Abstract
The use of statins as the preferred lipid-lowering therapy has clearly demonstrated its efficacy in the treatment of hypercholesterolemia, reducing also the risk of coronary events and cardiovascular disease mortality. In this study, we assessed single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene and their effect on atorvastatin response. We included 129 Chilean hypercholesterolemic patients undergoing 10 mg/day of atorvastatin therapy during 4 weeks. Lipid profile was determined before and after drug administration. Genotyping of SLCO1B1 rs4149056 (c.521T>C) SNP was performed with allele-specific polymerase chain reaction, whilst polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping the SLCO1B1 rs2306283 (c.388A>G) variant. After statin therapy, concentrations of TC, LDL-C and TG had a decrease from baseline (p < 0.05). Also, HDL-C levels increased (p < 0.05). Minor allele frequencies for the rs2306283 and rs4149056 variants were 0.547 and 0.136, respectively. LDL-C response to atorvastatin was not associated with the SLCO1B1 rs4149056 nor the rs2306283 polymorphisms (p > 0.05). However, the latter SNP was associated with HDL-C variability after atorvastatin medication (p = 0.02). This study indicates that LDL-C reduction following atorvastatin therapy is not influenced by the SNPs evaluated. In addition, the polymorphism rs2306283 at the SLCO1B1 gene determines greater HDL-C concentrations in response to atorvastatin medication in Chilean hypercholesterolemic subjects.
Highlights
Statins are competitive and reversible inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), the rate-limiting enzyme for cholesterol synthesis
In order to restore normal levels of sterols, the SREBP pathway is triggered [1], activating several genes such as the low-density lipoprotein receptor (LDLR), which in turn cause a compensatory increase in the expression of LDLRs in liver cells, enhancing plasmatic clearance of this lipoprotein and reducing circulating low-density lipoprotein cholesterol (LDL-C)
There are a number of patients presenting severe adverse drug reactions (ADRs) such as liver function disorders, muscle myopathy and rhabdomyolysis [4,5]
Summary
Statins are competitive and reversible inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), the rate-limiting enzyme for cholesterol synthesis. By this mechanism, statin medication effectively reduces intracellular cholesterol levels. In order to restore normal levels of sterols, the SREBP pathway is triggered [1], activating several genes such as the low-density lipoprotein receptor (LDLR), which in turn cause a compensatory increase in the expression of LDLRs in liver cells, enhancing plasmatic clearance of this lipoprotein and reducing circulating low-density lipoprotein cholesterol (LDL-C). Different studies indicate that clinical results using lipid-lowering therapy with statins hold great variability between patients, greatly limiting their beneficial effects [6,7]. Recent investigations have been focusing on genetic variations at hepatic efflux and influx transporters as the potential responsible for these differences, such as the SLCO1B1
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