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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.
* To whom correspondence should be addressed. E-mail: t-siddique{at}northwestern.edu.
Abstract-- 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.
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