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Paraoxonase cluster polymorphisms are associated with sporadic ALS.
M Saeed1, N Siddique, W Y Hung
1Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Neurology
|July 11, 2006
Summary
Genetic variants in the Paraoxonase (PON) gene cluster are associated with sporadic Amyotrophic Lateral Sclerosis (ALS). This suggests environmental toxins may trigger ALS in susceptible individuals.
Area of Science:
- Genetics
- Neuroscience
- Toxicology
Background:
- Paraoxonases (PONs) detoxify pesticides and nerve agents.
- Gulf War veterans show increased ALS risk, linked to PON1 gene polymorphisms.
- The study investigates sporadic ALS (SALS) and PON gene variants.
Purpose of the Study:
- To examine the association between sporadic ALS and variants in the PON gene cluster.
- To explore the role of genetic susceptibility in environmentally triggered ALS.
Main Methods:
- Utilized a large North American cohort (N=1,891) with family-based and case-control designs.
- Employed SNP genotyping (TaqMan assays) and analyzed data with statistical software.
- Diagnosed ALS using revised El Escorial criteria and excluded SOD1 mutations.
Main Results:
- A linkage disequilibrium (LD) block in PON2 and PON3 associated with SALS.
- Specific SNPs (rs10487132, rs11981433) showed association in trio models and were replicated.
- An intronic variant (rs17876088) distinguished detrimental and protective SALS haplotypes.
Conclusions:
- Significant association found between PON gene cluster variants and sporadic ALS.
- Results support the hypothesis that environmental toxicity can precipitate ALS in susceptible individuals.