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Human Molecular Genetics Advance Access published online on November 30, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi428
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received September 14, 2005
Accepted November 16, 2005

Article

Polymorphisms in the PON gene cluster are associated with Alzheimer disease

Porat M. Erlich 1, Kathryn L. Lunetta 2, L. Adrienne Cupples 2, Matthew Huyck 1, Robert C. Green 3, Clinton T. Baldwin 4, Lindsay A. Farrer 5 *, and for the MIRAGE Study Group

1 Department of Medicine (Genetics Program), Boston University School of Medicine, Boston, MA
2 Department of Biostatistics, Boston University School of Public Health, Boston, MA
3 Department of Medicine (Genetics Program), Boston University School of Medicine, Boston, MA; Department of Neurology, Boston University School of Medicine, Boston, MA; Department of Epidemiology, Boston University School of Public Health, Boston, MA
4 Department of Medicine (Genetics Program), Boston University School of Medicine, Boston, MA; Center for Human Genetics, Boston University School of Medicine, Boston, MA
5 Department of Medicine (Genetics Program), L-320, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118; Department of Neurology, Boston University School of Medicine, Boston, MA; Department of Genetics & Genomics, Boston University School of Medicine, Boston, MA; Department of Biostatistics, Boston University School of Public Health, Boston, MA; Department of Epidemiology, Boston University School of Public Health, Boston, MA

* To whom correspondence should be addressed.
Lindsay A. Farrer, E-mail: farrer{at}bu.edu


  Abstract

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 2 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.


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