Confirmation of the Microsomal Triglyceride Transfer Protein Genetic Effect on Lipids in Young African American Men From the CARDIA Study
To the Editor:
We previously studied the association between the −493 G/T polymorphism of the microsomal triglyceride transfer protein (MTP) gene and the lipid profile in young African American men from the CARDIA cohort.1 The total cholesterol and LDL cholesterol (LDL-C) levels were significantly higher in the TT genotype in the first 4 consecutive measures between 1985 and 1993, but not in the 5th measure in 1996. We analyzed the new data measured in 2001 from the same cohort to test whether the nonsignificant result in the 5th measure is due to diminished genetic effect with age or random variation of data.
The results from analysis of the 6th measure in 2001 showed a significant genetic effect, confirming the influence of the MTP promoter polymorphism in this cohort. Total cholesterol, LDL-C, and nonHDL-C (ie, total cholesterol minus HDL-C) in the TT genotype are higher than in the other two genotypes in the year 2001 data, which is consistent with results from the 1st to 4th measures (Table). The present results suggested that the nonsignificant results in the 5th data were more likely to be due to random variation. The TT genotype was associated with higher levels (mg/dL) of total cholesterol ranging from 2 to 19, LDL-C ranging from 9 to 17 (no difference in the 5th measure), and nonHDL-C ranging from 2 to 19 (Table). Longitudinal analysis by the generalized estimating equation (GEE) model2,3⇓ revealed no evidence of interaction between genotype and time: the coefficients were −0.41 (P=0.19) for total cholesterol, −0.04 (P=0.71) for HDL-C, and −0.38 (P=0.22) for nonHDL-C. Based on the GEE model, the TT genotype had average higher levels of total cholesterol, LDL-C, and nonHDL-C than the (GG+GT) group, by 11.48 (P=0.04), 9.98 (P=0.049), and 12.40 (P=0.03), respectively, during the 15-year follow-up. HDL-C levels were not significantly different among the three genotypes in all 6 examinations.
However, the studies of the −493 G/T MTP polymorphism have yielded conflicting results. The Framingham Offspring Study,4 in which the participants were primarily middle-aged (the mean age of 52 years) whites, reported no significant association, although they found that the TT genotype was associated with higher cholesterol levels. In contrast, studies of the Northern European men reported an opposite result to our finding, with the T allele associated with lower levels of total cholesterol, LDL-C, and triglycerides.5,6⇓ A functional study has shown that the T allele has 2-fold higher transcriptional activity than the G allele,5 which is hard to reconcile with the opposite effects of the TT genotype observed in Northern European men. It is possible that the MTP gene interacts with other genes or environment leading to a complex situation. However, more studies are necessary to address these intriguing findings.
In summary, analysis of the 15-year data reveals a significant genetic effect of the MTP promoter polymorphism on lipids. The genotypic effect did not change over time. More studies are needed to address the conflicting observations between blacks and whites, as well as between Americans and Northern Europeans.
- ↵Juo SH, Han Z, Smith JD, Colangelo L, Liu K. Common polymorphism in promoter of microsomal triglyceride transfer protein gene influences cholesterol, ApoB, and triglyceride levels in young African American men: results from the coronary artery risk development in young adults (CARDIA) study. Arterioscler Thromb Vasc Biol. 2000; 20: 1316–1322.
- ↵Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika. 1986; 73: 13–22.
- ↵Couture P, Otvos JD, Cupples LA, Wilson PW, Schaefer EJ, Ordovas JM. Absence of association between genetic variation in the promoter of the microsomal triglyceride transfer protein gene and plasma lipoproteins in the Framingham Offspring Study. Atherosclerosis. 2000; 148: 337–343.
- ↵Karpe F, Lundahl B, Ehrenborg E, Eriksson P, Hamsten A. A common functional polymorphism in the promoter region of the microsomal triglyceride transfer protein gene influences plasma LDL levels. Arterioscler Thromb Vasc Biol. 1998; 18: 756–761.
- ↵Ledmyr H, Karpe F, Lundahl B, McKinnon M, Skoglund-Andersson C, Ehrenborg E. Variants of the microsomal triglyceride transfer protein gene are associated with plasma cholesterol levels and body mass index. J Lipid Res. 2002: 43: 51–58.