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Human Molecular Genetics Advance Access originally published online on November 30, 2005
Human Molecular Genetics 2006 15(1):77-85; doi:10.1093/hmg/ddi428
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Polymorphisms in the PON gene cluster are associated with Alzheimer disease

Porat M. Erlich1, Kathryn L. Lunetta5, L. Adrienne Cupples5, Matthew Huyck1, Robert C. Green1,2,6, Clinton T. Baldwin1,4, Lindsay A. Farrer1,2,3,5,6,* for the MIRAGE Study Group{dagger}

1Department of Medicine (Genetics Program), 2Department of Neurology and 3Department of Genetics and Genomics and 4Center for Human Genetics, Boston University School of Medicine, Boston, MA, USA, 5Department of Biostatistics and 6Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA

* To whom correspondence should be addressed at: Genetics Program, L-320, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA. Tel: +1 6176385393; Fax: +1 6176384275; Email: farrer{at}bu.edu

Received September 14, 2005; Accepted November 16, 2005

Paraoxonase is an arylesterase enzyme that is expressed in the liver and found in the circulation in association with apoA1 and the high-density lipoprotein, and prevents the accumulation of oxidized lipids in low-density lipoproteins in vitro. Common polymorphisms in genes encoding paraoxonase are established risk factors in a variety of vascular disorders including coronary artery disease and carotid artery stenosis, but their association with Alzheimer disease (AD) is controversial. We tested the association of 29 SNPs in PON1, PON2 and PON3 with AD in 730 Caucasian and 467 African American participants of the MIRAGE Study, an ongoing multi-center family-based genetic epidemiology study of AD. Eight SNPs were associated with AD in the African American families (0.0001≤P≤0.04) and two SNPs were associated with AD in Caucasian families (0.01≤P≤0.04). Of note, the pattern of association for the PON1 promoter SNP –161[C/T] was the same in both ethnic groups (P=0.006). Haplotype analysis using sliding windows revealed 11 contiguous SNP combinations spanning the three PON genes with significant global test scores (0.006≤P≤0.04) in the two ethnic groups combined. The most significantly associated haplotype comprised SNPs in the region spanning the –161[C/T] SNP (P=0.00009). Our results demonstrate association between AD and variants in the PON gene cluster in Caucasians and African Americans.

{dagger} MIRAGE Study Group members are listed in the acknowledgements.


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