Genetic polymorphisms: importance for response to HMG-CoA reductase inhibitors

Zee, Anke‐Hilse Maitland‐van der; Klungel, Olaf H.; Stricker, Bruno H.; Kastelein, John J.P.; Leufkens, H.G.M.; Boer, Anthonius de

doi:10.1016/s0021-9150(01)00725-0

Cited by 63 publications

(22 citation statements)

References 72 publications

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“…Most patients taking these drugs respond favorably to them with substantial reductions in LDL-C. 1 Despite the generally good response to statins, some variation in response has been noted and the causes have been subject to a variety of investigations. Potential causes for the variation include compliance with taking the medication 2 as well as variation in the genes 3,4 involved in either the cholesterol/lipid pathways or uptake/metabolism of statins.…”

Section: Introductionmentioning

confidence: 99%

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An association study of 43 SNPs in 16 candidate genes with atorvastatin response

et al. 2005

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Variation in individual response to statin therapy has been widely studied for a potential genetic component. Multiple genes have been identified as potential modulators of statin response, but few study findings have replicated. To further examine these associations, 2735 individuals on statin therapy, half on atorvastatin and the other half divided among fluvastatin, lovastatin, pravastatin and simvastatin were genotyped for 43 SNPs in 16 genes that have been implicated in statin response. Associations with lowdensity lipoprotein cholesterol (LDL-C) lowering, total cholesterol lowering, HDL-C elevation and triglyceride lowering were examined. The only significant associations with LDL-C lowering were found with apoE2 in which carriers of the rare allele who took atorvastatin lowered their LDL-C by 3.5% more than those homozygous for the common allele and with rs2032582 (S893A in ABCB1) in which the two groups of homozygotes differed by 3% in LDL-C lowering. These genetic effects were smaller than those observed with the demographic variables of age and gender. The magnitude of all the differences found is sufficiently small that genetic data from these genes should not influence clinical decisions on statin administration.

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Section: Introductionmentioning

confidence: 99%

“…3,4 Initially, the LDL receptor gene was the primary target of study, but later efforts have included most genes involved in lipoprotein metabolism as well as others involved in statin pharmacokinetics. Studies have varied considerably in size and have included all statins on the market.…”

Section: Introductionmentioning

confidence: 99%

An association study of 43 SNPs in 16 candidate genes with atorvastatin response

et al. 2005

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“…In recent years, one of the focus of genetic investigation in cardiology has been to identify the genetic factors associated with variable response to statin treatment. 4,5 The sterol regulatory element-binding factor (SREBF)-SREBF cleavage-activating protein (SCAP) pathway controls the cellular cholesterol homeostasis. SREBFs are a small family of basic helix-loop-helix-leucine zipper transcription factors.…”

Section: Introductionmentioning

confidence: 99%

Determinants of variable response to simvastatin treatment: the role of common variants of SCAP, SREBF-1a and SREBF-2 genes

et al. 2005

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We investigated the effect of single-nucleotide polymorphisms in sterol regulatory element-binding factors-1a and -2 (SREBF-1a and SREBF-2) and SREBF cleavage-activating protein (SCAP) genes on lipid-lowering response to simvastatin. In all, 146 hypercholesterolemic patients of European descent were prospectively treated with simvastatin 20 mg/day for over 6 months. Of these 99 subjects completed the 6-month follow-up. Plasma lipids and lipoproteins were measured before and throughout the study. The mean percentage decrease in plasma total cholesterol (TC) was greater in subject carriers of SCAP 2386G allele compared with those homozygous for 2386A allele (À29.6713.4 vs À22.1713.8%, P ¼ 0.007). About 61% of the 2386G carriers were above-average responders for TC levels (DTC À27.8%), whereas only 29% of 2386A homozygous reached this reduction (P ¼ 0.009). Our data suggest that the SCAP 2386A4G gene polymorphism was a significant predictor of TC and triglyceride responses to simvastatin treatment.

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“…2,3 Important factors in interpreting this variability include the patient's overall health, prognosis, disease severity, quality of drug prescribing, compliance with prescribed pharmacotherapy and the genetic profile of the patient. 4 The search for genetic determinants of treatmenteffect heterogeneity has included more than 40 different genes involved in the pharmacokinetic and pharmacodynamic pathways of statin metabolism. 2,3 Among the most extensively studied pharmacodynamic genes is the APOE gene, encoding Apolipoprotein E. Apo E is a constituent of triglyceride-rich chylomicrons, very low-density lipoprotein particles, intermediate-density lipoproteins and a subclass of high-density lipoprotein cholesterol (HDL-C).…”

Section: Introductionmentioning

confidence: 99%

APOE gene polymorphisms and response to statin therapy

et al. 2009

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Published studies investigating the role of APOE gene on lipid response (total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides) to statin treatment have reported inconsistent results. A meta-analysis was conducted to estimate the lipid response to statin treatment among APOE genetic variants (e2 carriers, e3e3 homozygotes and e4 carriers). Twenty-four studies were included in the meta-analyses. The pooled mean reduction (Dm) in TC from baseline was significant for all variants (e2 carriers: Dm ¼ À27.7% (À32.5 to À22.8%), e3e3: Dm ¼ À25.3% (À28.0 to À22.6%) and e4 carriers: Dm ¼ À25.1% (À29.3 to À21.0%)). Significant changes in LDL-C, HDL-C and triglyceride levels were also noted for all genotypes, although these changes did not differ significantly among genotypic groups. There was significant heterogeneity among the studies. Given these non-significant effects of APOE genotypes on lipid responses, there is little reason to consider the use of APOE genetic testing for guiding treatment with statins.

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Genetic polymorphisms: importance for response to HMG-CoA reductase inhibitors

Cited by 63 publications

References 72 publications

An association study of 43 SNPs in 16 candidate genes with atorvastatin response

An association study of 43 SNPs in 16 candidate genes with atorvastatin response

Determinants of variable response to simvastatin treatment: the role of common variants of SCAP, SREBF-1a and SREBF-2 genes

APOE gene polymorphisms and response to statin therapy

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