Introduction
pidemiologic
studies confirm that the clustering of glucose intolerance,
hypertension, abdominal obesity, and dyslipidemia,
known as metabolic syndrome (MS), occurs
commonly in certain people.1 A wide variety of
ethnic groups, including Europeans, Afro-Americans, Asian Indians and Chinese,
Australian aborigines, Polynesians, and Micronesians, have been
found to have such clusterings.2 In 1988, Reaven1 focused on this
cluster, naming it “syndrome X,” with insulin resistance possibly being
the common etiologic factor of the individual components of the
syndrome.3,4 In 1998, World
Health Organization (WHO) proposed a unifying definition for the
syndrome and called it “metabolic syndrome” instead of “insulin-resistance syndrome.”
Metabolic syndrome is believed to be attributed to the collective effect
of genetic predisposing factors and certain environmental factors
such as diet and stress. There are several candidate genes involved
in metabolic syndrome, including the genes for the β2-
and β3-adrenergic receptor, lipoprotein lipase,
hormone-sensitive lipase, peroxisome proliferators-activated receptor,
insulin receptor substrate-1, glycogen synthase, and the angiotensin-converting
enzyme (ACE) gene polymorphism.5
The renin-angiotensin system (RAS) has
long been known to be an important regulator of blood pressure and
renal electrolyte homeostasis. This system has also been implicated
in the pathologic changes of organ damage through modulation of gene
expression, growth, fibrosis, and inflammatory response.6, 7 Studies have also
demonstrated that ACE insertion/deletion (I/D) polymorphism is
associated with development of diabetes mellitus (DM),8 hypertension,9 coronary artery
disease,10, 11 and diabetic
nephropathy.8,12 In a study of Pima
Indians, Hsieh et al13 revealed that
plasma ACE concentrations were associated with plasma triglyceride and
total cholesterol levels. Recently, several components of the RAS
were detected in adipose tissue, and local RAS may be involved in
the regulation of adipose tissue physiology and possibly in the
pathophysiology of obesity and obesity-associated hypertension.14–18 Therefore, ACE
might be a good candidate gene for causing metabolic syndrome. The objective of this study was to investigate whether
ACE gene I/D polymorphism is associated with metabolic syndrome in
Iranians with type 2 DM.
Materials and Methods
This study recruited 170 patients with type 2 DM who
consecutively attended the Diabetes Clinic of Imam Khomeini Hospital affiliated
to Tehran University of Medical Sciences (TUMS) from May, 2004 through April,
2006. The diagnosis of DM was based on the American Diabetes Association
criteria for type 2 DM—a fasting plasma glucose level >126 mg/dL and/or
glucose level exceeding 200 mg/dL after two hours in the 75-g oral glucose
tolerance test. A total of 170 (88 males and 82 females) patients with a
mean±SD age of 59.3±7.9 (range: 45 – 81) years completed the study. The patients
were treated by diet, exercise, and/or oral hypoglycemic agents (i.e.,
biguanides and/or sulfonylureas) and/or insulin. For each patient a
questionnaire including epidemiologic data such as age, gender, occupation,
duration of DM was completed. Information was obtained on demographic
characteristics and medical history of all patients concerning their age, gender,
history and duration of DM, hypertension, medications, and comorbidities.
ACE gene polymorphism was studied in 170 patients and
91 control subjects. Patients’ drug history such as taking antihypertensive and
lipid lowering drugs was not considered as an exclusion criteria. All subjects
underwent physical examination including measurements of height, weight, and
blood pressure (sitting position after at least 10 min rest). Patients with
clinical evidences of congestive heart failure (CHF) or liver insufficiency,
and systemic or local infections were excluded from the study. We obtained
informed consent from all participants. Controls did not have any abnormalities
regarding their physical examination, blood pressure, family history,
urinalysis, and routine laboratory blood tests; none of them were receiving any
medications at the time of participation.5
Metabolic syndrome was defined when a subject with
impaired fasting glucose or diabetes had two or more of the following components:
1) raised arterial pressure (above 160/90 mmHg) or being on antihypertensive drugs;
2) having a body mass index (BMI) of ≥30 kg/m2; 3) having microalbuminuria
(urinary albumin excretion of 20 µg/min or albumin/creatinine ratio of 20 mg/g
on at least two occasions) or more advanced nephropathy; and 4) raised plasma
triglycerides (>150 mg/dL) and/or decreased HDL cholesterol (<35 mg/dL
for men and <39 mg/dL for women). Because hypertriglyceridemia may be
related to hyperglycemia in patients with type 2 DM,19 the
definition of dyslipidemia in patients with type 2 DM was used only when
triglycerides or HDL cholesterol were at abnormal levels after a three-month
control of blood glucose.
