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A single-nucleotide polymorphism in the human p27kip1 gene (-838C>A) affects basal promoter activity and the risk of myocardial infarction.

ABSTRACT: BACKGROUND: Excessive proliferation of vascular smooth muscle cells and leukocytes within the artery wall is a major event in the development of atherosclerosis. The growth suppressor p27kip1 associates with several cyclin-dependent kinase/cyclin complexes, thereby abrogating their capacity to induce progression through the cell cycle. Recent studies have implicated p27kip1 in the control of neointimal hyperplasia. For instance, p27kip1 ablation in apolipoprotein-E-null mice enhanced arterial cell proliferation and accelerated atherogenesis induced by dietary cholesterol. Therefore, p27kip1 is a candidate gene to modify the risk of developing atherosclerosis and associated ischaemic events (i.e., myocardial infarction and stroke). RESULTS: In this study we found three common single-nucleotide polymorphisms in the human p27kip1 gene (+326T>G [V109G], -79C>T, and -838C>A). The frequency of -838A carriers was significantly increased in myocardial infarction patients compared to healthy controls (odds ratio [OR] = 1.73, 95% confidence interval [95%CI] = 1.12-2.70). In addition, luciferase reporter constructs driven by the human p27kip1 gene promoter containing A at position -838 had decreased basal transcriptional activity when transiently transfected in Jurkat cells, compared with constructs bearing C in -838 (P = 0.04). CONCLUSIONS: These data suggest that -838A is associated with reduced p27kip1 promoter activity and increased risk of myocardial infarction.

SUBMITTER: Gonzalez P

PROVIDER: S-EPMC400507 | biostudies-literature | 2004

REPOSITORIES: biostudies-literature

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A single-nucleotide polymorphism in the human p27kip1 gene (-838C>A) affects basal promoter activity and the risk of myocardial infarction.

González Pelayo P Díez-Juan Antonio A Coto Eliecer E Alvarez Victoria V Reguero Julian R JR Batalla Alberto A Andrés Vicente V

BMC biology 20040402

<h4>Background</h4>Excessive proliferation of vascular smooth muscle cells and leukocytes within the artery wall is a major event in the development of atherosclerosis. The growth suppressor p27kip1 associates with several cyclin-dependent kinase/cyclin complexes, thereby abrogating their capacity to induce progression through the cell cycle. Recent studies have implicated p27kip1 in the control of neointimal hyperplasia. For instance, p27kip1 ablation in apolipoprotein-E-null mice enhanced arte ...[more]

PMID: 15061869

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Project description:BACKGROUND: Mutation in SCARB1 gene, exon 8 rs5888, has been associated with altered lipid levels and cardiovascular risk in humans though the results have been inconsistent. We analysed the impact of SCARB1 single nucleotide polymorphism (SNP) rs5888 with plasma lipid profile and association with coronary artery disease (CAD) in a Lithuanian population characterized by high morbidity and mortality from CAD and high prevalence of hypercholesterolemia. METHODS: The study included 1976 subjects from a random sample (reference group) and an myocardial infarction (MI) group of 463 patients. Genotyping of SCARB1 (rs5888) was carried out using the real-time polymerase chain reaction method. RESULTS/PRINCIPAL FINDINGS: Analysis of rs5888 C/T gene polymorphism in the reference group revealed that male TT genotype carriers (25-74 years) had significantly higher total cholesterol and triglyceride concentrations (5.70 mmol/l vs. 5.49 mmol/l; p?=?0.036, and 1.70 mmol/l vs. 1.40 mmol/l, p?=?0.023, respectively) than CT carriers and the oldest males (65-74 years) TT carriers had significantly higher high density lipoprotein cholesterol concentrations in comparison to heterozygous (1.52 mmol/l vs. 1.36 mmol/l, p?=?0.033). The youngest female (25-44 years) TT genotype carriers had significantly lower low density lipoprotein cholesterol concentrations in comparison to C homozygous (2.59 mmol/l vs. 2.92 mmol/l, p?=?0.023). The frequency of the SCARB1 TT genotype in the oldest male MI group (65-74 years) was significantly lower than in the corresponding reference group subjects (9.4% vs. 22.3%, p?=?0.006). SCARB1 TT genotype was associated with decreased odds of MI in males aged 65-75 years (OR?=?0.24, 95% CI 0.10-0.56, p?=?0.001). CONCLUSIONS/SIGNIFICANCE: SCARB1 polymorphism is associated with lipid metabolism and CAD in an age- and gender- dependent manner. Analysis of SCARB1 SNP rs5888 C/T genotypes revealed an atheroprotective phenotype of lipid profile in older men and in young women TT genotype carriers in the reference group. SCARB1 TT genotype was associated with decreased odds of MI in aged men.

Dataset Information

A single-nucleotide polymorphism in the human p27kip1 gene (-838C>A) affects basal promoter activity and the risk of myocardial infarction.

Publications

A single-nucleotide polymorphism in the human p27kip1 gene (-838C>A) affects basal promoter activity and the risk of myocardial infarction.

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