Polymorphisms in the PON gene cluster are associated with Alzheimer disease

Porat M. Erlich, Kathryn L. Lunetta, L. Adrienne Cupples, Matthew Huyck, Robert C. Green, Clinton T. Baldwin, Lindsay A. Farrer, Sanford Auerbach, Abimbola Akomolafe, Patrick Griffith, Elizabeth Ofili, Jeffrey Browndyke, Donald Schmechel, Kathleen Welsh-Bohmer, Helena Chui, Charles DeCarli, Ranjan Duara, Tatiana Foroud, Martin Farlow, Robert FriedlandRodney Go, Alexander Kurz, Thomas Obisesan, Helen Petrovitch, Lon White, Norman Relkin, Marwan Sabbagh, Dessa Sadovnick, Magda Tsolaki

Research output: Contribution to journalArticle

70 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)77-85
Number of pages9
JournalHuman molecular genetics
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2006

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Erlich, P. M., Lunetta, K. L., Cupples, L. A., Huyck, M., Green, R. C., Baldwin, C. T., Farrer, L. A., Auerbach, S., Akomolafe, A., Griffith, P., Ofili, E., Browndyke, J., Schmechel, D., Welsh-Bohmer, K., Chui, H., DeCarli, C., Duara, R., Foroud, T., Farlow, M., ... Tsolaki, M. (2006). Polymorphisms in the PON gene cluster are associated with Alzheimer disease. Human molecular genetics, 15(1), 77-85. https://doi.org/10.1093/hmg/ddi428