|Frazier-Wood, Alexis -|
|Ordovas, Jose -|
|Straka, Robert -|
|Hixson, James -|
|Borecki, Ingrid -|
|Tiwari, Hemant -|
|Arnett, Donna -|
Submitted to: The Pharmacogenomics Journal
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: February 15, 2012
Publication Date: March 5, 2012
Citation: Frazier-Wood, A.C., Ordovas, J.M., Straka, R.J., Hixson, J.E., Borecki, I.B., Tiwari, H.K., Arnett, D.K. 2012. The PPAR alpha gene is associated with triglyceride, low-density cholesterol and inflammation marker response to fenofibrate intervention: the GOLDN study. The Pharmacogenomics Journal. DOI: 10.1038/TPJ.2012.9. Interpretive Summary: Peroxisome proliferator-activated receptor alpha (PPAR-alpha) is a nuclear receptor protein that in humans is encoded by the PPARA gene. PPAR-alpha is a major regulator of fat (lipid) metabolism in the liver. Activation of PPAR-alpha promotes uptake, utilization, and catabolism of fatty acids by upregulation of genes involved in fatty acid transport and peroxisomal and mitochondrial fatty acid Beta-oxidation. Synthetic ligands include the fibrate drugs, which are used to treat high cholesterol. To determine whether variation in the PPAR Alpha receptor gene was associated with lipid and inflammatory marker response, we conducted a 3-week trial of fenofibrate (a cholesterol regulating drug) in 861 men and women. We found significant associations between polymorphisms at the PPARA gene with low-density lipoprotein cholesterol and interleukin-2 responses to fenofibrate. Therefore, variants in the PPARA gene may contribute to predict fenofibrate responders from both lipids and inflammation perspectives.
Technical Abstract: As a peroxisome proliferator-activated receptor alpha (PPAR Alpha) agonist, fenofibrate favorably modulates dyslipidemia and inflammation markers, which are associated with cardiovascular risk. To determine whether variation in the PPAR Alpha receptor gene was associated with lipid and inflammatory marker response, we conducted a 3-week trial of fenofibrate in 861 men and women. Mixed linear models that controlled for age and sex, as well as family pedigree and study center, were constructed using single-nucleotide polymorphisms (SNPs) in the PPAR Alpha gene as predictors and changes in fasting triglycerides (TGs), cholesterol and inflammatory markers as outcomes. Significant associations with low-density cholesterol and interleukin-2 (P less than 0.001) responses to fenofibrate were found. Although there were suggestive associations with tumor necrosis factor-alpha and TG responses (P less than 0.05), these did not survive the correction for multiple testing. We conclude that variants in the PPAR Alpha gene may contribute to future pharmacogenomic paradigms seeking to predict fenofibrate responders from both an anti-dyslipidemic and anti-inflammatory perspective.