Effect 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 patients.
Fenofibrate is a peroxisome proliferator-activated receptor alpha (PPARalpha) 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), PPARalpha -L162V, apolipoprotein (apo) E and PPARgamma-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 PPARalpha -L162V carriers, whereas the simultaneous presence of apo E2 and PPARalpha -L162V tended to improve fenofibrate response among LPL-P207L heterozygotes. Finally, the LPL-D9N and PPARgamma -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.
Brisson
Diane
D
Community Genomic Medicine Centre, University of Montreal, Chicoutimi Hospital, Québec, Canada.
Ledoux
Karine
K
Bossé
Yohan
Y
St-Pierre
Julie
J
Julien
Pierre
P
Perron
Patrice
P
Hudson
Thomas J
TJ
Vohl
Marie-Claude
MC
Gaudet
Daniel
D
D000328:Adult; D000368:Aged; D001057:Apolipoproteins E / Q000235:genetics*; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage / Q000627:therapeutic use*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D015228:Hypertriglyceridemia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood / Q000235:genetics; D008071:Lipoprotein Lipase / Q000235:genetics*; D008074:Lipoproteins / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics*; D014280:Triglycerides / Q000097:blood / Q000235:genetics
D001057:Apolipoproteins E; D000960:Hypolipidemic Agents; D008055:Lipids; D008074:Lipoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; D008071:Lipoprotein Lipase; D011345:Fenofibrate