Paraoxonase-1 polymorphisms in Alzheimer's disease, Parkinson's disease, and AD-PD spectrum diseases

doi:10.1016/j.neurobiolaging.2010.08.010

Neurobiology of Aging

Volume 33, Issue 1, January 2012, Pages 204.e13-204.e15

https://doi.org/10.1016/j.neurobiolaging.2010.08.010 Get rights and content

Abstract

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.

Introduction

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.

Section snippets

Methods

We recruited 746 probable AD patients, 566 PD patients, 135 AD-PD patients, and 719 age-matched cognitively normal controls. Diagnostic criteria are detailed in the supplementary material. All individuals were genotyped for rs662 and rs854560 using TaqMan assays purchased from Applied Biosystems (Foster City, CA, USA). Because our cohort included Caucasians and African-Americans each ethnic group was analyzed separately provided there were >25 individuals within a disease category. Allelic

Results

Both SNPs had <1% missing data rate, 99.9% concordance rate in 1139 random duplicate samples, and were in Hardy-Weinberg equilibrium (HWE) among cases and controls. Demographic data are shown in Supplementary Table 1. We found no evidence for association between rs662 or rs854560 and AD, PD, or AD-PD in Caucasians; moreover, we found no evidence for association between rs662 or rs854560 and AD in African-Americans (Table 1). Logistic regression did not reveal any significant association under

Discussion

Previous genetic association studies of PON1 have shown intriguing but inconsistent links with AD and PD. Clarifying the role of PON1 in AD and PD is important because of its putative biological roles in pesticide metabolism, inflammation, and oxidative stress, as well as the involvement of these mechanisms in the pathogenesis of neurodegenerative disease. To this end, we studied a large and clinically characterized cohort of subjects with AD, PD, and AD-PD overlapping diseases and found no

Disclosure statement

The authors declare no actual or potential conflicts of interest.

This study was undertaken after receiving institutional review board approval.

Acknowledgements

The authors acknowledge the technical assistance of Weining Tang with sample processing and genotyping.

This work was supported by the Emory Alzheimer's Disease Research Center Grant AG025688 and Emory NINDS Neuroscience Core Facilities Grant NS055077.

References (0)

Cited by (23)

