Genetic variation in the PPARA gene is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study.
OBJECTIVE
Recently, minor alleles of two strongly linked polymorphisms in the PPARA gene, rs4253728 G>A and rs4823613 A>G, were related to decreased CYP3A4 expression and activity. We studied whether they were associated with the cholesterol-lowering effect of simvastatin.


METHODS
We identified 123 incident users with cholesterol measurements before and after starting statin therapy in a prospective population-based cohort study. Associations between PPARA polymorphisms and change in total and low-density lipoprotein (LDL)-cholesterol levels were analyzed using linear regression.


RESULTS
The minor G allele of the rs4823613 A>G polymorphism was associated with a 0.258 mmol/l (95% CI: -0.470 to -0.046) and a 0.294 mmol/l (95% CI: -0.495 to -0.093) larger reduction in total and LDL-cholesterol, respectively, after starting simvastatin therapy. Results were similar for the rs4253728 G>A polymorphism.


CONCLUSIONS
The minor alleles of the PPARA rs4253728 and rs4823613 polymorphisms are associated with a better total and LDL-cholesterol-lowering response to simvastatin, possibly through influence on CYP3A4.
Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000CA Rotterdam, The Netherlands.
Catherine E
CE
de Keyser
Matthijs L
ML
Becker
André G
AG
Uitterlinden
Albert
A
Hofman
Jan J
JJ
Lous
Laure
L
Elens
Loes E
LE
Visser
Ron Hn
RH
van Schaik
Bruno H
BH
Stricker
D000368:Aged; D000483:Alleles; D002784:Cholesterol / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D047493:PPAR alpha / Q000235:genetics*; D019821:Simvastatin / Q000008:administration & dosage*
D008078:Cholesterol, LDL; D047493:PPAR alpha; D002784:Cholesterol; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human