Premium
[P‐076]: Polymorphisms in paraoxonase genes PON1, PON2 and PON3 are associated with late onset Alzheimer disease
Author(s) -
Erlich Porat M.,
Lunetta Kathryn L.,
Cupples L. Adrienne,
Green Robert C.,
Baldwin Clinton T.,
Farrer Lindsay A.
Publication year - 2005
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2005.06.150
Subject(s) - pon1 , single nucleotide polymorphism , paraoxonase , snp , haplotype , genetics , genotyping , allele , biology , minor allele frequency , genetic association , genotype , gene , endocrinology , oxidative stress
Background: Serum paraoxonase isozymes are believed to protect against low density lipoprotein oxidation and thus affect the risk of coronary artery disease. They are encoded by a family of three paralogous genes residing in a cluster on chromosome 7q21 (PON1, PON2 and PON3). Recent evidence suggests an association between SNPs in PON1 and PON2 and Alzheimer disease (AD). Objective: To conduct a comprehensive investigation of association between SNPs in the PON gene cluster and AD. Methods: We genotyped 28 SNPs in the PON gene cluster in DNA specimens obtained from participants of the MIRAGE AD Study, including 267 Caucasian AD cases and 317 of their non-demented sibs and 238 African American AD cases and 172 of their non-demented sibs. SNPs were selected for genotyping based on their minor allele frequencies, predicted function, predicted haplotype representation and validation. Data for individual SNPs were evaluated using family-based association tests, generalized estimating equations and chi square tests of proportion. Haplotype analysis was conducted using HBAT. Conclusions: We observed association between AD and several SNPs and haplotypes throughout the PON gene cluster. In both Caucasians and African Americans a peak of significant association in the coding regions of PON2 and PON3 was found (p-values ranged between p 0.01 to p 0.0002). In Caucasian families a significant association was observed for a SNP in the promoter of PON1. This is the first comprehensive high-density SNP association study of paraoxonase genes and AD. Our results confirm and extend those of previous reports, which evaluated single SNPs in smaller datasets. Like APOE, paraoxonase is involved in the physiological pathway of lipidtransport. Our study highlights the importance of this pathway and, possibly, its related vascular pathologies (e.g. atherosclerosis) in the etiology of late onset AD. Further studies are needed to identify the functional variants in the PON gene cluster responsible for this association.