A new DNA polymorphism in the 5' untranslated region of the human SREBP-1a is related to development of atherosclerosis in high cardiovascular risk population.
Sterol-regulatory element binding proteins (SREBPs) are ubiquitous transcription factors that regulate the genes encoding key proteins in the control of cholesterol homeostasis. We looked for mutations or polymorphisms within the sequences of the SREBP-1a gene critical for the synthesis and/or activity of the protein in 204 asymptomatic men. A single G deletion at base pair -36 of the translation initiation site (designated G-) was found using single-strand conformation polymorphism (SSCP), in addition to three rare variants. This new marker was then assessed for its influence on the lipid parameters of 812 men at high cardiovascular risk, and on the presence of echographic atherosclerotic plaque in their peripheral arteries. The allelic frequency of the -36delG polymorphism was 0.58. At least one plaque was found in the carotid in 24% of subjects, in the femoral arteries of 48%, and in the aorta of 25%. There were significant associations between the -36delG polymorphism and mean total cholesterol (p=0.02) and LDL-cholesterol (P=0.02). There was a graded relationship between the G- allele and the presence of carotid plaque (r=0.084, P=0.02). In addition, there was a statistically significant interaction between the -36delG genotype and the apoE phenotype for plasma LDL-cholesterol (P=0.04) and apoB (P=0.05), suggesting a gene-gene interaction. Stepwise multiple regression analysis for lipid traits, risk factors, and apoE phenotype showed an independent association between carotid plaque and the -36delG polymorphism (beta=0.311, P=0.03). Thus, we have identified a new polymorphism in the 5' untranslated region of the SREBP-1a gene, and demonstrated its association with an atherogenic lipid profile and echographic plaques.
Laboratoire de Biochimie Appliquée, Faculté des Sciences Pharmaceutiques et Biologiques, Châtenay-Malabry, France. benoit.vedie@brs.ap-hop-paris.fr
B
B
Védie
X
X
Jeunemaitre
J L
JL
Mégnien
V
V
Atger
A
A
Simon
N
N
Moatti
D020121:5' Untranslated Regions / Q000235:genetics*; D000328:Adult; D001011:Aorta; D001161:Arteriosclerosis / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000209:etiology*; D002339:Carotid Arteries; D004247:DNA / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005263:Femoral Artery; D005787:Gene Frequency; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D012307:Risk Factors; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014463:Ultrasonography
D020121:5' Untranslated Regions; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D008055:Lipids; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D004247:DNA