Neurology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Correspondence:
Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when Correspondence are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Google Scholar
Right arrow Articles by Valdmanis, P. N.
Right arrow Articles by Rouleau, G. A.
PubMed
Right arrow Articles by Valdmanis, P. N.
Right arrow Articles by Rouleau, G. A.
Related Collections
Right arrow Amyotrophic lateral sclerosis
Right arrow Case control studies
Right arrow Association studies in genetics
NEUROLOGY 2008;71:514-520
© 2008 American Academy of Neurology

Association of paraoxonase gene cluster polymorphisms with ALS in France, Quebec, and Sweden

P. N. Valdmanis, BSc, E. Kabashi, PhD, A. Dyck, P. Hince, J. Lee, BA, P. Dion, PhD, M. D'Amour, MD, F. Souchon, MD, J. -P. Bouchard, MD, F. Salachas, MD, V. Meininger, MD, P. M. Andersen, MD, W. Camu, MD, N. Dupré, MD, MSc and G. A. Rouleau, MD, PhD

From the Center of Excellence in Neuromics (P.N.V., E.K., A.D., P.H., J.L., P.D., N.D., G.A.R.), University of Montreal and CHUM Research Center–Notre-Dame Hospital, Montreal, Quebec, Canada; Department of Human Genetics (P.N.V.), McGill University, Montreal, Quebec, Canada; CHUM Research Center (M.D., F.S.), St. Luc Hospital, Montreal, Quebec, Canada; Faculty of Medicine (J.-P.B., N.D.), Laval University, Department of Neurological Sciences, CHAUQ–Enfant-Jésus, Quebec City, Quebec, Canada; Fédération des maladies du système nerveux (F.S., V.M.), Division Paul Castaigne, Hôpital de la Salpêtrière, Paris, France; Department of Neurology (P.M.A.), Umeå University Hospital, Umeå, Sweden; Unité de Neurologie Comportementale et Dégénérative Molecular Unit (W.C.), Institute of Biology, Montpellier, France; Clinique du Motoneurone (W.C.), Service d'Explorations Neurologiques, Hôpital Guy de Chauliac, Montpellier, France; and Department of Medicine (G.A.R.), University of Montreal, Montreal, Quebec, Canada.

Address correspondence and reprint requests to Dr. Guy A. Rouleau, J.A. de Sève Pavilion, Room Y-3633, 1560, Sherbrooke St. East, Montreal, QC, Canada, H2L 4M1 guy.rouleau{at}umontreal.ca

Background: The paraoxonase gene cluster on chromosome 7 comprising the PON1–3 genes is an attractive candidate for association in amyotrophic lateral sclerosis (ALS) given the role of paraoxonase genes during the response to oxidative stress and their contribution to the enzymatic break down of nerve toxins. Oxidative stress is considered one of the mechanisms involved in ALS pathogenesis. Evidence for this includes the fact that mutations of SOD1, which normally reduce the production of toxic superoxide anion, account for 12% to 23% of familial cases in ALS. In addition, PON variants were shown to be associated with susceptibility to ALS in several North American and European populations.

Methods: We extended this analysis to examine 20 single nucleotide polymorphisms (SNPs) across the PON gene cluster in a set of patients from France (480 cases, 475 controls), Quebec (159 cases, 95 controls), and Sweden (558 cases, 506 controls).

Results: Although individual SNPs were not considered associated on their own, a haplotype of SNPs at the C-terminal portion of PON2 that includes the PON2 C311S amino acid change was significant in the French (p value 0.0075) and Quebec (p value 0.026) populations as well as all three populations combined (p value 1.69 x 10–6). Stratification of the samples showed that this variation was pertinent to ALS susceptibility as a whole, and not to a particular subset of patients.

Conclusions: These findings contribute to the increasing weight of evidence that genetic variants in the paraoxonase gene cluster are associated with amyotrophic lateral sclerosis.

Abbreviations: ALS = amyotrophic lateral sclerosis; EST = expressed sequence tag; FALS = familial amyotrophic lateral sclerosis; HDL = high-density lipoprotein; LD = linkage disequilibrium; LDL = low-density lipoprotein; LDU = linkage disequilibrium units; MA = minor allele; MAF = minor allele frequency; NA = not available; OR = odds ratio; SALS = sporadic amyotrophic lateral sclerosis; SNP = single nucleotide polymorphism.

Supplemental data at www.neurology.org

Supported by the Association pour la recherche sur la sclerose laterale amyotrophique, the Association Francaise contre les Myopathies, the French Group on MND, Genethon (for DNA extraction and cell lines), and the Muscular Dystrophy Association. P.N.V. is a recipient of a scholarship from the Fonds de Recherche en Sante Quebec. E.K. is a recipient of a Tim Noel Fellowship from the Canadian Institute of Health Research (CIHR) and ALS Canada. N.D. and G.A.R. also received support from the CIHR.

Disclosure: The authors report no disclosures.

Received January 7, 2008. Accepted in final form May 1, 2008.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2008 by AAN Enterprises, Inc.