Statin Pharmacogenomics: Lipid Response and Cardiovascular Outcomes

Abstract

Use of lipid-lowering agents, mainly statins, is a proven strategy to prevent cardiovascular disease events. Because most of the beneficial effect of statins is accounted for by the improved lipid profile, more than 40 genes have been studied to ascertain whether variation therein modulates lipid response or prevention of cardiovascular disease during statin therapy. In addition, recent studies have also shown that genetic variation may stratify pleiotropic statin effects. Although this review briefly covers the pharmacogenetic implications on biochemical markers such as low-density lipoprotein cholesterol, it mainly focuses on recent findings (after 2005) on cardiovascular disease outcomes during statin therapy. Pharmacogenomic analysis of large trials of statin treatment is becoming a predominant trend. Another future direction is genome-wide analysis, which will reveal additional candidate genes to be further tested in prospective trials. The results so far are preliminary, and successful replication of the findings is needed in large unrelated populations before the evidence for any polymorphism is solid enough for clinical applications.

Association of APOE polymorphisms with lipid-lowering efficacy of statins in atherosclerotic cardiovascular diseases

“…11 Of note, ε3 (79%) is the most common allele in the population of Europe and Asia, whereas ε4 (13.3%) and ε2 (7.3%) are less frequently observed. 12,13 Although there have been several studies on the role of APOE polymorphism in lipid-lowering therapy using statins, other studies have reached inconsistent conclusions. 14 The relationship between APOE genotypes and statin efficacy remains controversial and inconclusive.…”

Efecto de variantes de los genes ABCB1 y CYP3A4 sobre la respuesta terapéutica a atorvastatina en individuos chilenos hipercolesterolémicos

“…A la fecha, se han investigado más de 40 genes que afectan la respuesta a estatinas 10 , relacionados tanto con la farmacocinética (enzimas de metabolización y proteínas de transporte) como con la farmacodinámica del medicamento (receptores y vías de transducción de señal) 11 . Estas variaciones incluyen a genes que actúan en la absorción intestinal de colesterol como la apolipoproteína E (APOE), transportador de ATP (ABC); la producción de colesterol, como la HMG-CoA reductasa; el metabolismo de las lipoproteínas como la apolipoproteína B y el receptor de LDL, como además, de aquellos que actúan en la vía de la citocromo P450 [12][13][14][15] . Las estatinas son metabolizadas por vía hepática, principalmente por la familia de la citocromo P450.…”

Frequency of Common Variants in Genes Involved in Lipid-Lowering Response to Statins in Chilean Subjects with Hypercholesterolemia

“…Large interindividual pharmacokinetic differences observed among humans are partially due to genetic polymorphisms in drug-metabolizing enzymes such as cytochrome P450, or transporter proteins such a ABCB1 . These variations include genes involved in intestinal absorption of cholesterol and apolipoprotein E (APOE), ATP transporter (ATP binding cassette) the production of cholesterol, including HMG-CoA reductase, the metabolism of lipoproteins and apolipoprotein B and LDL receptor, also including the cytochrome P450 (Salazar et al, 2000;Kajinami et al, 2005;Wang et al, 2005;Kerola et al, 2010).…”