PECAM-1 GENE POLYMORPHISM (rs668) AND SUBCLINICAL MARKERS OF CAROTID ATHEROSCLEROSIS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
Popović D, Nikolajević Starčević J, Šantl Letonja M, Makuc J, Cokan Vujkovac A, Reschner H, Bregar D, Petrovič D
*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: 63

DISCUSSION

In the present study, we demonstrated an association between the rs668 GG genotype and carotid artery plaque incidence in patients with T2DM when adjusted to other risk factors. On the other hand, we did not find any effect of the rs688 genotype on the progression of atherosclerosis in patients with T2DM. Our study is the first demonstrating an association between the rs668 PECAM-1 and the presence of carotid plaques in patients with T2DM. In our study, we observed a greater number of plaques in subjects with the GG rs668 genotype. The importance of the PECAM-1 gene in the pathogenesis of atherosclerosis was demonstrated [21,25]. The decrease in areas with atherosclerotic lesion in PECAM-1 double knock-out mice was reported [21,25]. An association between the rs668 PECAM-1 and car-diovascular disorders was reported several times, but not in all studies [29-33]. Similarly, an association between the rs668 PECAM-1 gene and either the increased levels of soluble PECAM-1 or ischemic stroke was found in the Chinese population [21]. An association between the rs668 PECAM-1 gene and increased levels of soluble PECAM-1 was confirmed in the setting of patients with acute MI [28]. Similarly, Fang et al. [29] demonstrated an association between the rs668 PECAM-1 gene and either increased levels of soluble PECAM-1 or the severity of coronary artery disease in the Asian Indian population in Singapore. Reschner et al. [17] reported an association between the PECAM-1 rs668 (the CC genotype) and MI in Caucasians with T2DM. Finally, the effect of several polymorphisms of the PECAM-1 gene on cardiovascular disease was confirmed by Listi et al. [30] in the Northern Italian population. These findings were not confirmed in the general population from Germany, as rs688 was not found to be an independent risk factor for coronary artery disease (CAD) [31]. In a recently published meta-analysis of 15 studies, including 7636 subjects, no association between the rs668 PECAM-1 and cardiovascular diseases was demonstrated [35]. Moreover, the progression of subclinical markers of carotid atherosclerosis was statistically significantly faster in subjects with T2DM in comparison with subjects without T2DM. This finding is in accordance with expectations of other researchers as well [32,33]. Our study has some limitations due to its actual design (cross-sectional design at the enrollment of subjects with T2DM and control subjects) and relatively small sample size (i.e., less than 1000 subjects with T2DM), however the study was appropriately powered to detect the differences in subclinical markers of carotid atherosclerosis upon enrollment as well as during follow-up. The lack of the effect of rs688 on the progression of atherosclerosis might be due to a rather short interval between the first and control examinations (3.8 0.5 years). Moreover, it is impossible to exclude the impact of interactions with other potentially relevant variables on the development of atherosclerosis. The second limitation of the study is the lack of an intermediate phenotype, i.e., serum PECAM levels. We presume that the effect of rs668 is via increased serum PECAM levels. In conclusion, our study demonstrated a minor effect of the rs668 PECAM-1 on the markers of carotid atherosclerosis in subjects with T2DM, as the GG genotype of the rs668 PECAM-1 was associated with a higher incidence of carotid plaques in subjects with T2DM. With that kind of associations established in genetic studies, we presumed that we might predict the genetic risk of carotid atherosclerosis in subjects with T2DM.



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