Original ArticlesEffect of apolipoprotein E, peroxisome proliferator-activated receptor alpha and lipoprotein lipase gene mutations on the ability of fenofibrate to improve lipid profiles and reach clinical guideline targets among hypertriglyceridemic patientsBrisson, Dianea; Ledoux, Karinea; Bossé, Yohanb; St-Pierre, Juliea,b; Julien, Pierreb; Perron, Patricea; Hudson, Thomas J.c; Vohl, Marie-Claudeb,d; Gaudet, DanielaAuthor Information aCommunity Genomic Medicine Centre, University of Montreal, Chicoutimi Hospital, Québec, bLipid Research Centre, Laval University, Québec, cMontreal Genome Centre, McGill University Health Centre, Montreal, Québec and dDepartment of Food Sciences and Nutrition, Laval University, Québec, Canada D. Brisson is recipient of a doctoral studentship from Fournier Pharma, the Canadian Institutes for Health and Research and the ‘Réseau en santé cardiovasculaire-FRSQ'. K. Ledoux received a studentship from the ‘Fonds de la recherche en santé du Québec-Fonds pour la formation de chercheurs et l'aide à la recherche (FRSQ-FCAR santé)’ and the ‘Association Diabète Québec'. Y. Bossé is recipient of a doctoral studentship from the ‘Fonds de la recherche en santé du Québec-Fonds pour la formation de chercheurs et l'aide à la recherche (FRSQ-FCAR santé)'. J. St-Pierre is recipient of a doctoral award from the Heart and Stroke Foundation of Canada and the Medical Research Council of Canada. M.C. Vohl is a research scholar from the FCAR. T.J. Hudson is recipient of a clinician-scientist award from the Canadian Institutes for Health and Research. D. Gaudet is the chairholder of the Canada Research Chair in preventive genetics and community genomics (http://www.chairs.gc.ca). Correspondence to Daniel Gaudet, Montreal University Community Genomic Medicine Centre, and Lipid Research Group, Chicoutimi Hospital, 305 St-Vallier, Chicoutimi, Québec, G7H 5H6, Canada Tel: +1 418 541 1077; fax: +1 418 541 1116; e-mail: [email protected] Received 26 July 2001 Accepted 3 December 2001 Pharmacogenetics: June 2002 - Volume 12 - Issue 4 - p 313-320 Buy Abstract Fenofibrate is a peroxisome proliferator-activated receptor alpha (PPARα) agonist which regulates the transcription of genes encoding proteins involved in triglyceride (TG)-rich lipoproteins and lipoprotein lipase (LPL) metabolism. The aim of the present study was to investigate the relation between TG-related parameters considered in different clinical guidelines used in industrialized countries for the management of lipid disorders (namely fasting plasma TG, high density-lipoprotein cholesterol (HDL-C), non-HDL-C concentrations and total-C/HDL-C ratio) and the presence of LPL-null (P207L), LPL-defective (D9N), PPARα -L162V, apolipoprotein (apo) E and PPARγ-P12A gene mutations, in a sample of 292 hypertriglyceridemic subjects treated with fenofibrate for 3 months. Although fenofibrate induced a decrease in plasma TG level and an increase in HDL-C level in all studied genotypes, mutation-specific differences were observed. After adjustment for age, gender, body mass index and the presence of apo E2 genotype, the LPL-P207L mutation was associated with residual post-treatment hypertriglyceridemia [TG > 2.0 mmol/l, odds ratio (OR) = 3.07, P = 0.005] and total-C/HDL-C ratio > 5 (OR = 2.68;P = 0.03). This effect was significantly related to higher plasma TG concentrations at baseline among carriers of a LPL-null mutation. Compared to apo E3 and E4 variants, the apo E2 allele was associated with a better response to fenofibrate on all lipid parameter, especially among PPARα -L162V carriers, whereas the simultaneous presence of apo E2 and PPARα -L162V tended to improve fenofibrate response among LPL-P207L heterozygotes. Finally, the LPL-D9N and PPARγ -P12A mutations did not affect fenofibrate lipid-lowering action. This study suggests that frequent genetic variations in genes encoding proteins involved in TG-rich lipoprotein metabolism could modulate the response to fenofibrate treatment, as defined in clinical guidelines. © 2002 Lippincott Williams & Wilkins, Inc.