Association of Paraoxonase1 enzyme and its genetic single nucleotide polymorphisms with cardio-metabolic and neurodegenerative diseases
2020, Gene Reports
Citation Excerpt :
In addition to PON1 activity there are studies which reported the association of PON1 SNPs with AD. In a study, which included African, American and Caucasians, no association was observed between PON1 polymorphisms and AD (Wingo et al., 2012). However, another study conducted on Chinese population that included a total of 1000 subjects (cases and controls) reported PON1 Q192R polymorphism associated with the risk of AD, and R allele was reported to have protective function against AD in Chinese ethnic population (He et al., 2006).
Paraoxonase1 (PON1) is an antioxidant enzyme on HDL particle and is associated with hydrolase, esterase and lactonase activities. It has a potential to hydrolyze diverse number of substrates such as lipid peroxides, hydroperoxides, esters and lactones and is also accomplished with a capability of preventing LDL-C, phospholipid and cell membrane oxidation and generation of oxidized LDL-C and other potent reactive species which are contributors of atherosclerosis and other inflammatory diseases. The enzyme is multifunctional showing anti-oxidative, anti-inflammatory, anti-atherogenic, anti-diabetic, anti-microbial, organophosphate detoxifying properties, and has the capability to hydrolyze N acyl homoserine lactones which are common mediators that are involved in bacterial cell-cell communication process known as quorum sensing and is thus involved in giving protection from bacterial infections besides also having reputed functions in preventing from cancers, senescence/ageing, detoxification of xenobiotic compounds, and in several neurodegenerative disease including ischemic stroke, multiple sclerosis, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. There are several single nucleotide polymorphisms present in promoter and coding regions of PON1 gene. Most commonly reported are C108T promoter region and Q192R and L55M coding region polymorphisms which are known to change PON1 expression and also concentration and activity of PON1 enzyme in serum and in turn predispose to cardio-metabolic and neurodegenerative diseases. The purpose of this review is to present overall information on the scenario of PON1 enzyme and its genetic variants in several metabolic, cardio-metabolic and neurodegenerative diseases that may help clinicians to tackle various diseases particularly the one related to cardiometabolic and neurodegenerative disorders.
Pesticides exposure as etiological factors of Parkinson's disease and other neurodegenerative diseases-A mechanistic approach
2014, Toxicology Letters
The etiology of most neurodegenerative disorders is multifactorial and consists of an interaction between environmental factors and genetic predisposition. The role of pesticide exposure in neurodegenerative disease has long been suspected, but the specific causative agents and the mechanisms underlying are not fully understood. For the main neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis there are evidences linking their etiology with long-term/low-dose exposure to pesticides such as paraquat, maneb, dieldrin, pyrethroids and organophosphates. Most of these pesticides share common features, namely the ability to induce oxidative stress, mitochondrial dysfunction, α-synuclein fibrillization and neuronal cell loss. This review aims to clarify the role of pesticides as environmental risk factors in genesis of idiopathic PD and other neurological syndromes. For this purpose, the most relevant epidemiological and experimental data is highlighted in order to discuss the molecular mechanisms involved in neurodegeneration.
Paraoxonase and arylesterase activity and total oxidative/anti-oxidative status in patients with idiopathic Parkinson's disease
2014, Journal of Clinical Neuroscience
This study investigated serum paraoxonase (PON1) and arylesterase activity along with determination of oxidative status via measurement of total oxidant status (TOS), total anti-oxidant status (TAS) and oxidative stress index (OSI) in patients with Parkinson’s disease (PD) and compared results with data from healthy controls. A total of 82 subjects, including 42 patients with idiopathic PD, newly diagnosed and untreated (24 men, 18 women, aged 47–66 years) and 40 healthy controls were enrolled in this study. We aimed to evaluate the oxidative status of PD patients via measurement of serum TOS and TAS and estimation of OSI using new automated methods. PON1 and arylesterase activities were measured spectrophotometrically. Serum total cholesterol, high density lipoprotein cholesterol, low density lipoprotein (LDL) cholesterol and triglyceride levels were measured using routine methods. TAS levels of PD patients were significantly lower than that of controls (p < 0.05). TOS levels of PD patients were higher than those of controls (p < 0.05). PON1 and arylesterase activities of PD were lower than those of controls (p < 0.05). Serum levels of total and LDL cholesterol were significantly reduced in PD patients. In conclusion, the presence of high TOS and OSI levels together with low levels of TAS in PD patients supports the important role of oxidative stress in the pathophysiology of PD. Since oxidative stress is involved in neurodegeneration, selecting anti-oxidants, metal chelators or other compounds boosting endogenous enzymatic and non-enzymatic defense mechanisms seems to be an obvious choice as treatment for PD.
