Effects of SREBF-1a and SCAP polymorphisms on plasma levels of lipids, severity, progression and regression of coronary atherosclerosis and response to therapy with fluvastatin

Abstract

Sterol regulatory elements binding factor-1a (SREBF-1a) and SREBF cleavage activating protein (SCAP) regulate lipids homeostasis. Polymorphisms in SREBF-1a and SCAP could affect plasma levels of lipids and risk of atherosclerosis. We determined association of SREBF-1a -36del/G and SCAP 2386A/G genotypes with plasma levels of lipids, severity and progression/regression of coronary atherosclerosis, and response to treatment with fluvastatin in a well-characterized Lipoprotein Coronary Atherosclerosis Study population. Plasma lipids and quantitative indices of coronary atherosclerosis were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo in 372 subjects. Fluvastatin reduced plasma levels of total cholesterol by 16%, LDL-C by 25%, and ApoB by 16% and increased plasma levels of HDL-C by 9% and apoA-1 by 7%. Distributions of SREBF-1a SCAP genotypes were 60 GG, 172 del-G and 140 del-del and 88 GG, 188 GA and 96 AA, respectively. There were no significant differences in baseline plasma levels of lipids or indices of severity of atherosclerosis among the genotypes of each gene. There was a strong graded genotype-treatment interaction between SREBF-1a genotypes and change in apoA-I levels in response to fluvastatin (16.5% increase in GG, 10.5% in del/G, and 0.4% in del/del groups). Modest interactions between SREBF-1a genotypes and changes in HDL-C, and apoC-III levels in response to fluvastatin were also present. No genotype-treatment interaction for progression or regression of coronary atherosclerosis was detected. There were no significant interactions between SCAP genotypes and response to therapy. Thus we detected a strong graded interaction between SREBF-1a -36del/G genotypes and response of plasma apoA-I to treatment with fluvastatin.

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.…”

“…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].…”

Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

“…23 Considering this finding and the strong LD in the region around SREBF1 on 17p11.2, it is possible that the association observed with the RAI1 marker is actually picking up signal from a SREBF1 variant, or vice versa. In dbSNP (http:// www.ncbi.nlm.nih.gov/projects/SNP/) and the scientific literature, several SNPs have been reported to change the amino acid composition of SREBP1 or to influence the level of cholesterol synthesis, [24][25][26] but none of these SNPs are deposited in HapMap and we have therefore not been able to conclude on their LD to the associated SNPs of the present study. The SREBF2 gene is located on chromosome 22q13.2.…”

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

“…13,14 In one study, Salek et al 13 reported the effect of SCAP and SREBF-1a polymorphisms on hypolipidemic response to fluvastatin treatment. In that investigation, they found a significant genotype-treatment interaction between SREBF-1a polymorphism and changes in apolipoprotein (apo) A-I, apo C-III and HDL-C levels, but did not find any association with SCAP genotypes.…”