Abstract
The microsomal triglyceride transfer protein (MTP) is required for the assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins from liver and intestine. We set out to study the phenotypic modulation of all common genetic variants in the MTP gene. In addition, we aimed at characterizing the association between the various polymorphisms. A total of 564 healthy men were genotyped for the MTP -493 G/T, -400 A/T, and -164 T/C promoter polymorphisms, as well as the Q/H 95, I/T 128, Q/E 244, and H/Q 297 missense polymorphisms. The -493 G/T, -164 T/C, and I/T 128 polymorphisms showed to be in almost complete linkage disequilibrium. Subjects homozygous for the less common -493 T, -164 C, and T 128 alleles showed significantly lower plasma total and LDL cholesterol levels and plasma LDL apoB levels, and also significantly higher body mass index (BMI) and plasma insulin levels compared with carriers of the common alleles. The associations between plasma total cholesterol and MTP -493 genotype was verified in a cohort consisting of 1,117 disease-free control subjects of the West of Scotland Coronary Prevention Study (WOSCOPS). None of the other polymorphisms showed any significant change in either lipid and lipoprotein levels or anthropometric variables. In summary, two promoter polymorphisms and one missense polymorphism in the MTP gene alter plasma total and LDL cholesterol levels, plasma LDL apoB levels, BMI, and insulin levels. This may, in turn, have implications for genetic regulation of cardiovascular risk factors.
Highlights
The microsomal triglyceride transfer protein (MTP) is required for the assembly and secretion of apolipoprotein B-containing lipoproteins from liver and intestine
Functional MTP is an absolute requirement for the assembly and cellular secretion of apolipoprotein B (apoB)-containing lipoproteins, and mutations causing dysfunction of the 97 kDa subunit results in abetalipoproteinemia [7,8,9]
The Ϫ493 G/T, Ϫ164 T/C, and I/T 128 polymorphisms were in almost complete linkage disequilibrium with DЈ values varying between 0.95 and 0.97 (P Ͻ 0.001)
Summary
The microsomal triglyceride transfer protein (MTP) is required for the assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins from liver and intestine. Two promoter polymorphisms and one missense polymorphism in the MTP gene alter plasma total and LDL cholesterol levels, plasma LDL apoB levels, BMI, and insulin levels. This may, in turn, have implications for genetic regulation of cardiovascular risk factors.—Ledmyr, H., F. These missense polymorphisms, previously reported in Caucasians, are Q/H 95, I/T 128, Q/E 244, and H/Q 297 [16] Against this background, we hypothesized that the three promoter polymorphisms as well as the four amino acid changes in the coding region of the MTP gene may influence plasma lipid and lipoprotein levels. We set out to study this in a large cohort of healthy 50-year-old men in which there was detailed information on plasma lipids, metabolic, hormonal, and anthropometric variables
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