on February 27, 2003
Published online before print February 27, 2003, doi: 10.1161/01.ATV.0000064383.88696.24
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Submitted on October 10, 2002
Accepted on February 11, 2003
Evidence That Peroxisome Proliferator-Activated Receptor Delta Influences Cholesterol Metabolism in Humans
Josefin Skogsberg ;
From the Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Hospital, SE-171 76 Stockholm, Sweden.
* To whom correspondence should be addressed. E-mail: Ewa.Ehrenborg{at}ks.se.
Objective--The objective of this work was to explore the role of peroxisome proliferator-activated receptor delta (PPARD) in lipid metabolism in humans.
Methods and Results--PPARD is a nuclear receptor involved in lipid metabolism in primates and mice. We screened the 5' region of the human gene for polymorphisms to be used as tools in association studies. Four polymorphisms were detected: -409C/T in the promoter region, +73C/T in exon 1, +255A/G in exon 3, and +294T/C in exon 4. The frequencies of the rare alleles were 4.2%, 4.2%, 1.2% and 15.6%, respectively, in a population-based group of 543 healthy men. Only the +294T/C polymorphism showed significant association with a metabolic trait. Homozygotes for the rare C allele had a higher plasma LDL-cholesterol concentration than homozygotes for the common T allele, which was verified in an independent cohort consisting of 282 healthy men. Transfection studies showed that the rare C allele had higher transcriptional activity than the common T allele. Electrophoretic mobility shift assays demonstrated that the +294T/C polymorphism influenced binding of Sp-1. An interaction with the PPAR alpha L162V polymorphism was also detected for several lipid parameters.
Conclusions--These findings suggest that PPARD plays a role in cholesterol metabolism in humans.
Key words: genetics • cholesterol • peroxisome proliferator-activated receptor • polymorphism
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