Negative results Rare and common paraoxonase gene variants in amyotrophic lateral sclerosis patients Marka van Blitterswijk a , Anna Blokhuis a , Michael A. van Es a , Paul W.J. van Vught a , Paulina A. Rowicka a , Helenius J. Schelhaas b , Anneke J. van der Kooi c , Marianne de Visser c , Jan H. Veldink a,1 , Leonard H. van den Berg a,1, * a Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands b Department of Neurology and Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands c Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Received 11 December 2011; received in revised form 2 January 2012; accepted 12 January 2012 Abstract Polymorphisms in the paraoxonase family (PON) have been reported in patients with amyotrophic lateral sclerosis (ALS), but a recent meta-analysis did not show a clear association. Recently, PON mutations have also been identified in ALS patients. In this study, we assessed the frequency of PON variants in 1118 sporadic ALS patients, 93 familial ALS patients, and 1240 control subjects of Dutch descent. We identified PON mutations in 1.4% of sporadic ALS patients, 2.1% of familial ALS patients, and 2.5% of control subjects. There were no significant differences in mutational burden for rare variants or in allele frequencies of polymorphisms between patients and control subjects. Thus, this study does not support the premise that mutations or polymorphisms in PON contribute to ALS susceptibility. Keywords: Amyotrophic lateral sclerosis; Motor neuron disease; Familial ALS; Genetics; Paraoxonase; Mutations. © 2012 Elsevier Inc. All rights reserved. 1. Introduction The paraoxonase (PON) family contains 3 members (PON1, PON2, and PON3), which are located on chro- mosome 7. Their genes are approximately 70% similar and most likely derived from a common precursor. PON1 was identified due to its ability to hydrolyze organophos- phates and pesticides, including paraoxon; PON2 and PON3 lack this ability; they are lactonases/lactonizing enzymes. It has been shown that polymorphisms in PON1 influ- ence the quantity and quality of PON1, thereby affecting the efficiency of organophosphates detoxification. Be- cause exposure to solvents or chemicals may be associ- ated with amyotrophic lateral sclerosis (ALS), PON poly- morphisms have been studied in ALS patients. To date, 6 studies have reported an association between genetic variants in the PON gene cluster and ALS. Nonetheless, a meta-analysis, which included genome-wide associa- tion studies (GWAS), could not detect a clear association between single nucleotide polymorphisms (SNPs) in PON and ALS, when taking the burden of multiple test- ing into account (Wills et al., 2009). This could indicate that rare deleterious variants in PON are involved in the pathogenesis of ALS. A recent study investigated this hypothesis, and detected mutations that were predicted to alter PON’s function in ALS patients (Supplementary Table 1) (Ticozzi et al., 2010), however, only a relatively small number of control subjects were screened for PON mutations. Thus, to clarify the role of PON variants in ALS, we decided to investigate the frequency of rare and common PON variants in a large cohort of ALS patients * Corresponding author at: Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Heidelber- glaan 100, 3584 CX, Utrecht, The Netherlands. Tel.: +31 88 7557939; fax: +31 30 2542100. E-mail address: L.H.vandenBerg@umcutrecht.nl (L.H. van den Berg). 1 Contributed equally to this work. Neurobiology of Aging 33 (2012) 1845.e1–1845.e3 www.elsevier.com/locate/neuaging 0197-4580/$ – see front matter © 2012 Elsevier Inc. All rights reserved. 10.1016/j.neurobiolaging.2012.01.007