This study investigated whether the I405V and Taq1B polymorphisms modify subclinical atherosclerosis in an asymptomatic population sample.
Previous studies present controversial data on the role of Taq1B and I405V in atherosclerosis and CVD. The B2 allele is associated with lower internal carotid artery IMT in men, but other studies do not identify associations between the Taq1B polymorphism and cIMT[17, 18]. The present study demonstrated that cIMT did not differ between either allele of the polymorphisms. However, inverse correlations between cIMT and CETP activity were demonstrated in both polymorphisms (Table 3), which suggest a potential atheroprotective role for CETP in these individuals. A potential anti-inflammatory role for CETP was demonstrated previously wherein the induction of acute inflammation produced lower mortality due to sepsis and lower cytokine circulation in mice that express human CETP. Reductions in CETP concentrations in human patients with sepsis are more pronounced in non-survivors.
We identified positive correlations between cIMT and PLTP and oxLDL Ab in the presence of the V and B2 alleles. Previous studies have suggested that PLTP increases the risk of cardiovascular disease in humans, and the balance of evidence suggests a pro-atherogenic role for oxLDL Ab titers in the development of atherosclerosis. These positive correlations and the lack of correlations of these variables in both common B1B1 and II allele homozygotes (CETP p≤0.318 and 0.091, oxLDL Ab p≤ 0.709 and 0.386 and PLTP p≤0.823 and 0.470, respectively) (data not shown) suggest a possible pro-atherogenic role of these markers associated with the polymorphisms. Our sample size was relatively small and different between groups. Therefore, further studies are underway in our lab to further confirm these correlations.
The presence of the V allele was associated with lower CETP (24%) and PLTP (29%) activities and higher HDL2-C (13%) concentrations. Patients with coronary disease typically exhibit fewer large HDL particles (HDL2), and the concentration of these large particles is a better predictor of future cardiovascular events than HDL-C concentration.
Lipoprotein (a) plasma levels were also significantly increased in the presence of the B2 allele. High levels of lipoprotein (a) are significantly associated with the presence, severity and extent of carotid atherosclerosis, but this increase was not observed as a possible pro-atherogenic factor.
No significant differences in CETP activity and HDL-C levels were observed in Taq1B polymorphism, despite a 15.4% reduction in CETP activity in presence of the B2 allele. These results are consistent with a previous study in another Brazilian population, in which no association between Taq1B genotypes and HDL-C levels was observed.
A univariate analysis (Table 4) followed by a multivariate logistic stepwise analysis (Table 5) demonstrated that the presence of the B2 allele was independently associated with a mean 5.1-fold increased risk for higher cIMT and age interacted with the allele effect. The presence of the B2 allele in the ≥ 50 years age group exhibited the highest risk of higher cIMT in the Chi-Square analysis (data not shown).
The effects of the Taq1B variant on circulating plasma lipids may be related to other functional mutations within the CETP gene locus that are in LD, which may explain the association in our study. However, other factors than the CETP activity may exert different atherosclerotic repercussions in Taq1B and I405V polymorphisms. A multivariate analysis was performed to verify the independence of the associations between the qualitative binary variable cIMT above or below 66th percentile (0.795mm), CETP and PLTP plasma activities and the potential confounding factors, including gender, age, BMI, SBP and HDL-C. Only age exhibited a significant statistical association (OR: 1.247, CI 95%OR: 1.129 – 1.377), which was a strong determinant of cIMT (data not shown). The absence of interactions of other tested parameters with higher cIMT in this study suggests that other non-determined factors were affected by the genotypes and related to carotid atherosclerotic disease.
Our results focused on several biomarkers that were assessed for the first time in the Brazilian population, and the results were partially based on the correlations between a relatively small numbers of individuals. These results merit further exploration due to the high frequency of the investigated polymorphisms in the present Brazilian sample. Identifying the impact of these polymorphisms is an ongoing aim of our research group.