Lack of an association between Paraoxonase 1 gene polymorphisms (Q192R, L55M) and Alzheimer's disease: A meta-analysis
2012, Neuroscience Letters
Citation Excerpt :
It is biologically reasonable to hypothesize that the PON1 polymorphisms might contribute to the increased AD risk. A variety of molecular epidemiological studies have evaluated the association between PON1 polymorphisms (Q192R, L55M) and AD risk [5,6,13,15,18,27,28,30,32–34]. However, results in different studies were inconsistent.
The association between Paraoxonase 1 (PON1) gene polymorphisms (Q192R, L55M) and Alzheimer's disease (AD) risk has been reported inconsistent results. To assess the association between PON1 polymorphisms and AD risk, a meta-analysis was performed. Based on comprehensive searches of the PubMed, Embase, Web of Science, Weipu, and CBM databases, a total of 10 studies including 3081 AD cases and 3054 controls were identified. The pooled odds ratio (OR) with 95% confidence interval (95% CI) were performed. There was no significant association between PON1 Q192R polymorphism and AD risk in all comparison models (R vs. Q, OR = 0.89, 95% CI = 0.82–0.96; RR vs. QQ, OR = 0.83, 95% CI = 0.68–1.01; RR + RQ vs. QQ, OR = 0.86, 95% CI = 0.75–0.97; and RR vs. QR + QQ, OR = 0.94, 95% CI = 0.81–1.11). For the PON1 L55M polymorphism, lack of an association was also found (L vs. M, OR = 0.95, 95% CI = 0.86–1.05; LL vs. MM, OR = 0.67, 95% CI = 0.51–0.88; LL vs. ML + MM, OR = 0.82, 95% CI = 0.69–0.98; and LL + ML vs. MM, OR = 0.75, 95% CI = 0.58–0.96). On subgroup analysis by ethnicity, similar results were found. Conclusively, the present meta-analysis revealed that PON1 gene polymorphisms (Q192R, L55M) were unlikely to contribute to AD susceptibility.
Rare and common paraoxonase gene variants in amyotrophic lateral sclerosis patients
2012, Neurobiology of Aging
Citation Excerpt :
We were unable to detect significant differences, and thus our findings support studies that reported a lack of association between common PON variants and ALS. Our findings are also in line with a recent report that described a lack of association between PON SNPs and other neurodegenerative diseases, these included Alzheimer's disease (AD), Parkinson's disease (PD), and AD-PD spectrum diseases (Wingo et al., 2012). PON was previously sequenced in SALS and FALS patients, and this resulted in the identification of missense mutations (Ticozzi et al., 2010).
Polymorphisms in the paraoxonase family (PON) have been reported in patients with amyotrophic lateral sclerosis (ALS), but a recent meta-analysis did not show a clear association. Recently, PON mutations have also been identified in ALS patients. In this study, we assessed the frequency of PON variants in 1118 sporadic ALS patients, 93 familial ALS patients, and 1240 control subjects of Dutch descent. We identified PON mutations in 1.4% of sporadic ALS patients, 2.1% of familial ALS patients, and 2.5% of control subjects. There were no significant differences in mutational burden for rare variants or in allele frequencies of polymorphisms between patients and control subjects. Thus, this study does not support the premise that mutations or polymorphisms in PON contribute to ALS susceptibility.
Paraoxonase 1 polymorphisms L55M and Q192R were not risk factors for Parkinson's disease: A HuGE review and meta-analysis
2012, Gene
Citation Excerpt :
References in the papers found via computer search were examined to identify additional studies (Fig. 1). We conducted the meta-analysis of twelve studies, nine involved Caucasians (Akhmedova et al., 1999, 2001; Carmine et al., 2002; Clarimon et al., 2004; Dick et al., 2007; Kelada et al., 2003; Manthripragada et al., 2010; Taylor et al., 2000; Wingo et al., 2012) and three involved Asians (Kondo and Yamamoto, 1998; Momose et al., 2002; Wang and Liu, 2000). Some data of the genotypes were got from the author (Dick et al., 2007).
The Paraoxonase 1 (PON1) has been studied as a potential candidate gene for Parkinson's disease risk, but direct evidence from genetic association studies remains inconclusive. We performed a meta-analysis pooling data from all relevant studies in order to determine the effects of two PON 1 polymorphisms (L55M and Q192R) on Parkinson's disease.
We applied a random effects to combine odds ratio (OR) and 95% confidence intervals. Q statistic was used to evaluate the homogeneity, and Egger's test and Funnel plot were used to assess publication bias. In secondary analyses, we examined dominant and recessive models as well.
Concerning the PON1 L55M polymorphism, we identified 9 eligible studies (a total of 2582 cases and 3997 controls). The random effects pooled OR was OR = 1.29, (0.90, 1.84). Concerning the Q192R polymorphism, we identified 7 eligible studies (a total of 2582 cases and 3997 controls). The random effects pooled OR was OR = 1.08(0.81, 1.43). Analysis with dominant and recessive genetic models yielded the same inferences as genotype-based comparisons for both of the two polymorphisms.
The results of this meta-analysis suggested that both PON1 L55M and Q192R were not responsible for PD.

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Abstract of online articleNegative resultParaoxonase-1 polymorphisms in Alzheimer's disease, Parkinson's disease, and AD-PD spectrum diseases