پلی مورفیسم پاراکسوناز 1 در بیماری آلزایمر، بیماری پارکینسون، و بیماری های طیف AD-PD

Paraoxonase-1 (PON1) is a serum arylsulfatase that metabolizes organophosphate pesticides and protects low-density lipoprotein from oxidation. Case-control studies of PON1 genetic variants in Alzheimer's disease (AD) and Parkinson's disease (PD) have revealed some positive albeit inconsistent associations with 2 PON1 coding polymorphisms: Q192R (rs662) and L55M (rs854560). Because AD and PD exist along a spectrum of disorders with shared epidemiologic, clinical, and pathologic features, here we evaluated PON1 variants in a cohort of 746 AD, 566 PD, 132 AD-PD, and 719 cognitively normal age-matched controls. In the combined AD and Caucasian PD cohorts we had 80% power to detect a relative risk of at least 1.25 and 1.35, respectively, for each polymorphism. We found no association between 2 PON1 coding polymorphisms and AD in African Americans or Caucasians, and no association with PD or AD-PD in Caucasians. There was also no evidence of an interaction between PON1 and apolipoprotein E for any of these diseases. Our results suggest that either these functional PON1 polymorphisms are not associated with AD and PD spectrum disorders, or that the relative risk conferred is small.

Paraoxonase-1 (PON1) has been implicated in a variety of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis. PON1 hydrolyzes organophosphate pesticide, and appears to play a role in oxidative stress and atherosclerosis (Davies et al., 1996; Durrington et al., 2001; Mackness et al., 2001). Existing genetic studies of PON1 and AD and PD often associate 2 coding single nucleotide polymorphisms (SNPs), rs662 (Q192R) and rs854560 (L55M), with either disease (see supplemental material for references). These studies were limited to detecting relatively large effect sizes due to their small sample size or the need to correct for multiple tests. Hence we examined 2 PON1-coding SNPs in our combined cohort of AD and Caucasian cohort of PD patients with 80% power to detect a relative risk of at least 1.25 and 1.35, respectively (Purcell et al., 2003). Because these diseases share a variety of epidemiological, clinical, and pathological features, we hypothesized that the PON1 polymorphisms previously associated with AD or PD could confer additional risk for the spectrum of cases that share characteristics of both AD and PD: AD-PD overlap diseases.