Research Article: KIF6 gene as a pharmacogenetic marker for lipid-lowering effect in statin treatment

Date Published: October 10, 2018

Publisher: Public Library of Science

Author(s): Cristina Ruiz-Iruela, Ariadna Padró-Miquel, Xavier Pintó-Sala, Neus Baena-Díez, Assumpta Caixàs-Pedragós, Roser Güell-Miró, Rosa Navarro-Badal, Xavier Jusmet-Miguel, Pilar Calmarza, José Luis Puzo-Foncilla, Pedro Alía-Ramos, Beatriz Candás-Estébanez, Ying-Mei Feng.


The therapeutic response to statins has a high interindividual variability with respect to reductions in plasma LDL-cholesterol (c-LDL) and increases in HDL cholesterol (c-HDL). Many studies suggest that there is a relationship between the rs20455 KIF6 gene variant (c.2155T> C, Trp719Arg) and a lower risk of cardiovascular disease in patients being treated with statins.

The aim of this study was to investigate whether or not the c.2155T> C KIF6 gene variant modulates the hypercholesteremic effects of treatment with simvastatin, atorvastatin, or rosuvastatin.

This was a prospective, observational and multicenter study. Three hundred and forty-four patients who had not undergone prior lipid-lowering treatment were recruited. Simvastatin, atorvastatin or rosuvastatin were administered. Lipid profiles and multiple clinical and biochemical variables were assessed before and after treatment.

The c.2155T> C variant of the KIF6 gene was shown to influence physiological responses to treatment with simvastatin and atorvastatin. Patients who were homozygous for the c.2155T> C variant (CC genotype, ArgArg) had a 7.0% smaller reduction of LDL cholesterol levels (p = 0.015) in response to hypolipidemic treatment compared to patients with the TT (TrpTrp) or CT (TrpArg) genotype. After pharmacological treatment with rosuvastatin, patients carrying the genetic variant had an increase in c-HDL that was 21.9% lower compared to patients who did not carry the variant (p = 0.008).

Being a carrier of the c.2155T> C variant of the KIF6 gene negatively impacts patient responses to simvastatin, atorvastatin or rosuvastatin in terms of lipid lowering effect. Increasing the intensity of hypolipidemic therapy may be advisable for patients who are positive for the c.2155T> C variant.

Partial Text

Statins are drugs that specifically inhibit 3-hydroxy-3-methyl-glutaril-CoA reductase, a rate limiting enzyme of the pathway responsible for the synthesis of endogenous cholesterol. Among the lipid-lowering drugs, statins are the ones most often employed to prevent atherosclerosis [1]. In 2015, simvastatin and atorvastin were the third and fifth most prescribed generic drugs in Spain, respectively [2]. However, the therapeutic response to these drugs has a high interindividual variability: the reduction in plasma LDL-cholesterol (c-LDL) resulting from drug intake ranges from 20% to 60%. A similar variability is observed with respect to increases in plasma HDL cholesterol (c-HDL) [3]. The impact genetic variants may have on the effectiveness of statins is currently being investigated [4, 5, 6], with the aim of developing personalized and cost-effective medications.

The objective of this study was to examine how the c.2155T> C variant of the KIF6 gene influences the hypolipidemic and hypocholesterolemic responses to simvastatin, atorvastatin, and rosuvastatin. Responses were quantified by measuring differences in the plasma concentration of c-LDL, Non-HDL cholesterol (c-Non-HDL), and c-HDL after treatment.

Statins are highly effective prophylactics against arteriosclerosis. Nevertheless, a high proportion of patients consuming statins develop some type of cardiovascular disease. These outcomes suggest that genetic factors may influence patient responses to treatment with statins [23]. Numerous genes, such as SLCO1B1, CETP, ABCA, HMGCR, and CYP3A4 are currently being investigated [24, 25] as possible factors affecting statin therapy outcomes. Of these, there has been a particular focus on KIF6 gene and its variant c.2155T> C (Trp719Arg).

The c.2155T> C variant of the KIF6 gene influences patient responses to treatment with simvastatin and atorvastatin. Patients homozygous for the variant (CC, ArgArg) had a smaller decrease in the c-LDL and c-Non-HDL. Therefore, these patients did not respond as well to hypolipidemic therapies as patients who were homozygous TT (TrpTrp) or heterozygous TC (TrpArg). The c.2155T> C variant is associated with a less pronounced increase in c-HDL upon rosuvastatin treatment.




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