Introduction
Aldosterone synthase plays an important role in
determining the levels of aldosterone secretion as one of the main
effectors of the renin-angiotensin-aldosterone system (RAAS).
Polymorphisms of the aldosterone synthase gene, CYP11B2,
have attracted attention in the development of diabetes,
hypertension and cardiovascular diseases.
The aldosterone synthase gene (CYP11B2) is
assigned to chromosome 8 near the highly homologous CYP11B1
encoding 11-β-hydroxylase (1).
Several frequent polymorphisms have been reported in the
CYP11B2 gene. These polymorphisms are suggested to be
associated with serum aldosterone levels (2), hyperaldosteronism (3), plasma glucose levels and glucose
intolerance (4), type II diabetes
mellitus (DM) (5), left ventricular
size and mass (6,7), arterial stiffness (8), myocardial infarction (9,10) and
hypertension (11–14), although these associations remain to
be clarified.
High blood pressure, abnormal levels of lipid and
glucose are the main risk components of metabolic syndrome (MetS),
which is a highly prevalent disorder worldwide. Therefore, we
hypothesized that the CYP11B2 genetic polymorphism plays a
role in MetS development. Nevertheless, the associations of
CYP11B2 polymorphisms and risk assessment of MetS have not
been studied extensively.
Thus, we investigated associations of the
CYP11B2 polymorphisms of -344T>C (rs1799998), K173R
(rs4539) and intron 2 conversion (IC) with MetS patients in a
Korean population.
Materials and methods
Study population
A total of 320 MetS patients [mean age ± standard
deviation (SD), 50.94±8.434] and 320 healthy control subjects (mean
age ± SD, 49.86±11.76 years) were included in this study. We used
the National Cholesterol Education Program Adult Treatment Panel
III definition for MetS (15) with
slight modifications, including waist circumference (WC) (≥90 cm in
men, ≥85 cm in women); increased triglycerides level (≥150 mg/dl);
high-density lipoprotein (HDL)-cholesterol (<40 mg/dl in men,
<50 mg/dl in women); increased blood pressure (≥130/85 mmHg or
antihypertensive medication) and increased fasting blood glucose
(≥100 mg/dl or type II DM). Individuals with ≥3 traits of the risk
factors described above were defined as MetS patients. The control
group comprised healthy individuals without a history of
hypertension, DM, cardiovascular or other diseases to exclude those
with MetS.
The biospecimen and data used in this study werew
provided by the Jeju National University Hospital Biobank, a member
of the National Biobank of South Korea, which is supported by the
Ministry of Health and Welfare. All samples obtained were from
Korean individuals and were collected together with written
informed consent according to protocol approved by the
Institutional Review Board of the Jeju National University Hospital
in June 2002.
Polymorphism analysis
Total genomic DNA was extracted according to the
manufacturer’s instructions (Qiagen, Inc., Valencia, CA, USA).
Polymerase chain reaction-restriction fragment length polymorphism
(PCR-RFLP) techniques were used to detect CYP11B2
polymorphisms with slight modifications of the method used by Gu
et al (12). The PCR for the
-344T/C polymorphism was performed using sense (5′-GTG TCA GGG CAG
GGG GTA-3′) and antisense (5′-AGG CGT GGG GTC TGG ACT-3′) primers.
DNA was amplified for 35 cycles with denaturation at 94°C for 30
sec, annealing at 60°C for 30 sec and extension at 72°C for 1 min.
