title: Novel associations of nonstructural Loci with paraoxonase activity.
abstract: The high-density-lipoprotein-(HDL-) associated esterase paraoxonase 1 (PON1) is a likely contributor to the antioxidant and antiatherosclerotic capabilities of HDL. Two nonsynonymous mutations in the structural gene, PON1, have been associated with variation in activity levels, but substantial interindividual differences remain unexplained and are greatest for substrates other than the eponymous paraoxon. PON1 activity levels were measured for three substrates-organophosphate paraoxon, arylester phenyl acetate, and lactone dihydrocoumarin-in 767 Mexican American individuals from San Antonio, Texas. Genetic influences on activity levels for each substrate were evaluated by association with approximately one million single nucleotide polymorphism (SNPs) while conditioning on PON1 genotypes. Significant associations were detected at five loci including regions on chromosomes 4 and 17 known to be associated with atherosclerosis and lipoprotein regulation and loci on chromosome 3 that regulate ubiquitous transcription factors. These loci explain 7.8% of variation in PON1 activity with lactone as a substrate, 5.6% with the arylester, and 3.0% with paraoxon. In light of the potential importance of PON1 in preventing cardiovascular disease/events, these novel loci merit further investigation.
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, P.O. Box 760549, San Antonio, TX 78245-0549, USA.
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Quillen
authors.forename: David L
authors.initials: DL
authors.lastname: Rainwater
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Dyer
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Carless
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Curran
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Johnson
authors.forename: Harald H H
authors.initials: HH
authors.lastname: Göring
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Cole
authors.forename: Sue
authors.initials: S
authors.lastname: Rutherford
authors.forename: Jean W
authors.initials: JW
authors.lastname: Maccluer
authors.forename: Eric K
authors.initials: EK
authors.lastname: Moses
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.forename: Michael C
authors.initials: MC
authors.lastname: Mahaney