Pharmacogenetic determinants of variability in lipid-lowering response to pravastatin therapy

Abstract

Pravastatin is mainly taken up from the circulation into the liver via organic anion-transporting polypeptide 1B1 (SLCO1B1 gene product). We examined the contribution of genetic variants in the SLCO1B1 gene and other candidate genes to the variability of pravastatin efficacy in 33 hypercholesterolemic patients. In the initial phase of pravastatin treatment (8 weeks), heterozygous carriers of the SLCO1B1*15 allele had poor low-density lipoprotein cholesterol (LDL-C) reduction relative to non-carriers (percent reduction: -14.1 vs -28.9%); however, the genotype-dependent difference in the cholesterol-lowering effect disappeared after 1 year of treatment. Cholesterol 7a-hydroxylase (CYP7A1) and apolipoprotein E (APOE) are known to contribute to lipid metabolism. Homozygous carriers of the CYP7A1 -204C allele or heterozygotes for both CYP7A1 -204C and APOE 4 alleles showed significantly poorer LDL-C reduction compared to that in other genotypic groups after 1 year of treatment (-24.3 vs -33.1%). These results suggest that the SLCO1B1*15 allele is associated with a slow response to pravastatin therapy, and the combined genotyping of CYP7A1 and APOE genes is a useful index of the lipid-lowering effect of pravastatin.

The effects of a single nucleotide polymorphism in SLCO1B1 on the pharmacodynamics of pravastatin

“…The attenuation of response in the CC homozygotes was larger than that seen in the SEARCH study but the number of CC participants was small and the differences were not statistically significant. Our results contrast with three studies of pravastatin that showed larger attenuations of the pravastatin response in the TC heterozygotes (total cholesterol reductions of 13.1% in TCs vs. 19.1% in TTs [3], 9.8% in TCs vs. 20.9% in TTs [4] and 14.5% in TCs vs. 22.4% in TTs [5]), which were statistically Short report significant in two out of the three studies [3][4][5]. Differences in the timing of lipid measurements and the ethnicity of the study populations may have contributed to the contrast in results.…”

“…The largest study was by the SEARCH group who showed a small although statistically significant decrease in the LDL-cholesterol lowering response in carriers of the rs4149056 rare C allele (LDL reductions 1.28% Ϯ 0.25% smaller per copy of the SNP, P < 0.0001) after dosing with 40 mg simvastatin [2]. This contrasts with three small studies of pravastatin showing larger effects of rs4149056 on the lipid lowering response [3][4][5]. Simvastatin is given as a lactone prodrug but only the acid form of the drug is transported by OATP1B1 [6].…”

“…A retrospective power calculation shows that the sample available could have detected a 13.1% difference in LDL response between the CC and TC + TT subjects with an 80% power and 5% significance, but only a 4.5% difference was seen, and a larger study is required to investigate this group further. The inclusion of additional time points after treating with pravastatin would also be useful as one study suggested that rs4149056 affects the timing of cholesterol reduction after treatment [4].…”

Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

“…Similarly, a lower LDL-cholesterol response (−1.28% per allele) has been reported for simvastatin by the SEARCH collaborative group [14]. It has been suggested previously that the SLCO1B1 genotype is only predictive of a slower response to pravastatin treatment as genotype-associated reduction in TC was only observed in the assessment after 8 weeks, but not after a 1-year treatment [42]. Furthermore, a population-based survey showed an influence of genetic variants in the efflux transporter ABCB1 genotype on simvastatin efficacy in men by showing that previously identified SNPs are associated with larger reduction of lipid parameters than carriers of the wild-type haplotype [43].…”

The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy

“…Takane et al 51 reinforce the importance of knowing when cholesterol data were obtained. They conducted a retrospective analysis of 33 Japanese hypercholesterolaemic patients treated with pravastatin.…”