Published Online
on May 10, 2004

A more recent version of this article appeared on May 18, 2004

This Article Full Text (PDF) All Versions of this Article: 109/19/2279    most recent 01.CIR.0000130070.96758.7bv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ledmyr, H. Search for Related Content PubMed PubMed Citation Articles by Ledmyr, H. Related Collections Biochemistry and metabolism Gene regulation Myocardial cardiomyopathy disease Genetics of cardiovascular disease Lipid and lipoprotein metabolism

Submitted on July 17, 2003
Revised on January 21, 2004
Accepted on February 6, 2004

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.

^* To whom correspondence should be addressed. E-mail: fredrik.karpe{at}oxlip.ox.ac.uk.

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

This article has been cited by other articles:

				M. Gastaldi, S. Diziere, C. Defoort, H. Portugal, D. Lairon, M. Darmon, and R. Planells Sex-specific association of fatty acid binding protein 2 and microsomal triacylglycerol transfer protein variants with response to dietary lipid changes in the 3-mo Medi-RIVAGE primary intervention study Am. J. Clinical Nutrition, December 1, 2007; 86(6): 1633 - 1641. [Abstract] [Full Text] [PDF]

				T. M. Morgan, H. M. Krumholz, R. P. Lifton, and J. A. Spertus Nonvalidation of Reported Genetic Risk Factors for Acute Coronary Syndrome in a Large-Scale Replication Study JAMA, April 11, 2007; 297(14): 1551 - 1561. [Abstract] [Full Text] [PDF]

				H. Ledmyr, L. Ottosson, M. Sunnerhagen, and E. Ehrenborg The Ile128Thr polymorphism influences stability and ligand binding properties of the microsomal triglyceride transfer protein J. Lipid Res., July 1, 2006; 47(7): 1378 - 1385. [Abstract] [Full Text] [PDF]

				M. Beekman, G. J. Blauw, J. J. Houwing-Duistermaat, B. W. Brandt, R. G. J. Westendorp, and P. E. Slagboom Chromosome 4q25, microsomal transfer protein gene, and human longevity: novel data and a meta-analysis of association studies. J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2006; 61(4): 355 - 362. [Abstract] [Full Text] [PDF]

				B. Lundahl, C. Skoglund-Andersson, M. Caslake, D. Bedford, P. Stewart, A. Hamsten, C. J. Packard, and F. Karpe Microsomal triglyceride transfer protein -493T variant reduces IDL plus LDL apoB production and the plasma concentration of large LDL particles Am J Physiol Endocrinol Metab, April 1, 2006; 290(4): E739 - E745. [Abstract] [Full Text] [PDF]