HMGCR rs17671591 SNP Determines Lower Plasma LDL‐C after Atorvastatin Therapy in Chilean Individuals

Abstract

Lipid-lowering response to statin therapy shows large interindividual variability. At a genome-wide significance level, single nucleotide polymorphisms (SNPs) in PCSK9 and HMGCR have been implicated in this differential response. However, the influence of these variants is uncertain in the Chilean population. Hence, we aimed to evaluate the contribution of PCSK9 rs7552841 and HMGCR rs17671591 SNPs as genetic determinants of atorvastatin response in Chilean hypercholesterolaemic individuals. One hundred and one hypercholesterolaemic patients received atorvastatin 10 mg/day for 4 weeks. Plasma lipid profile (TC, HDL-C, LDL-C and TG) was determined before and after statin treatment, and SNPs were identified by allelic discrimination using TaqMan â SNP Genotyping Assays. Adjusted univariate and multivariate analyses' models were used for statistical analyses, and a p-value <0.05 was considered significant. From baseline (week 0) to the study end-point (week 4), significant reductions were observed in plasma TC, LDL-C and TG (p < 0.001), while HDL-C levels were increased (p < 0.001). Multivariate analysis showed no association between lipid levels and atorvastatin therapy for the PCSK9 variant. However, the HMGCR rs17671591 T allele contributed to basal HDL-C concentration variability along with a higher increase in this lipid fraction after statin medication. In addition, this allele determined greater plasma LDL-C reductions after therapy with atorvastatin. Our data suggest that the HMGCR rs17671591 polymorphism can constitute a genetic marker of lower plasma LDL-C and enhanced HDL-C concentration after atorvastatin therapy in the Chilean population.

Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia

“…HMGCR encodes a key enzyme involved in cholesterol synthesis, and SREBF2 encodes SREBPs regulating the expression of LDL receptors. In one study, the HMGCR rs17671591 T allele compared with the wild‐type C allele showed an enhanced LDL‐level lowering and HDL‐level raising effect in Chilean patients treated with atorvastatin (8% greater reduction in LDL level, p=0.021; 7.7% greater increase in HDL level, p=0.039) . Attenuated LDL‐level lowering in response to atorvastatin therapy was demonstrated in patients with another HMGCR polymorphism, rs12916 T allele, indicating an importance of this gene in relation to the statin response .…”

“…In one study, the HMGCR rs17671591 T allele compared with the wild-type C allele showed an enhanced LDL-level lowering and HDL-level raising effect in Chilean patients treated with atorvastatin (8% greater reduction in LDL level, p=0.021; 7.7% greater increase in HDL level, p=0.039). 52 Attenuated LDL-level lowering in response to atorvastatin therapy was demonstrated in patients with another HMGCR polymorphism, rs12916 T allele, indicating an importance of this gene in relation to the statin response. 50 Another study in Chilean patients showed -SREBF2 G1784C polymorphism was associated with attenuated response to atorvastatin (GG had 9% smaller Tc-level reduction vs GC and 8% smaller reduction vs CC, p=0.015; GG had 15% smaller LDL-level reduction vs GC and 12% smaller reduction vs CC, p=0.013).…”

<i>PCSK9</i> rs7552841 is associated with plasma lipids profiles in female Chinese adolescents without posttraumatic stress disorder

“…It has been reported that PCSK9 can regulate plasma levels of LDL-C, while some of the single nucleotide polymorphisms at PCSK9 are associated with plasma lipids profiles (12)(13)(14)16,29). Recently, the association of PCSK9 rs7552841 polymorphism with plasma lipids has been explored in two laboratories in China and Chile (22)(23)(24). Significant differences were found by the Chinese laboratory of the plasma levels of TG, TC and LDL-C between the T allele carriers and the CC homozygotes of PCSK9 rs7552841 in a Chinese Jing population, but not in Chinese Han population (22).…”

“…The results reported by the Chilean laboratory showed that there were no significant differences Table 5. Effects of PTSD on the association of PCSK9 rs7552841 with anthropometric and biochemical characteristics of plasma lipids between the T allele carriers and the CC homozygotes of PCSK9 rs7552841 in 101 Chilean hypercholesterolaemic individuals before and after 10 mg/day of atorvastatin therapy (24). These discrepancies may be explained by ethnicities, healthy status, medication status and even the sample size because the Chilean investigation was carried out in a smaller population.…”

“…After adjusting age, gender, body mass index (BMI), smoking and alcohol consumption, PCSK9 rs7552841 was found to be associated with not only hypercholesterolaemia but also hypertriglyceridaemia (23). On the other hand, no significant differences of plasma lipid levels were observed between the T allele carriers and the CC homozygotes in a Chinese Han population (22), and in 101 Chilean hypercholesterolaemic individuals before or after 10 mg/day of atorvastatin therapy although the T allele carrier showed a trend towards less increases of HDL-C after the treatment (24). Obviously, more studies are needed to clarify the above discrepancies of the associations reported before between PCSK9 rs7552841 and plasma lipids profiles.…”