The microsomal triglyceride transfer protein gene-493T variant lowers cholesterol but increases the risk of coronary heart disease.

Ledmyr, H; McMahon, A; Ehrenborg, E; Nielsen, L; Neville, M; Lithell, H; MacFarlane, P; Packard, C; Karpe, F

Journal article

The microsomal triglyceride transfer protein gene-493T variant lowers cholesterol but increases the risk of coronary heart disease.

Abstract:: 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.

Publication status:: Published

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APA Style

Ledmyr, H., McMahon, A., Ehrenborg, E., Nielsen, L., Neville, M., Lithell, H., MacFarlane, P., Packard, C., & Karpe, F. (2004). The microsomal triglyceride transfer protein gene-493T variant lowers cholesterol but increases the risk of coronary heart disease. Circulation, 109(19), 2279–2284.

MLA Style

Ledmyr, H., et al. “The Microsomal Triglyceride Transfer Protein Gene-493T Variant Lowers Cholesterol but Increases the Risk of Coronary Heart Disease.” Circulation, vol. 109, no. 19, 2004, pp. 2279–84.

Chicago Style

Ledmyr, H, A McMahon, E Ehrenborg, L Nielsen, M Neville, H Lithell, P MacFarlane, C Packard, and F Karpe. 2004. “The Microsomal Triglyceride Transfer Protein Gene-493T Variant Lowers Cholesterol but Increases the Risk of Coronary Heart Disease.” Circulation 109 (19): 2279–84.
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