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

Abstract

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.

Atorvastatin effects on SREBF1a and SCAP gene expression in mononuclear cells and its relation with lowering-lipids response

“…Despite of the relationship of SREBF1 -36delG and SCAP A2386G polymorphisms on serum lipids in response to fluvastatin and simvastatin reported previously [17,18], we did not find significant association between these variants and response to atorvastatin. These results are suggestive that polymorphisms in SREBF1 and SCAP may play a minor role in determining the pharmacological response to statins.…”

“…These results are similar to that found in other populations (SREBF1: 51%-63%; SCAP: 43%-53%) [16,18,19,32,33].…”

“…SREBF1 gene has an indel polymorphism in the promoter region (-36del/G) that was associated with an atherogenic lipid profile and increased risk for cardiovascular disease [16]. SREBF1 -36delG variant was also related to variation on plasma apoA-I in response to fluvastatin [17] but not simvastatin [18]. A common polymorphism of the SCAP gene (A2386G, Ile796Val), located at its carboxyl terminal domain that interacts with SREBP1 [19], was found to be a significant predictor of cholesterol and triglyceride responses to simvastatin [18], but not to pravastatin therapy [20].…”

Single-nucleotide polymorphisms: a perspective of cardiovascular prevention

“…In a study to evaluate response to statin, Fiegenbaum et al 11 evaluated the effect of SNPs in sterol regulatory element-binding factors-1a (SREBF), SREBF-2 and SREBF cleavage activating protein (SCAP) on lipid reducing response mediated by the use of simvastatin. The results suggest that polymorphism in the gene SCAP 2386A>G was a significant predictor of response to treatment with statin for levels of total cholesterol and TGC.…”

Efeitos de hipolipemiantes sobre a expressão de CYP3A4 e CYP3A5 in vitro e in vivo

“…Fatores que modificam a biodisponibilidade de fármacos podem afetar de forma significativa a resposta farmacológica, por alteração da concentração plasmática ou da eficácia do composto farmacologicamente ativo (HOFFMAN et al, 2001;EVANS, MCLEOD, 2003 (SALAZAR et al, 2000a;GUZMÁN et al, 2000;GARCÍA-OTíN et al, 2002;VOHL et al, 2002;SORKIN et al, 2005;FIEGENBAUM et al, 2005a, FIEGENBAUM et al, 2005b. (IAKOUBOVA et al, 2008).…”