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(Circulation. 2004;109:2279-2284.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

The Microsomal Triglyceride Transfer Protein Gene-493T Variant Lowers Cholesterol But Increases the Risk of Coronary Heart Disease

Helena Ledmyr, BSc; Alex D. McMahon, PhD; Ewa Ehrenborg, MD, PhD; Lars B. Nielsen, MD, PhD; Matt Neville, DPhil; Hans Lithell, MD, PhD; Peter W. MacFarlane, DSc; Christopher J. Packard, DSc; Fredrik Karpe, PhD, FRCP, on behalf of the WOSCOPS executive;

From the King Gustaf V Research Institute (H.L., E.E., F.K.), Karolinska Hospital, Stockholm, Sweden; Robertson Centre for Biostatistics (A.D.M.), University of Glasgow, UK; Department of Clinical Biochemistry (L.B.N.), Rigshospitalet, University of Copenhagen, Denmark; Oxford Centre for Diabetes, Endocrinology and Metabolism (M.N., F.K.),, Nuffield Department of Clinical Medicine, University of Oxford, UK; Department of Public Health and Caring Sciences (H.L.), Uppsala University, Sweden; and Departments of Cardiology (P.W.M.) and Pathological Biochemistry (C.J.P.), Royal Infirmary, University of Glasgow, UK.

Correspondence to Dr Fredrik Karpe, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, UK. E-mail fredrik.karpe{at}oxlip.ox.ac.uk

Received July 17, 2004; de novo received October 14, 2004; revision received January 21, 2004; accepted February 6, 2004

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.

Conclusion— 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.

Key Words: hypercholesterolemia • lipids • myocardial infarction • myocardium • statins

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