The amplified PCR products were 228 bp and digested with a
restriction endonuclease, HaeIII (New England Biolabs,
Beverly, MA, USA) at 37°C for 17 h. The primer sequences used to
detect the K173R polymorphism were 5′-GAA AAG GCT GCA GCT CGA ACA
CAA-3′ (sense) and 5′-GCA TGG CCC ACA CCT TCT A-3′ (antisense). DNA
was amplified for 35 cycles with denaturation at 94°C for 30 sec,
annealing at 65°C for 30 sec and extension at 72°C for 1 min. Bands
of 371 bp were amplified by PCR and digested with a restriction
endonuclease Bsu36I (New England Biolabs). The IC
polymorphism was analyzed using two separate PCRs, one to amplify
the wild-type gene (W) and another to amplify the conversion gene
(C). The forward primer sequence for the wild-type gene was 5′-TGG
AGA AAA GCC CTA CCC TGT-3′, whereas 5′-CAG AAA ATC CCT CCC CCC
TA-3′ was used for the conversion gene. The same reverse primer:
5′-AGG AAC CTC TGC ACG GCC-3′ was used for the two PCRs. PCR
conditions were run for 35 cycles with denaturation at 94°C for 30
sec, annealing at 60°C for 30 sec and extension at 72°C for 1 min.
The size of PCR products in each reaction was ~418 bp and was
directly detected by 2% agarose gel electrophoresis.
Measurements of clinical and
anthropometric traits
For measurements of biochemical traits, venous blood
of the study subjects was collected into EDTA tubes after overnight
fasting. The levels of plasma glucose, triglycerides and
HDL-cholesterol were measured enzymatically on an automatic
analyzer (TBA 200FR NEO; Toshiba Medical Systems, Tokyo,
Japan).
Anthropometric traits containing body mass index
(BMI) and WC were measured. BMI was calculated as weight (kg)
divided by height (m2). Using a flexible tape, WC was
measured at the smallest horizontal circumference between the
costal margin and iliac crest. Measurements of blood pressures were
obtained on the right arm at a seated position after 10 min of
rest.
Statistical analysis
Data were expressed as means ± SD. Clinical
characteristics were compared by the Student’s unpaired t-test. The
χ2 test was used to compare genotype and allele
frequencies of CYP11B2 polymorphisms between the cases and
controls and to test for Hardy-Weinberg equilibrium. Associations
of the studied polymorphisms with MetS prevalence were calculated
using adjusted odds ratios (AORs) and 95% confidence intervals (95%
CIs) from multivariate logistic regression adjusted for age and
gender. StatsDirect statistical software, version 2.4.4
(StatsDirect, Ltd., Altrincham, UK) was used to calculate the AOR
and 95% CIs. P<0.05 was considered to indicate statistically
significant differences. Haplotypes for multiple loci were
estimated using the expectation-maximization algorithm with
SNPAlyze (version 5.1; Dynacom Co., Ltd., Yokohama, Japan). The
linkage disequilibrium (LD) between loci was measured using the
absolute value of Lewontin’s D (16).
Results
Comparison of patient
characteristics
MetS patients had significantly higher values for
MetS risk parameters such as BMI, glucose, blood pressure,
triglycerides and WC (P<0.0001), but lower levels of
HDL-cholesterol (P<0.0001) than the control subjects (Table I).
 | Table IComparison of demographic
characteristics between MetS patients and controls. |
Table I
Comparison of demographic
characteristics between MetS patients and controls.
| Characteristics | Control | MetS patients | Pa |
|---|
| No. | 320 | 320 | |
| Age, years (mean ±
SD) | 50.94±8.434 | 49.86±11.76 | 0.183 |
| BMI (mean ± SD) | 23.87±2.715 | 27.40±2.646 | <0.001 |
| FBS (mean ± SD) | 87.35±10.09 | 104.41±26.67 | <0.001 |
| TG (mean ± SD) | 86.53±39.57 | 211.89±170.81 | <0.001 |
| HDL-cholesterol (mean
± SD) | 57.01±13.57 | 44.44±10.41 | <0.001 |
| SBP (mean ± SD) | 117.99±12.03 | 133.61±14.53 | <0.001 |
| DBP (mean ± SD) | 70.84±8.531 | 81.95±10.43 | <0.001 |
| WC (mean ± SD) | 72.07±9.159 | 85.38±10.28 | <0.001 |
Genotype and allele frequencies of the
polymorphisms for MetS and control subjects
A comparison was made of the genotype and allele
frequencies of the CYP11B2 -344T>C, K173R and IC
polymorphisms between the MetS and control groups (Table II). The genotype frequencies for
all of the polymorphisms were in accordance with the Hardy-Weinberg
equilibrium in the two groups. The genotype and allele frequencies
of the -344T>C, K173R and IC polymorphisms were not
significantly different between the MetS and control groups.
