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From the Davee Department of Neurology and Clinical Neurosciences (M.S., N.S., W.-Y.H., E.U., E.L., R.L.S., S.L.H.), Feinberg School of Medicine, Northwestern University, Chicago, IL; Center for Human Genetics Research (J.L.H.), Vanderbilt University Medical Center, Nashville, TN; Center for Human Genetics (M.P.-V.), Duke University Medical Center, Durham, NC; and Department of Cell and Molecular Biology (T.S.), Northwestern University Institute of Neuroscience, Chicago, IL.
Address correspondence and reprint requests to Dr. Teepu Siddique, Davee Department of Neurology and Clinical Neurosciences and Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Tarry Building, Room 13-715, 303 East Chicago Avenue, Chicago IL 60611; e-mail: t-siddique{at}northwestern.edu
Background: Paraoxonases (PONs) are involved in the detoxification of organophosphate pesticides and chemical nerve agents. Due to a reported possible twofold increased risk of ALS in Gulf War veterans and the associations of PON1 polymorphisms with the neurologic symptom complex of the Gulf War syndrome, the authors investigated the association between sporadic ALS (SALS) and PON gene cluster variants in a large North American Caucasian family–based and case-control cohort (N = 1,891).
Methods: Clinically definite and probable ALS was diagnosed according to the revised El Escorial criteria, exclusion of family history of ALS, and SOD1 mutation analysis. Single nucleotide polymorphism (SNP) genotyping was done using TaqMan assays on ABI7900HT. Data were analyzed using SPSS, Haploview, FBAT, and THESIAS.
Results: A haploblock of high linkage disequilibrium (LD) spanning PON2 and PON3 was associated with SALS. The SNPs rs10487132 and rs11981433 were in strong LD and associated with SALS in the trio (parents-affected child triad) model. The association of rs10487132 was replicated in 450 nuclear pedigrees comprising trios and discordant sibpairs. No association was found in case-control models, and their haplostructure was different from that of the trios with overall reduced LD. Resequencing identified an intronic variant (rs17876088) that differentiated between detrimental and protective SALS haplotypes.
Conclusion: This study demonstrates evidence of significant association of variants in the Paraoxonase gene cluster with sporadic ALS and is compatible with the hypothesis that environmental toxicity in a susceptible host may precipitate ALS.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the September 12 issue to find the title link for this article.
Editorial, see page 738
See also page 766
This article was previously published in electronic format as an Expedited E-Pub on July 5, 2006, atwww.neurology.org.
Supported by the National Institute of Neurological Disorders and Stroke (NS050641, NS046535), the Les Turner ALS Foundation, the V. E. Schaff ALS Research Fund, the H. Post Research Professorship, the Wenske Foundation, the Falk Medical Research Trust, Abbott Labs Duane and Susan Burnham Professorship, and the David C. Asselin MD Memorial Fund.
Disclosure: The authors report no conflicts of interest
Received January 23, 2006. Accepted in final form April 25, 2006.
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