Common Polymorphism in the MTP Promoter Attenuates the Dyslipidemic and Proatherogenic Effects of Excess Body Weight
To the Editor:
In overweight subjects, an elevated supply of intracellular lipid stimulates the microsomal triglyceride transfer protein (MTP)-dependent assembly of apoB-containing lipoproteins in both intestinal and hepatic tissues, with subsequent secretion into the circulation. The severity of the dyslipidemia which results is however highly variable among overweight subjects, suggesting that genetic background may modulate the dyslipidemic effect of excess weight. In this context, a functional polymorphism in the MTP gene promoter region was recently described in which homozygotes for a G-to-T substitution, located 493 bp upstream from the transcription initiation site, display lower plasma levels of apoB-containing lipoproteins than carriers of the −493G allele. Hypothetically, such a functional polymorphism of the MTP promoter may attenuate the dyslipidemic effects of excess body weight and, in this way, equally attenuate the development of atherosclerotic disease in overweight subjects. We evaluated this hypothesis in 326 normotensive nondiabetic subjects with a broad range of body mass indices (BMI; 16.6 to 40.0kg/m2) who were consecutively evaluated at the Endocrinology Department of La Pitié-Salpetriere Hospital in Paris, France and were considered to be at low cardiovascular risk (n=189) or were enrolled as healthy volunteers in the Stanislas Cohort, Nancy, France (n=137). The MTP −493G/T promoter genotype was determined as described by Karpe et al.1 Plasma levels of total cholesterol and triglycerides were determined by nephelometry, and HDL-cholesterol concentration was determined enzymatically with a commercially available kit (Biomerieux). Ultrasonographic evaluation of the extracranial carotid arteries was performed with a duplex system (ACUSON Sequoia 512). The sum of the intima media thickness (IMT) of the right and left carotid artery walls was determined as an index of global carotid disease.
Genotype frequencies behaved within the limits of the Hardy Weinberg law and were similar to those reported in previous studies. There was no significant difference in age (47±9, 46±9, and 46±9 years), BMI (24.7±3.6, 24.3±4.3, and 23.2±2.9 kg/m2), or sex (male 40%, 37%, and 55%) among the three MTP genotypes. Total cholesterol (237±50 versus 236±45 mg/dL), HDL-cholesterol (62±21 versus 62±17 mg/dL), LDL-cholesterol (152±50 versus 152±44 mg/dL), and triglycerides levels (103±40 versus 99±37 mg/dL) did not differ significantly between the G/T and G/G genotypes. However, both sets of carriers of the −493G MTP allele displayed plasma concentrations of lipids that were significantly different from those of homozygotes for the −493T MTP allele (total cholesterol 216±41 mg/dL; triglycerides 97±40 mg/dL; HDL-cholesterol 65±19 mg/dL; LDL-cholesterol 134±30 mg/dL; P<0.01).
A significant interaction was observed between the impact of the −493 MTP genotype on lipid profile and the covariates BMI and age (P<0.05). A significant positive association was observed between the tertiles of BMI and levels of LDL-cholesterol and triglycerides in subjects carrying the −493G MTP allele (P<0.05). In contrast, plasma lipid and apolipoprotein levels in subjects homozygous for the −493T MTP allele did not vary with BMI. Similarly, a significant negative association was observed between BMI tertiles and plasma HDL-cholesterol concentrations in carriers of the −493G MTP allele (P<0.0001), but not in homozygotes for the −493T MTP allele. In 74 randomly selected subjects in this group (TT=22), carotid ultrasonography was performed. A significant difference in carotid IMT was observed among subjects homozygous for the −493T allele, those with the −493G/T genotype, and those with the −493G/G genotype after adjustment to control for the influence of sex, age, and BMI (0.12±0.03 versus 0.14±0.02 versus 0.15±0.04, respectively; P<0.01). Interestingly, this difference in carotid IMT among genotype groups was still significant after controlling for LDL-cholesterol (P<0.001). Carriers of the −493G MTP allele with a BMI greater than the median value (23.3 kg/m2) presented a carotid IMT which was 22% greater (P=0.01) than those in subjects with a BMI below this median value (Figure). In contrast, carotid IMT in homozygotes for the −493T MTP allele whose BMI was above the median were only 9% greater than those of subjects with a BMI below the median.
In conclusion, the present data indicate that a common polymorphism of the MTP promoter gene (6% to 10% of general population)1 may modulate the development of dyslipidemia and atherosclerotic disease in overweight subjects. Overweight subjects homozygous for the −493T MTP allele display a less atherogenic lipoprotein profile and lower carotid IMT as compared with carriers of the G allele. Collectively, these findings demonstrate the highly variable presentations of dyslipidemia and atherosclerotic disease in overweight subjects, and indicate that MTP potentially plays an important role in the development of obesity-induced dyslipidemia and atherosclerotic disease.