Response to micronized fenofibrate treatment is associated with the peroxisome-proliferator-activated receptors alpha G/C intron7 polymorphism in subjects with type 2 diabetes.
OBJECTIVE
The association between polymorphisms in candidate genes related to lipoprotein metabolism and the reduction in plasma triglyceride (TG) in response to fenofibrate treatment was evaluated in subjects with type 2 diabetes treated with micronized fenofibrate (200 mg/day) for at least 3 years in the Diabetes Atherosclerosis Intervention Study.


METHODS
The cholesteryl ester transfer protein Taq1B, LPL S447X, hepatic lipase -514 C-->T, peroxisome-proliferator-activated receptors alpha (PPARA) L162V and G/C intron 7 polymorphisms and the apolipoprotein E2/E3/E4 alleles were genotyped using PCR and restriction enzyme digestion. Subjects were divided into high TG-responders (with > 30% TG relative reduction after treatment) and low TG-responders.


RESULTS
The frequency of the PPARA intron 7 G/G genotype was higher in high TG-responders than in low TG-responders (85% vs. 69%, P < 0.05). There was no significant difference between the percentage of high TG-responders and low TG-responders for any of the other genetic polymorphisms examined. In stepwise logistic regression, baseline TG and only the PPARA intron 7 polymorphism among the others were selected in the model as significant predictors of TG-response (odds ratio: 3.10, 95% CI: 1.28-7.52, P = 0.012 for PPARA polymorphism). With age, gender, body mass index, smoking status and HbA1c as additional factors, baseline TG (P< 0.0001), intron 7 (P = 0.013), body mass index (P = 0.040) and LPL-S447X (P = 0.084) were significant predictors of TG-response.


CONCLUSIONS
These results indicate that elevated baseline TG levels and PPARA gene intron 7 G/G genotype were associated with TG reduction > 30% after fenofibrate treatment in patients with type 2 diabetes.
Foucher
Christelle
C
Laboratoires Fournier S.A. Centre de Recherches, Department of Clinical Research and Medical Affairs, Daix, France. c.foucher@fr.fournierpharma.com
Rattier
Stephanie
S
Flavell
David M
DM
Talmud
Philippa J
PJ
Humphries
Steve E
SE
Kastelein
John J P
JJ
Ayyobi
Amir
A
Pimstone
Simon
S
Frohlich
Jiri
J
Ansquer
Jean-Claude
JC
Steiner
George
G
D053329:Apolipoprotein E2; D001057:Apolipoproteins E / Q000235:genetics; D015992:Body Mass Index; D002352:Carrier Proteins / Q000097:blood; D002784:Cholesterol / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage / Q000627:therapeutic use*; D006023:Glycoproteins / Q000097:blood; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007438:Introns; D008071:Lipoprotein Lipase / Q000097:blood; D008297:Male; D008875:Middle Aged; D047493:PPAR alpha / Q000235:genetics*; D011110:Polymorphism, Genetic; D014280:Triglycerides / Q000097:blood / Q000235:genetics; D044465:White People
D053329:Apolipoprotein E2; D001057:Apolipoproteins E; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006023:Glycoproteins; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D014280:Triglycerides; D002784:Cholesterol; D008071:Lipoprotein Lipase; D011345:Fenofibrate