Abstract

The bile acid-activated nuclear receptor farnesoid X receptor (FXR) plays an important role in lipid and glucose metabolism, and in addition, it regulates multiple drug transporters involved in statin disposition. We examined whether a functional single nucleotide polymorphism (SNP) in FXR (-1G>T) influenced the lipid-lowering effect of rosuvastatin. In 385 Chinese patients with hyperlipidemia who had been treated with rosuvastatin 10 mg daily for at least 4 weeks, the association between the FXR -1G>T SNP and lipid response to rosuvastatin was analyzed. The FXR -1G>T SNP was not associated with baseline lipids but was significantly associated with the LDL cholesterol (LDL-C) and total cholesterol response to rosuvastatin. Carriers of the T-variant allele (GT+TT = 68+3) had 4.4% (95% CI: 1.2, 7.5%, P = 0.006) and 2.6% (95% CI: 0.3, 5.0%; P < 0.05) greater reductions in LDL-C and total cholesterol, respectively, compared with those with homozygous wild-type alleles. The association between the FXR polymorphism and the LDL-C response to rosuvastatin remained significant after adjusting for other covariants. This association of the variant allele of the FXR -1G>T polymorphism with a greater LDL-C response to rosuvastatin may suggest that this polymorphism influences the expression of the hepatic efflux transporters involved in biliary excretion of rosuvastatin.

Highlights

  • The bile acid-activated nuclear receptor farnesoid X receptor (FXR) plays an important role in lipid and glucose metabolism, and in addition, it regulates multiple drug transporters involved in statin disposition

  • Given the importance of the FXR in lipid metabolism and in regulating the expression of the drug transporter genes that are involved in rosuvastatin disposition, we examined the association between the functional single nucleotide polymorphism (SNP) FXR -1G>T and the lipid response to rosuvastatin in Chinese patients with hypercholesterolemia

  • This study is the first to report that the common polymorphism (-1G>T) in FXR resulting in significantly reduced function of the gene was associated with a greater LDL cholesterol (LDL-C) response to rosuvastatin in Chinese patients with hypercholesterolemia and that this association remained significant after adjusting for the potential confounding factors

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Summary

Introduction

The bile acid-activated nuclear receptor farnesoid X receptor (FXR) plays an important role in lipid and glucose metabolism, and in addition, it regulates multiple drug transporters involved in statin disposition. FXR functions as a bile acid receptor, studies have identified that FXR regulates multiple drug metabolizing enzyme or drug transporter genes by binding to FXR response elements and promoting transcription of target genes, suggesting that FXR may play an important role in determining the pharmacokinetics and pharmacodynamics of numerous drugs [4]. Loss of function single nucleotide polymorphisms (SNP) in the coding region of the SLCO1B1 and ABCG2 genes were associated with altered statin exposure and lipid-lowering effects [5,6,7], but these SNPs did not appear to affect overall protein expression [4, 8]. The decreased transport activity of SLCO1B1 and ABCG2 associated with these SNPs is thought to result from membrane-trafficking defects [4, 9, 10]

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