HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) Data Supplement Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wills, A. -M. Articles by Brown, R. H. Search for Related Content PubMed PubMed Citation Articles by Wills, A. -M. Articles by Brown, R. H., Jr Related Collections All Neuromuscular Disease Anterior nerve cell disease Amyotrophic lateral sclerosis All Toxicology Other toxicology Gene expression studies Cerebrospinal Fluid Association studies in genetics

Paraoxonase 1 (PON1) organophosphate hydrolysis is not reduced in ALS

From the Day Neuromuscular Research Laboratory, Department of Neurology (A.-M.W., J.E.L., R.H.B.), Biostatistics Center (H.Z.), and Neurology Clinical Trials Unit, Department of Neurology (A.J.C., M.E.C.), Massachusetts General Hospital, Harvard Medical School, Boston, MA; and Departments of Genome Sciences and Medicine (R.J.R., C.E.F.), Division of Medical Genetics, University of Washington, Seattle.

Address correspondence to Dr. Anne-Marie Wills, CNY 114-3125, 114 16th St., Charlestown, MA 02129 awills{at}partners.org

Objective: Four recent studies report a genetic association of the paraoxonase locus with sporadic amyotrophic lateral sclerosis (ALS). We tested the hypothesis that this association correlates with functional changes in paraoxonase 1 (PON1, MIM 168820).

Methods: Sera from 140 ALS participants; 153 age-, race-, and sex-matched controls; and 30 matched CSF samples were tested for paraoxonase, diazoxonase, and arylesterase activities. Participants with ALS were genotyped using tagging single nucleotide polymorphisms across the PON locus. Survival data and enzyme activity were correlated with genotype.

Results: There was a trend toward increased paraoxonase activity in ALS compared with controls (mean control paraoxonase 701.9 ± 469.7 U/L, mean ALS 792.5 ± 574.1 U/L; p = 0.066 after correction) which correlated with increased frequency of the homozygous arginine (RR) variant of PON1_Q192R (p = 0.004). There was no significant difference in PON1 protein levels, or arylesterase or diazoxonase activities. Organophosphate hydrolysis rates had no effect on ALS survival.

Conclusions: Contrary to expectations, PON1 protein, paraoxonase, diazoxonase, and arylesterase activities were not reduced in amyotrophic lateral sclerosis (ALS). The increase in PON1_R192 frequency in ALS in our study supports previous genetic susceptibility studies. Our findings suggest that the influence of PON1 polymorphisms on ALS susceptibility is not due to reduced organophosphate hydrolysis.

Abbreviations: ALS = amyotrophic lateral sclerosis; HR = hazard ratio; MAF = minimum allele frequency; OR = odds ratio; PON1 = paraoxonase 1; SNP = single nucleotide polymorphism.

Supplemental data at www.neurology.org

Supported by NIH grants ES09883 and ES04696 (C.E.F.) and grants 5R01NS050557-02 and 5R01NS05050641-04 (R.H.B.), the Francis and Ingeborg Heide Schumann Fellowship in Parkinson Disease, and the American Academy of Neurology Foundation/ALS Clinician Scientist Development Fellowship (A.-M.W.) R.H.B. also receives support from the Angel Fund, the ALS Therapy Alliance, Project ALS, the Al-Athel ALS Research Foundation, and the Pierre L. de Bourgknecht ALS Research Foundation.

Disclosure: The authors report no conflicts of interest.

Received August 22, 2007. Accepted in final form October 30, 2007.