PON1 – Amyotrophic Lateral Sclerosis Susceptibility

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motor neurons. Early case–control studies reported that a common PON1 promoter haplotype and SNPs within PON1 were associated with sporadic ALS risk in cohorts of 597 cases versus 692 controls (p=2.75×10⁻⁵) ([PMID:18618303]) and nominal associations in combined North American and European sets ([PMID:18695162]). However, a large meta-analysis of 4,037 ALS cases and 4,609 controls incorporating GWAS data found no significant association of PON1 Q192R (rs662) or other PON1 variants after multiple-testing correction (OR 1.06, p=0.22) ([PMID:19321847]). Targeted sequencing in 1,118 sporadic and 93 familial ALS patients versus 1,240 controls identified PON1 rare variants at similar frequencies in patients and controls (1.4% vs 2.5%) ([PMID:22330174]). No Mendelian segregation of PON1 variants has been documented in ALS families.

Functional characterization of PON1 has elucidated its roles in organophosphate detoxification and protection against lipid oxidation, but no cell or animal models have demonstrated PON1 dysfunction causing motor neuron degeneration. Thus, experimental evidence does not corroborate a pathogenic mechanism in ALS. Taken together, the genetic data are conflicting and functional studies lack disease‐relevant context, designating the PON1–ALS relationship as disputed. PON1 genotyping currently lacks utility for ALS risk assessment or diagnostic decision‐making.

References

• Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases • 2008 • A common haplotype within the PON1 promoter region is associated with susceptibility to sporadic ALS. PMID:18618303
• Neurology • 2009 • A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS. PMID:19321847
• Neurobiology of aging • 2012 • Rare and common paraoxonase gene variants in amyotrophic lateral sclerosis patients. PMID:22330174

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