Paraoxonase activity, but not haplotype utilizing the linkage disequilibrium structure, predicts vascular disease.
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.


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.
Jarvik
Gail P
GP
Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Wash, USA. pair@u.washington.edu
Hatsukami
Thomas S
TS
Carlson
Chris
C
Richter
Rebecca J
RJ
Jampsa
Rachel
R
Brophy
Victoria H
VH
Margolin
Sadie
S
Rieder
Mark
M
Nickerson
Deborah
D
Schellenberg
Gerard D
GD
Heagerty
Patrick J
PJ
Furlong
Clement E
CE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D043303:Aryldialkylphosphatase / Q000235:genetics* / Q000378:metabolism*; D002340:Carotid Artery Diseases / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D012044:Regression Analysis
D043303:Aryldialkylphosphatase; C468406:PON1 protein, human