However, when the data were stratified by gender, the recessive
(TT+TC vs. CC) distribution of the -344T>C polymorphism showed a
significant association (OR=0.438, 95% CI: 0.208–0.922, P=0.030)
with increased MetS risk only in the male group (Table III).
| Table IIThe genotype and allele frequencies of
the CYP11B2 -344T>C, K173R and IC polymorphisms between
control subjects and patients with MetS. |
Table II
The genotype and allele frequencies of
the CYP11B2 -344T>C, K173R and IC polymorphisms between
control subjects and patients with MetS.
| Genotype | Controls (n=320) | MetS (n=320) | AOR (95% CI) | Pa |
|---|
| CYP11B2
-344T>C |
| TT | 157 (49.1) | 157 (49.1) | 1.000
(Reference) | |
| TC | 138 (43.1) | 145 (45.3) | 1.087
(0.771–1.532) | 0.634 |
| CC | 25 (7.8) | 18 (5.6) | 0.630
(0.322–1.230) | 0.176 |
| Dominant (TT vs.
TC+CC) | | | 1.005
(0.723–1.396) | 0.979 |
| Recessive (TT+TC vs.
CC) | | | 0.583
(0.302–1.126) | 0.108 |
| T allele | 452 (70.6) | 459 (71.7) | 1.000
(Reference) | |
| C allele | 188 (29.4) | 181 (28.3) |
0.923(0.714–1.193) | 0.539 |
| CYP11B2
K173R |
| KK | 164 (51.3) | 148 (46.2) | 1.000
(Reference) | |
| KR | 136 (42.5) | 156 (48.8) | 1.261
(0.897–1.774) | 0.183 |
| RR | 20 (6.2) | 16 (5.0) | 0.761
(0.368–1.576) | 0.462 |
| Dominant (KK vs.
KR+RR) | | 1.196
(0.859–1.665) | 0.288 | |
| Recessive (KK+KR
vs. RR) | | 0.661
(0.325–1.346) | 0.254 | |
| CYP11B2
IC |
| K allele | 464 (72.5) | 452 (70.6) | 1.000
(Reference) | |
| R allele | 176 (27.5) | 188 (29.4) | 1.056
(0.816–1.367) | 0.680 |
| WW | 215 (67.2) | 232 (72.5) | 1.000
(Reference) | |
| WC | 90 (28.1) | 75 (23.4) | 0.821
(0.561–1.202) | 0.310 |
| CC | 15 (4.7) | 13 (4.1) | 0.712
(0.319–1.585) | 0.405 |
| Dominant (WW vs.
WC+CC) | | | 0.804
(0.562–1.151) | 0.234 |
| Recessive (WW+WC
vs. CC) | | | 0.743
(0.335–1.651) | 0.466 |
| W allele | 520 (81.3) | 539 (84.2) | 1.000
(Reference) | |
| C allele | 120 (18.7) | 101 (15.8) | 0.815
(0.599–1.109) | 0.1929 |
| Table IIIThe genotype and allele frequencies
of the CYP11B2 -344T>C, K173R and IC polymorphisms
between the control subjects and MetS patients in men. |
Table III
The genotype and allele frequencies
of the CYP11B2 -344T>C, K173R and IC polymorphisms
between the control subjects and MetS patients in men.
| Genotype | Controls
(n=152) | MetS (n=254) | AOR (95% CI) | Pa |
|---|
| CYP11B2
-344T/C |
| TT | 78 (51.3) | 122 (48.0) | 1.000
(Reference) | |
| TC | 57 (37.5) | 118 (46.5) | 1.293
(0.842–1.986) | 0.240 |
| CC | 17 (11.2) | 14 (5.5) | 0.480
(0.221–1.042) | 0.064 |
| Dominant (TT vs.