After a 12-hr overnight fasting, 10 mL of 15% EDTA
anticoagulated blood sample and five mL of blood without anticoagulant were
obtained from each patient and the control group. Samples were centrifuged
within two hours. Urinary albumin concentrations were measured by immunoturbidmetry
(Cecile Instruments, USA). The detection limit was 2 mg/L.
DNA
isolation and determination of ACE genotypes
Genomic DNA was isolated from peripheral blood
leukocytes according to a standard salting out method.20 For
amplification, a flanking primer pair was used and when necessary, a primer
pair that recognizes the insertion specific sequence was also employed for
confirmation of the specificity of the amplification reactions.21–22
PCR was performed with 20 pM of each primer. The sense primer was 5'-CTG
GAG ACC ACT CCC ATC CTT TCT-3' and the antisense primer was 5'-GAT GTG GCC ATC ACA TTC GTC AGA T-3.'. The reaction was done in a final
volume of 25 μL, containing 0.5 µg genomic DNA, 2 mM MgCl2, 10
mM Tris- HCl (pH=8.3), 0.2 mM of each dNTP, and 0.5 unit of Taq polymerase. PCR
was done with an initial denaturation at 94˚C for one minute. Then the DNA
was amplified for 30 cycles with denaturation at 94˚C for 30 seconds,
annealing at 58˚C for 30 seconds, and extension at 72˚C for one minute
followed by a final extension at 72˚C for eight minute.
After electrophoresis in a 2% ethidium bromide-stained
agarose gel, the PCR products were visualized under UV light. In case of
deletion (D allele) a 190-bp fragment and in case of insertion (I allele) a 490-bp
fragment were obtained. Therefore, there will be three genotypes after
electrophoresis: a 490-bp band (genotype II), a 190-bp band (genotype DD), and
both a 490- and a 190-bp band (ID genotype). Mistyping of ID heterozygote as D
homozygotes may occur. Thus, each sample which had the DD genotype was
submitted to PCR amplification using the forward primer of 5'-TCG GAC
CAC AGC GCC CGC CAC TAC-3' and a reverse primer of 5'-TCG
CCA GCC CTC CCA TGC CCA TAA-3.' with identical PCR conditions except
for an annealing temperature of 67˚C. The reaction yielded a 335-bp
amplicon only in the presence of an I allele and no product when the samples
were homozygous for DD.
Statistical
analysis
The results are expressed as means±SD. All statistical
analyses were performed using the SPSS for Windows™, version 11.5. The
statistical difference in genotype distribution and allele frequencies among
the groups was assessed by the χ2-test. Other variables were
compared using Student’s t-test for normally-distributed variables. One-way
ANOVA followed by Scheffe’s test were used to compare the group means. A
P value < 0.05 was considered significant and all P
values are the results of two-sided tests.
Results
The results are summarized in Table 1. The patients with
type 2 DM, with and without MS, were well-matched for gender, age, duration of
diabetes, and HbA1C. The mean±SD age of the diabetic subjects with
MS (59.6±8.1 years) was slightly higher than that of the diabetic subjects
without MS (58.6±7.6 years). The patients with MS had significantly higher
systolic and diastolic blood pressure values (P<0.05) than those
without the syndrome. The studied groups were compared with respect to clinical
findings and biochemical parameters. LDL-C and BMI increased significantly in
patients with MS compared to those without MS (P<0.05).
|
Table 1. Clinical and biochemical characteristics of the diabetic patients and normal
control subjects.
|
|
|
Type 2 diabetic patients with metabolic syndrome
(n=119)
|
Type 2 diabetic patients without metabolic syndrome
(n=51)
|
Normal control subjects
(n=91)
|
*P value
MS vs.
