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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1465.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Paraoxonase Activity, But Not Haplotype Utilizing the Linkage Disequilibrium Structure, Predicts Vascular Disease

Gail P. Jarvik; Thomas S. Hatsukami; Chris Carlson; Rebecca J. Richter; Rachel Jampsa; Victoria H. Brophy; Sadie Margolin; Mark Rieder; Deborah Nickerson; Gerard D. Schellenberg; Patrick J. Heagerty; Clement E. Furlong

From the Departments of Medicine (Division of Medical Genetics) (G.P.J., R.J.R., R.J., V.H.B., S.M., C.E.F.), Epidemiology (G.P.J.), Genome Sciences (G.P.J., C.C., M.R., D.N., C.E.F.), Neurology (G.D.S.), and Biostatistics (P.J.H.), University of Washington, and the Puget Sound Veterans Affairs Health Care System (T.S.H., G.D.S.), Seattle, Wash.

Correspondence to Gail Jarvik, MD, PhD, University of Washington Medical Center, Division of Medical Genetics, Box 357720, Seattle, WA 98195-7720. E-mail pair{at}u.washington.edu

Objective— The effects of paraoxonase (PON1) activity and of genetic variation in the PON1 promoter and coding region on carotid artery disease (CAAD) were investigated.

Methods and Results— We identified functional promoter polymorphisms and examined their effects in a cohort with and without CAAD. We used the full sequences in 23 white subjects to determine the linkage disequilibrium (LD) structure of the PON1 region and to direct the grouping of haplotypes for disease association testing. There are several discrete regions of the PON1 gene with strong local LD, but the useful levels of LD do not extend across the entire gene. Indeed, PON1_{-162/-108/55/192} haplotype did not predict additional variation in PON1 activities compared with the 4 genotypes separately. PON1 hydrolysis activity predicted CAAD status, but this was not attributable to the promoter or coding region polymorphisms or haplotype or to the effects of smoking or statin use on PON1 activity.

Conclusions— PON1 does not have LD across the gene, and use of haplotypes in association studies should consider the LD structure. PON1 activity predicts CAAD, yet 4 functional polymorphisms do not. Additional investigations of genetic and environmental factors that influence PON1 activity as a risk factor for vascular disease are warranted.

Key Words: carotid • haplotype • oxidation • paraoxonase

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