ASSOCIATION OF THE ACE rs4646994 AND rs4341 POLYMORPHISMS WITH THE PROGRESSION OF CAROTID ATHEROSCLEROSIS IN SLOVENIAN PATIENTS WITH TYPE 2 DIABETES MELLITUS
Merlo S1, Novák J2,3,4, Tkáčová N2, Nikolajević Starčević J5, Šantl Letonja M6, Makuc J7, Cokan Vujkovac A7, Letonja J5, Bregar D5, Zorc M5, Rojko M5, Mankoč S5, Kruzliak P8, Petrovič D5
*Corresponding Author: Professor Daniel Petrovič, M.D., Ph.D., Institute of Histology and Embryology, Faculty of Medicine University Ljubljana, Korytkova 2, SI-1000 Ljubljana, Slovenia. Tel: +386-1-543-7367. Fax: +386-1- 543-7361. E-mail: daniel.petrovic@mf.uni-lj.si
page: 37

DISCUSSION

In this study, we demonstrated the effect of the DD genotype of the rs4646994 (ACE I/D) polymorphism on atherosclerosis progression in subjects with T2DM. Statistically significant differences in a 3.8- year observation period were found in the change in the sum of carotid plaques for the rs4646994 polymorphism. Our findings are in accordance with the findings of Saitou et al. [5], who on a cohort of 222 T2DM patients reported faster progression of atherosclerosis in subjects with the D allele. Moreover, in our study, we did not demonstrate an association between tested polymorphisms (rs4646994, rs4341) and either CIMT or CIMT progression in an almost 4-year period. In 1994, it was reported for the first time that ACE levels correlate with CIMT in healthy persons [6]. As the ACE I/D polymorphism is known to affect circulating ACE levels (subjects with the DD genotype having the highest serum ACE levels compared to subjects with other genotypes) [7], subsequent studies have already been conducted to identify a possible association of the ACE I/D genotype with atherosclerosis, both on general and diabetic populations, providing contradictory results [5-10]. Using smaller or larger cohorts of the general population, association of the ACE I/D polymorphism with carotid atherosclerosis was confirmed in some studies [6-8] and opposed by others [9]. Finally, large meta-analyses confirmed statistically significant association of ACE I/D with CIMT in the general population [10]. In studies that did not focus on the general population but on patients with T2DM, Kogawa et al. [11] in 1997, studied femoral and CIMT in healthy persons and patients with T2DM, and showed that only in T2DM patients was there a significant association of the D allele with higher CIMT. Since the study of Kogawa et al. [11], studies focusing on the association of CIMT and the ACE I/D polymorphism provided contradictory results, similar to studies conducted in the general population. In the diabetic heart study no association was found between ACE I/D and CIMT [12], similar to the study focusing on the offspring of patients with T2DM [13]. On the other hand, Sticchi et al. [14] reported a higher risk of carotid stenosis in D allele carriers, and Zhou et al. [15] reported higher lipid levels in older patients with T2DM carrying the D allele, which could promote atherosclerosis progression. Certain limitations of our study should be noted. First is the moderate sample size of our study. However, all the participants were enrolled from an ethnically homogenous population, which minimizes possible biases from population stratification. Second, the results of our study may be affected by statin therapy, and antihypertensive agents, and these facts were not appreciated in the statistical analysis. In conclusion, our study represents the first larger study focusing on the effect of two ACE polymorphisms (rs4646994 and rs4341) on the progression of carotid atherosclerosis in subjects with T2DM. We demonstrated that those subjects with T2DM with the DD genotype of the rs4646994 (ACE I/D) polymorphism had faster progression of atherosclerosis in comparison with subjects with other genotypes.



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