NMS
|
*P value
MS vs.
normal
control
|
|
Age( yr)
|
58.6±7.5
|
59.5±8.1
|
49.3. ±6.2
|
0.73
|
<0.001
|
|
Sex (M/F)
|
59/60
|
29/22
|
44/47
|
0.87
|
0.76
|
|
Diabetic duration yr
|
13.4±4.5
|
12.2±4.2
|
—
|
0.09
|
—
|
|
HbA1C (%)
|
8.8±1.8
|
8.1±2.1
|
—
|
0.07
|
—
|
|
ACE activity (IU/L)
|
63.8±25.3
|
65.9±32.7
|
39.4±
21.4
|
0.87
|
<0.001
|
|
Data are presented as mean±SD. Comparisons were made
using Student’s t-test (for continues variables) and one-way ANOVA
followed by Scheffe’s test were used to compare the group means.
Statistically significant; *P<0.05; MS=metabolic syndrome; NMS=diabetic
with no metabolic syndrome.
|
The mean BMI, blood pressure, total cholesterol, LDL-C,
HDL-C, VLDL-C, and triglyceride levels in the diabetic patients were
significantly higher than the controls (P<0.001). The mean age of the
MS patients (59.6±8.1 years) was higher than the control subjects
(49.3±6.2 years).
Allele and genotype frequencies of the ACE gene in the
studied population are shown in Table 2 and Figures 1 and 2.
|
|
|
Figure 1. Detection of ACE I/D polymorphism.
M, 100 – 1000 bp DNA ladder; DD homozygous: a single 190-bp product; ID
heterozygous: both 190- and 490-bp; II homozygous: a single 490-bp product.
|
|
Table 2. Allele and genotype frequencies of ACE gene
insertion/deletion polymorphism in patients with type 2 diabetes mellitus
without metabolic syndrome, type 2 diabetes mellitus with metabolic syndrome
and control subjects.
|
|
|
Type 2 diabetic patients
(n=170)
|
Type 2 diabetic patients with metabolic syndrome
(n=119)
|
Type 2 diabetic patients without metabolic syndrome
(n=51)
|
Normal control subjects
|
*P value
MS vs.
NMS
|
*P value
T2DM vs.
control
|
|
DD
|
43(25.3%)
|
32(26.9%)
|
11(21.6%)
|
12(13.2%)
|
0.57
|
0.026
|
|
ID
|
99(58.2%)
|
67(56.3%)
|
32(62.7%)
|
43(47.3%)
|
0.50
|
0.09
|
|
II
|
28(16.5%)
|
20(16.8%)
|
8(15.7%)
|
36(39.5%)
|
0.86
|
<0.001
|
|
Alleles
|
|
|
|
|
|
|
|
D
|
185(54.4%)
|
131(55.1%)
|
54(52.9%)
|
67(36.8%)
|
0.723
|
<0.001
|
|
I
|
165(48.5%)
|
107(44.9%)
|
48(47.1%)
|
115(47.1%)
|
0.723
|
<0.001
|
|
The distribution and comparisons of
alleles and genotype frequencies of ACE polymorphism gene in each case was
made using χ2 test, Fisher’s exact test, and likelihood
ratio. χ2=19.04; df=2, P < 0.001.
Statistically
significant; *P<0.05, MS=metabolic syndrome; NMS=diabetic with no metabolic
syndrome, T2DM=type 2 diabetes mellitus.
|
Both patients and controls were in Hardy-Weinberg
equilibrium. The frequencies of DD, ID, and II genotypes among the studied
group were 26.9%, 56.3%, and 15.7% in patients with MS, 21.6%, 62.7%, and 15.7%
in patients without MS, and 13.2%, 47.3%, and 39.6% in the control subjects,
respectively. The frequency of DD genotype in patients with type 2 DM (25.3%)
was significantly higher (OR=1.1, 95% CI: 1.1 – 4.48; P= 0.026) than the
control group (13.2%). However, the frequency of DD genotype was not
significantly different between those with (26.9%) and without (21.6%) MS (P=0.56).