TC+CC) | | | 1.108
(0.738–1.663) | 0.621 |
| Recessive (TT+TC
vs. CC) | | | 0.438
(0.208–0.922) | 0.030 |
| T allele | 213 (70.1) | 362 (71.3) | 1.000
(Reference) | |
| C allele | 91 (29.9) | 146 (28.7) | 0.918
(0.670–1.258) | 0.595 |
| CYP11B2
K173R |
| KK | 79 (52.0) | 115 (45.3) | 1.000
(Reference) | |
| KR | 61 (40.1) | 125 (49.2) | 1.319
(0.862–2.019) | 0.202 |
| RR | 12 (7.9) | 14 (5.5) | 0.734
(0.319–1.688) | 0.466 |
| Dominant (KK vs.
KR+RR) | | | 1.228
(0.816–1.848) | 0.326 |
| Recessive (KK+KR
vs. RR) | | | 0.629
(0.281–1.410) | 0.260 |
| K allele | 219 (72.0) | 355 (69.9) | 1.000
(Reference) | |
| R allele | 85 (28.0) | 153 (30.1) | 1.055
(0.768–1.450) | 0.741 |
| CYP11B2
IC |
| WW | 105 (69.1) | 184 (72.5) | 1.000
(Reference) | |
| WC | 38 (25.0) | 59 (23.2) | 0.933
(0.578–1.507) | 0.778 |
| CC | 9 (5.9) | 11 (4.3) | 0.686
(0.273–1.721) | 0.422 |
| Dominant (WW vs.
WC+CC) | | | 0.886
(0.567–1.382) | 0.593 |
| Recessive (WW+WC
vs. CC) | | | 0.699
(0.281–1.738) | 0.441 |
| W allele | 248 (81.6) | 427 (84.1) | 1.000
(Reference) | |
| C allele | 56 (18.4) | 81 (15.9) | 0.862
(0.590–1.258) | 0.440 |
Haplotype frequencies of the
polymorphisms for MetS and control subjects
To expand the available association data, we
evaluated the effectiveness of allelic combinations using
haplotypes of CYP11B2 three polymorphic loci (-344T>C,
K173R and IC) (Table IV).
Haplotype analysis revealed that the C-R-W haplotype was
significantly more frequent in the MetS patients than in the
control subjects, suggesting an association with increased MetS
susceptibility (OR=1.412, 95% CI: 1.075–1.856, P=0.016). In
addition, the T-R-W, C-K-W and C-R-C haplotype showed a
significantly lower association with the risk of MetS.
| Table IVHaplotype frequencies of
CYP11B2 -344T>C, K173R and IC polymorphisms between
patients with MetS and controls. |
Table IV
Haplotype frequencies of
CYP11B2 -344T>C, K173R and IC polymorphisms between
patients with MetS and controls.
| Haplotype | Controls (2n=640,
%) | MetS (2n=640,
%) | OR (95% CI) | Pa |
|---|
| CYP11B2
-344T>C/K173R/IC |
| T-K-W | 309 (48.3) | 340 (53.1) | 1.214
(0.975–1.512) | 0.094 |
| T-K-C | 93 (14.5) | 85 (13.2) | 0.901
(0.656–1.237) | 0.572 |
| T-R-W | 47 (7.4) | 29 (4.5) | 0.599
(0.372–0.964) | 0.044 |
| T-R-C | 3 (0.5) | 6 (0.9) | 2.009
(0.500–8.073) | 0.506 |
| C-K-W | 50 (7.9) | 21 (3.2) | 0.400
(0.238–0.675) | 0.001 |
| C-K-C | 12 (1.9) | 7 (1.1) | 0.579
(0.226–1.480) | 0.356 |
| C-R-W | 114 (17.8) | 150 (23.4) | 1.412
(1.075–1.856) | 0.016 |
| C-R-C | 12 (1.9) | 3 (0.5) | 0.247
(0.069–0.878) | 0.034 |
Haplotype frequencies of the
polymorphisms according to gender
When the haplotype data were stratified by gender,
the patterns of association with MetS were found to be
gender-specific (Table V). The
C-R-W haplotype was significantly associated with MetS
susceptibility (OR=1.429, 95% CI: 1.006–2.031, P=0.047) in men only
as compared to the total number of subjects. By contrast, the C-K-W
haplotype in men and the T-K-C haplotype in women was significantly
associated with a lower risk of MetS.
