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

Abstract

on behalf of the WOSCOPS executive 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 PreventionStudy 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 (nϭ18), 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.

Molecular screening of the microsomal triglyceride transfer protein: association between polymorphisms and both abdominal obesity and plasma apolipoprotein B concentration

“…Indeed, some authors reported an association between À493G>T and adiposity as well as between this genotype and LDL particle size (Ledmyr et al 2002;Juo et al 2000). This polymorphism may also be associated with an increased risk of cardiovascular disease without being related to plasma lipoprotein/lipid levels (Ledmyr et al 2004). However, Couture et al found no difference in plasma lipid levels or adiposity indices between carriers and noncarriers of the mutation in the Framingham Offspring study (Couture et al 2000).…”

Nutrigenetics: links between genetic background and response to Mediterranean-type diets

“…Nevertheless, the FABP2 genotype did not interact noticeably with the amplitude of response to the dietary intervention (12) . The MTTP gene encodes the microsomial transfer protein (MTP), an intra-cellular protein involved in VLDL and chylomicrons assembly in the liver and small intestine, and shows a common mutation in the promoter sequence (2493 G/T polymorphism) (16,17) . We found that men and women exhibit a different pattern for insulin values at baseline with highest values in T/T men and lowest values in T/T women (12) .…”

Association of a microsomal triglyceride transfer protein gene polymorphism with blood pressure in Japanese women

“…(12). Polymorphisms of MTP have been associated with the serum concentration of low density lipoprotein-cholesterol (13,14) as well as with the susceptibility to coronary heart disease (18) and with longevity (19). We have now examined the relation of the -493G›T polymorphism of MTP to blood pressure and the prevalence of hypertension in community-dwelling Japanese men and women.…”

“…One possible explanation for this discrepancy might be that the phenotype associated with the -493G›T polymorphism of MTP is modulated by visceral obesity and hyperinsulinemia (17). The -493G›T polymorphism was recently shown to be associated with the prevalence of coronary heart disease (18). Furthermore, a haplotype marker of MTP was associated with longevity, suggesting that MTP might modify human life-span (19).…”