The role of common variants of ABCB1, CYP3A4, and CYP3A5 genes in lipid-lowering efficacy and safety of simvastatin treatment.
OBJECTIVE
Our objective was to investigate the interactions between common polymorphisms in ABCB1, CYP3A4, and CYP3A5 genes and the lipid-lowering efficacy and safety of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin.


METHODS
One hundred sixteen hypercholesterolemic patients were prospectively screened by physical examination, medical history, and clinical laboratory evaluation and were included in this study. Subjects entering the study were treated with 20 mg/d simvastatin. Plasma lipid and lipoprotein levels were measured before treatment, after 2 months of treatment, and after 6 months of treatment. Ninety-nine patients completed the 6-month follow-up and were included in the association analysis for treatment efficacy. Seventeen subjects who had adverse drug reactions (ADRs) to simvastatin (ADR group) could not complete the 6-month follow-up and were included in the association analyses for safety. Myalgia was observed in 15 of 17 subjects and was the only ADR included in the association analyses, but other common ADRs were also observed. Myalgia was defined as proximal or diffuse muscle pain, tenderness, or weakness, or both pain and weakness, with normal or slightly increased serum creatine phosphokinase levels. ABCB1 (1236C>T, 2677G>A/T, and 3435C>T), CYP3A4 (-392A>G), and CYP3A5 (6986A>G) allele variants were determined by polymerase chain reaction and restriction mapping.


RESULTS
After adjustment for covariates, carriers of the ABCB1 1236T variant allele had a greater reduction in total cholesterol and low-density lipoprotein cholesterol with simvastatin treatment, as compared with homozygotes with the wild-type allele (-29.0% [95% confidence interval (CI), -25.9 to -32.5] versus -24.2% [95% CI, -19.0 to -29.3] [P = .042] and -39.6% [95% CI, -35.8 to -44.0] versus -33.8% [95% CI, -27.4 to -40.2] [P = .042], respectively). Similar results were observed for the 2677G>A/T polymorphism and haplotype data. The 1236T, 2677non-G, and 3435T alleles were less frequent in ADR cases than in the non-ADR group (P < .05 for all single-nucleotide polymorphisms). Haplotype analyses also demonstrated a reduction of the T-non-G-T haplotype frequency (20%) in patients in whom myalgia developed during simvastatin treatment, as compared with the non-ADR group (41.4%) (P = .03). No significant associations were observed between the CYP3A4 -392A>G and CYP3A5*3 allele variants and the efficacy or tolerability of simvastatin.


CONCLUSIONS
Our data suggest an association of ABCB1 gene polymorphisms and the efficacy and safety of simvastatin.
Fiegenbaum
Marilu
M
Departamento de Genética, Centro de Diagnóstico Cardiológico, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre, RS, Brazil.
da Silveira
Fabiano R
FR
Van der Sand
Cézar R
CR
Van der Sand
Luiz Carlos
LC
Ferreira
Maria E W
ME
Pires
Renan C
RC
Hutz
Mara H
MH
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000009:adverse effects* / Q000627:therapeutic use*
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D019821:Simvastatin; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human