. 5p. 1 Chart, 1 Graph.
Subjects: Amyotrophic lateral sclerosis, Motor neurons, Poisons, Age of onset, Genes, Age factors in disease, Disease susceptibility, Esterases, Genetic polymorphisms, Longitudinal method
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. [ABSTRACT FROM AUTHOR]
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Database: Psychology and Behavioral Sciences Collection
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Abstract:<bold>Introduction: </bold>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.<bold>Materials and Methods: </bold>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).<bold>Results: </bold>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.<bold>Discussion: </bold>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. [ABSTRACT FROM AUTHOR]
ISSN:15901874
DOI:10.1007/s10072-019-03834-2