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BACKGROUND: The microsomal triglyceride transfer protein (MTP) transfers lipids into apolipoprotein B-containing lipoproteins for secretion from liver, intestine, and heart. The T-variant of a functional polymorphism in the MTP promoter, MTP-493G/T, has been associated with reduced low-density lipoprotein cholesterol concentrations. We hypothesize that this polymorphism impacts on coronary heart disease (CHD) risk. METHODS AND RESULTS: The effect of the polymorphism was therefore tested in the West of Scotland Coronary Prevention Study biobank (580 cases and 1160 controls). MTP-493T carrier status was associated with significantly increased risk of CHD despite a small reduction in total cholesterol. Compared with the genotypic group with the lowest event rate (MTP-493GG, pravastatin treatment), the respective odds ratios (95% confidence interval) in the placebo group for CHD events were: GG, 1.23 (0.92 to 1.63); GT, 1.53 (1.12 to 2.08); and TT, 2.78 (1.53 to 5.05), suggestive of a gene-dose effect. The excess risk for CHD of the MTP-493T-variant was eliminated by pravastatin treatment. The Uppsala Longitudinal Study of Adult Men (ULSAM), which is a 20-year follow-up study of CHD, was used as an independent confirmatory database. These unexpected findings prompted the investigation of non-plasma lipid factors that could associate the MTP gene with CHD risk. In a limited number of subjects (n=18), heart muscle biopsies showed a MTP-493T genotype-specific depression of MTP mRNA expression. CONCLUSIONS: The MTP-493T variant confers an increased risk of CHD that is unrelated to plasma lipids and lipoproteins, but eliminated by pravastatin treatment. A direct effect of the MTP polymorphism on myocardial lipid metabolism and vulnerability upon ischemic damage cannot be excluded.

Original publication

DOI

10.1161/01.CIR.0000130070.96758.7b

Type

Journal article

Journal

Circulation

Publication Date

18/05/2004

Volume

109

Pages

2279 - 2284

Keywords

Abetalipoproteinemia, Anticholesteremic Agents, Biopsy, Carrier Proteins, Case-Control Studies, Cholesterol, LDL, Codon, Cohort Studies, Coronary Disease, Disease Susceptibility, Double-Blind Method, Genotype, Haplotypes, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipid Metabolism, Lipoproteins, Longitudinal Studies, Male, Middle Aged, Myocardial Infarction, Myocardium, Polymorphism, Genetic, Pravastatin, Promoter Regions, Genetic, Prospective Studies, RNA, Messenger, Risk, Scotland, Sweden