On the other hand, the frequency of D allele in patients with type 2 DM (54.4%)
was significantly (P<0.001) higher than the control group (36.8%);
the frequency in patients with MS (55.1%) did not significantly (P=0.72)
differ from that in the patients without MS (52.9%). Tables 3 and 4 show that
the phenotype characteristics of the diabetic patients did not depend on the ACE
genotypes. ACE I/D polymorphism was correlated with ACE activity levels (P<0.001).
The mean±SD ACE activity of MS patients (63.8±25.4
IU/L) was significantly higher than that of the control subjects (39.4±21.4
IU/L) (P<0.001).
|
Table 3. Clinical and biochemical
characteristics of diabetic patients with metabolic syndrome stratified
according to their ACE genotype.
|
|
Variable
|
DD
|
ID
|
II
|
P*
|
|
Age (yr)
|
59.2±8.63
|
60.49±8.25
|
57±6.16
|
0.232
|
|
Sex (M/F)
|
15/17
|
33/34
|
11/9
|
0.847
|
|
Diabetic
duration (yr)
|
12.7±4.7
|
13.9±4.2
|
12.9±4.4
|
0.442
|
|
BMI (kg/m2)
|
27.8±5
|
28.8±13.8
|
28.8±5.6
|
0.755
|
|
Systolic blood
pressure (mmHg)
|
140.8±19.6
|
139.4±24.6
|
140.8±25.8
|
0.948
|
|
Diastolic blood
pressure (mmHg)
|
89.3±11.5
|
89.6±11.4
|
87.5±11
|
0.772
|
|
FBS (mg/dL)
|
228.2±69.5
|
209.3±46.5
|
233.2±63
|
0.131
|
|
Total cholesterol
(mg/dL)
|
222.8±52
|
212.8±38.7
|
219.5±51
|
0.560
|
|
Triglyceride (mg/dL)
|
225.1±1.4.3
|
197.3±19
|
181±88.6
|
0.176
|
|
HDL-C (mg/dL)
|
44±11.5
|
42.8±10.1
|
42.1±7.2
|
0.789
|
|
LDL-C (mg/dL)
|
131.8±32.2
|
123.7±29.1
|
121.6±35.4
|
0.397
|
|
VLDL-C (mg/dL)
|
40.9±12.4
|
37.2±11.6
|
34.4±11.2
|
0.133
|
|
HbA1C (%)
|
8.5±1.9
|
8.7±1.6
|
9.2±2.1
|
0. 350
|
|
ACE activity (IU/L)
|
91.6±23.4
|
58.4±16
|
37.1±7.9
|
<0.001
|
|
Hypertension (n)
|
32
|
67
|
20
|
0.14
|
|
Data are presented as mean± SD. Comparisons were made using ANOVA.
Statistically significant;*P<
0.05 between DD, I, and II.
|
|
Table 4. Clinical and biochemical characteristics of the diabetic
patients without metabolic syndrome stratified according to their ACE
genotype.
