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.
RCT Entities:
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.
Authors: Ying Liu; Donna M Conlon; Xin Bi; Katherine J Slovik; Jianting Shi; Hailey I Edelstein; John S Millar; Ali Javaheri; Marina Cuchel; Evanthia E Pashos; Jahangir Iqbal; M Mahmood Hussain; Robert A Hegele; Wenli Yang; Stephen A Duncan; Daniel J Rader; Edward E Morrisey Journal: Cell Rep Date: 2017-05-16 Impact factor: 9.423
Authors: Anna Aminoff; Helena Ledmyr; Petra Thulin; Kerstin Lundell; Leyla Nunez; Elisabeth Strandhagen; Charlotte Murphy; Ulf Lidberg; Jukka Westerbacka; Anders Franco-Cereceda; Jan Liska; Lars Bo Nielsen; Mats Gåfvels; Maria Nastase Mannila; Anders Hamsten; Hannele Yki-Järvinen; Dag Thelle; Per Eriksson; Jan Borén; Ewa Ehrenborg Journal: J Lipid Res Date: 2010-01 Impact factor: 5.922
Authors: Marcin Krzystanek; Tanja Xenia Pedersen; Emil Daniel Bartels; Jacob Kjaehr; Ellen Marie Straarup; Lars Bo Nielsen Journal: J Biol Chem Date: 2010-01-26 Impact factor: 5.157