INFLUENCIA DE VARIANTES GENÉTICAS EN LA RESPUESTA AL TRATAMIENTO CON ESTATINAS. ESTUDIO PROSPECTIVO Y MULTICÉNTRICO

Abstract

Statins are drugs that inhibit 3-hydroxy-3-methyl-glutaril- CoA reductase, a rate limiting enzyme of the colesterol synthesis pathway. Statins are widely used for the primary and secondary prevention of atherosclerosis. However, patient responses to these drugs are highly variable with respect to reducing plasma concentrations of LDL cholesterol (LDL-C) and increasing plasma concentrations of HDL colesterol (HDL-C). The impact that genetic variants may have on the effectiveness of statins therapy is currently being investigated with the aim of reaching personalized and cost-effective treatments._x000D_ In this context, the study of genetic variants within genes involved in lipid transport and metabolism (CETP -cholesteryl ester transfer protein-, ABCA1 -binding cassette subfamily A member 1- and KIF6 -Kinesin Family Member 6- ) and in statin pharmacokinetics (CYP2D6 -cytochrome P450 family 2 subfamily D member 6- and CYP2C9 -cytochrome P450 family 2 subfamily D member 9- ), whose scientific evidence remains unconfirmed._x000D_ In order to more deeply understand the impact of these gene variants on the efficacy of statin treatment, a prospective and multicenter study including 344 patients was performed to determine the influence of the following gene variants on patient response to simvastatin, atorvastatin, and rosuvastatin: the CETP variants rs708272 and rs5882, the ABCA1 variant rs2230806, the CYP2D6 variants rs35742686, rs3892097, and rs5030655, and the CYP2C9 variants rs1799853 and rs1057910. _x000D_ The efficacy of statin treatment was determined using multivariate regression models to analyze both the achievement of lipid therapeutic targets and the percentual variation in lipid profiles before and after therapy._x000D_ ABCA1 variant rs2230806 and CYP2D6 rs35742686 influence patient response to treatment with statins. Variant carriers are less likely to achieve LDL-C or cholesterol non-HDL (non-HDL-C) therapeutic targets. In addition, carriers of the TT genotype of rs2230806 have a 12% lower LDL-C in response to treatment with simvastatin and atorvastatin than CT or CC genotype. CETP gene variants rs708272 and rs5882 affect patient responses to rosuvastatin, however a larger sample size is required to corroborate these results._x000D_ _x000D_ _x000D_ _x000D_ The rs20455 C variant of the KIF6 gene also influences treatment response when using simvastatin and atorvastatin. Homozygous patients for the variant (CC genotype) had a smaller decrease (8.1%) in the LDL-C and non-HDL-C. Therefore, these patients did not respond as well to hypolipidemic therapies as patients who were homozygous (TT) or heterozygous (TC). Regarding to rosuvastatin treatment, C variant is associated with a less pronounced increase (22%) in HDL-C compared to patients without the variant._x000D_ _x000D_ _x000D_ _x000D_ Taking into account the results obtained in the present doctoral thesis, the study of these genetic variants in the clinical practice could be a powerful tool to personalize patient treatment, improving the achievement of therapeutical goals and, ultimately, decreasing the overall cardiovascular risk.

Date of Award	30 Nov 2020
Original language	Spanish
Supervisor	Francesca Canalias Reverter (Tutor), Ariadna Padró Miquel (Director) & Beatriz Candás-Estébanez (Director)