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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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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.

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Author information

Author notes

  1. Vincenzo Silani and Nicola Ticozzi jointly supervised this work.

Authors and Affiliations

  1. Department of Neurology - Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, Piazzale Brescia 20, 20149, Milan, Italy

    Federico Verde, Cinzia Tiloca, Claudia Morelli, Alberto Doretti, Barbara Poletti, Luca Maderna, Stefano Messina, Isabella Fogh, Antonia Ratti, Vincenzo Silani & Nicola Ticozzi

  2. Unit of Bioinformatics and Genomic Statistics, Istituto Auxologico Italiano, IRCCS, Via Zucchi 18, 20095, Cusano Milanino, Italy

    Davide Gentilini

  3. Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy

    Davide Gentilini

  4. Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, UK

    Isabella Fogh

  5. Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, via Vanvitelli 32, 20129, Milan, Italy

    Antonia Ratti

  6. Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano, Via Francesco Sforza 35, 20122, Milan, Italy

    Vincenzo Silani & Nicola Ticozzi

  7. “Aldo Ravelli” Center for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, via Festa del Perdono 7, 20122, Milan, Italy

    Vincenzo Silani

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  1. Federico Verde
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Correspondence to Federico Verde.

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The authors declare that they have no conflict of interest.

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The study was in accordance with the ethical standards of the institutional research committee. Patients gave their written informed consent to the study.

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Verde, F., Tiloca, C., Morelli, C. et al. PON1 is a disease modifier gene in amyotrophic lateral sclerosis: association of the Q192R polymorphism with bulbar onset and reduced survival. Neurol Sci 40, 1469–1473 (2019). https://doi.org/10.1007/s10072-019-03834-2

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