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
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PATIENTS AND METHODS
This study included 595 consecutive subjects
with T2DM, admitted to the diabetes outpatient clinics
of the general hospitals at Murska Sobota and
Slovenj Gradec, Slovenia, and from the outpatient
department at the Medical Center Medicor, Ljubljana,
Slovenia. The inclusion criteria for the control group
was the absence of T2DM, and consisted of employees
of the General Hospital Murska Sobota, Slovenia.
Another inclusion criteria for the subjects with T2DM
and for the subjects in the control group was the age
from 40 to 70. The exclusion criteria for subjects
with T2DM and for the subjects in the control group
was a history of either myocardial infarction (MI) or
ischemic stroke. The study protocol was approved by
the Slovene Medical Ethics Committee (98/08/10).
The patients and control subjects were enrolled and
followed in the period from 2008 to 2014.
Patients were classified as having T2DM according
to the current report of the American Diabetes Association
[26]. After informed consent was obtained
from the patients, a detailed interview was conducted
concerning smoking habits, the duration and treatment
of diabetes, arterial hypertension, and hyperlipidemia.
Patients were asked whether they were
smokers at the time of recruitment (current smoker).
Subjects with T2DM with systolic blood pressure
≥140.0 mm Hg or diastolic blood pressure ≥85.0 mm
Hg and/or subjects who were taking anti hypertensive
drugs were considered to be hypertensive.
All ultrasound examinations were performed by
two experienced doctors blinded to the participants’
diabetes status. The carotid intima-media thickness
(CIMT), defined as the distance from the leading
edge of the lumen-intima interface to the leading edge
of the media-adventitia interface, was measured as
previously described [27]. Plaques were defined as a
focal intima-media thickening, and divided into five
types according to their echogenic/ echolucent characteristics,
as previously described [27]. The interobserver
reliability for carotid plaque characterization
was found to be substantial (κ = 0.64, p <0.001).
After the patients with T2DM and subjects without
T2DM (control group) were enrolled, they were
prospectively followed-up for a few years. From the
group with T2DM, 426 responded and participated in
the control ultrasound examination of the neck artery,
whereas, 132 re-sponded from the group of subjects
without T2DM; 3.8 ± 0.5 years passed between the
first and the control ultrasound examination.
Biochemical Analyses. Fasting blood samples
for biochemical analysis were collected twice patients:
upon enrollment and upon follow-up after a
few years. Analyses were made at the hospital ac credited laboratory. The following parameters were
determined: total cholesterol, triglycerides, highdensity
lipoprotein (HDL), low-density lipoprotein
(LDL), blood sugar and high-sensitive C-reactive
protein (hsCRP).
Genotyping. Genomic DNA was extracted from
100 μL of whole blood using a FlexiGene DNA isolation
kit (Qiagen GmbH, Hilden, Germany), in accordance
with the recommended protocol. The rs668
polymorphism of the PECAM-1 gene was determined
with the KASPar assay (LGC Genomics Ltd., Hoddesdon,
Hertfordshire, UK) system.
Statistical Analyses. Continuous variables that
were normally distributed, were reported in the form
of mean ± standard deviation (SD). Variables that
were not normally distributed, were presented in the
form of median (inter-quartile range). The normality
of distribution of continuous variables was examined
using the Kolmogorov-Smirnov test. We used the
Student’s t test or the analysis of variance (ANOVA)
to compare the numerical values of the continuous
variables, to identify the distribution of variables. If
the variables were asymmetrically distributed, we
used the Mann-Whitney U test or the Kruskal-Wallis
H test. The χ2 test was used to compare the frequency’s
categorical variables, statistical evaluation of
differences in the frequencies of different alleles and
genotypes between the two groups, as well as in the
case of determining the Hardy-Weinberg equilibrium.
The Pearson analyses was performed to examine
the correlation between the independent variables.
The results showed a high degree of correlation between
the serum levels of total and LDL cholesterol
(r = 0.86; p <0.001), as well as systolic and diastolic
blood pressure (r = 0.65; p <0.001). In the case of a
high degree correlation between two variables, only
one variable from each pair was included in the multivariate
statistical models.
The change in the value of ultrasound markers
of carotid artery atherosclerosis was calculated by
deducting the values measured at two ultrasound examinations.
The criteria for a statistically significant
difference was a p value of less than 0.05. To reduce
the possibility of error due to the small number of subjects,
we used the Bonferroni correction. All statistical
analyses were performed using the Statistical Package
for the Social Sciences (SPSS) computer program for
Windows, version 20 (SPSS Inc., Chicago, IL, USA).
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