|
|
Variable
|
DD
|
ID
|
II
|
P*
|
|
Age (yr)
|
57.1±7.1
|
58.4±7.7
|
61.3±7.9
|
0.484
|
|
Sex (M/F)
|
3/8
|
20/12
|
6/2
|
0.07
|
|
Diabetic
duration (yr)
|
11.1±2.1
|
12.1±3.9
|
14.2±6.9
|
0.288
|
|
BMI (kg/m2)
|
23.8±4.3
|
25.6±3.4
|
21.9±3.3
|
0.03
|
|
Systolic blood
pressure (mmHg)
|
140.4±23.8
|
132.9±17
|
124.4±14.2
|
0.177
|
|
Diastolic blood
pressure (mmHg)
|
86.8±9.8
|
83.4±9.2
|
83.8±8.1
|
0.581
|
|
FBS (mg/dL)
|
199.3±63.4
|
218.7±68.1
|
173.5±31.8
|
0.184
|
|
Total cholesterol
(mg/dL)
|
213.6±35.1
|
199.5±41.4
|
189.7±22.9
|
0.380
|
|
Triglyceride (mg/dL)
|
223.2±120.9
|
189.9±94.2
|
153.2±37.9
|
0.290
|
|
HDL-C (mg/dL)
|
44.1±41
|
44.6±7.1
|
40.2±9.9
|
0.305
|
|
LDL-C (mg/dL)
|
113.6±46.3
|
117.8±38.3
|
100.6±17.1
|
0.523
|
|
VLDL-C (mg/dL)
|
40.5±14.2
|
35.3±13.2
|
31.6±6.4
|
0.303
|
|
HbA1C (%)
|
7.5±0.9
|
8.5±2.5
|
7.2±1.2
|
0.193
|
|
ACE activity (IU/L)
|
90.1±26.1
|
65.2±32.6
|
35.9±3.6
|
0.001
|
|
Data are presented as mean± SD. Comparisons
were made using ANOVA. Statistically significant;*P< 0.05 between DD, ID, and II.
|
Discussion
An insertion or deletion of a 287-bp fragment in the
16th intron of the ACE gene produces three genotypes—DD, II, and ID.19–20
Since the ACE I/D polymorphism is associated with overall plasma ACE
concentration, ACE might be a good candidate gene for causing type 2 DM and its
complications.1,2,6 Although the I/D polymorphism is in the intronic
region of the ACE gene, many studies have shown that the DD genotype is
strongly associated with increased serum ACE levels. For instance, Stephens et
al showed that the DD genotype leads to a higher ACE expression and activity and
therefore might predispose individuals to type 2 DM and its complications.21
In this study, we examined ACE gene polymorphism in patients
with type 2 DM with and without
MS and a control group. We found that the frequency of DD genotype as well as D
allele was significantly increased in diabetic patients in comparison to the control
group (P < 0.001), while the difference between patients with and
without MS was not statistically significant (P = 0.57). Our findings
are in agreement with some other studies,7,22,23 Hsieh et
al and Feng et al showed significant positive associations between ACE DD
genotypes and presence of type 2 DM.13, 24
Most evidence appears to show that the D allele is a
risk factor for development and progression of micro- or macrovascular diabetic
complications. Our results demonstrate a high prevalence (70%) of MS in Iranian
patients with type 2 DM, a finding comparable with a Scandinavian report.7,8 This finding
suggests that the etiology of diabetes, obesity, dyslipidemia, hypertension,
and nephropathy may have a common factor(s), and it also provides clues to the
high incidence of macro- or microvascular complications in patients with type 2
DM.
It has been found that an I/D polymorphism of ACE gene
affects the serum ACE level.23 ACE gene
polymorphism has been known to contribute to the ethnic differences in response
to ACE inhibitor treatment.25 In
Caucasians, 44% of the variance in circulating ACE activity is accounted for by
genetic polymorphism.26–28 Our results showed that ACE genotypes
significantly correlated with plasma ACE levels in both patients with and
without MS (P < 0.001). Velasques et al Gunes et al, and Rigat et al have
shown an association between ACE DD genotype and ACE activity. 29,30,25
Our study also indicated that ACE I/D poly-
morphism
is associated with hypertension in patients with type 2 DM (DD/II; P=0.04).
Sassano et al and Bhavani et al did not show a positive correlation between the
DD genotype of ACE gene polymorphism and hypertension.31,32 This
result also is not in accordance with some other studies.33–36
This observation emphasizes the importance of
geographical and ethnic backgrounds of the subjects participating in this
study. Other factors such as study design, number of studied subjects, type of
diabetes, and assessment methods used in type 2 DM may all contribute to the
lack of consistency among different studies.
In conclusion, we did not find any association between
ACE genotype polymorphism and MS in Iranian patients with type 2 DM, but we
found that D allele may increase the risk of type 2 DM.
Acknowledgment
The authors would like to thank Dr. A. R. Esteghamati
for his helpful advice and the Department of Endocrinology and Metabolism Research Center (EMRC), Vali-e-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran.
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