| Table VHaplotype frequencies of the
CYP11B2 polymorphisms according to gender. |
Table V
Haplotype frequencies of the
CYP11B2 polymorphisms according to gender.
| Male | Female |
|---|
|
|
|
|---|
| Haplotype | Controls
(2n=304) | MetS (2n=508) | OR (95% CI) | Pa | Controls
(2n=336) | MetS (2n=132) | OR (95% CI) | Pa |
|---|
| CYP11B2
-344T>C/K173R/IC |
| T-K-W | 148 (48.7) | 268 (52.8) | 1.177
(0.886–1.564) | 0.277 | 161 (47.8) | 77 (58.5) | 1.522
(1.013–2.286) | 0.051 |
| T-K-C | 42 (13.7) | 69 (13.5) | 0.981
(0.649–1.482) | 0.916 | 51 (15.3) | 10 (7.5) | 0.458
(0.225–0.932) | 0.032 |
| T-R-W | 22 (7.1) | 21 (4.2) | 0.553
(0.299–1.023) | 0.074 | 26 (7.8) | 7 (5.4) | 0.668
(0.283–1.578) | 0.426 |
| T-R-C | 2 (0.5) | 4 (0.7) | 1.198
(0.218–6.585) | 1.000 | 1 (0.3) | 3 (2.2) | 7.791
(0.803–75.62) | 0.070 |
| C-K-W | 22 (7.2) | 12 (2.3) | 0.310
(0.151–0.636) | 0.002 | 29 (8.5) | 9 (6.7) | 0.775
(0.356–1.684) | 0.578 |
| C-K-C | 8 (2.5) | 6 (1.3) | 0.442
(0.152–1.287) | 0.163 | 4 (1.3) | 1 (0.8) | 0.634
(0.070–5.725) | 1.000 |
| C-R-W | 57 (18.6) | 126 (24.8) | 1.429
(1.006–2.031) | 0.047 | 57 (16.9) | 19 (14.4) | 0.823
(0.469–1.446) | 0.578 |
| C-R-C | 5 (1.7) | 2 (0.5) | 0.236
(0.046–1.226) | 0.110 | 7 (2.2) | 6 (4.7) | 2.238
(0.738–6.790) | 0.207 |
D prime (D′) was calculated to assess the level of
LD between the K173R and -344T>C polymorphisms in the controls
plus patients. Polymorphisms CYP11B2, K173R and -344T>C
were in moderate level of LD (D′=0.67).
Discussion
CYP11B2, a component of the RAAS, plays an important
role in determining the levels of aldosterone secretion. Its
transcripts levels are low in normal adrenals, but are
significantly increased in aldosterone-producing adenomas (17).
Although the results of CYP11B2 polymorphisms
are conflicting among various populations, previous studies have
shown that several CYP11B2 polymorphisms are associated with
its protein production (2,3). Human vascular diseases such as left
ventricular size and mass (6,7),
arterial stiffness (8), myocardial
infarction (9,10) and hypertension (11–14)
are associated with CYP11B2 polymorphisms. Plasma glucose
levels and glucose intolerance (4)
and type II diabetes (5) have also
been associated with CYP11B2 polymorphisms, suggesting the
involvement of CYP11B2 in MetS development. These observations lead
to the hypothesis that the CYP11B2 gene is associated with
MetS. Therefore, in view of the importance of CYP11B2, we
determined whether there is an association of CYP11B2
-344C>T, K173R and IC polymorphisms with Korean MetS
patients.
In the present study, the -344T/C, K173R and IC
polymorphisms of the CYP11B2 did not exhibit significant
differences between the MetS and control groups. The recessive
(TT+TC vs. CC) distribution of the -344T>C polymorphism and
haplotypes of the CYP11B2 gene were, however, associated
with susceptibility of MetS patients. At present, few studies have
investigated the correlation of CYP11B2 polymorphisms to
MetS, with studies mainly focusing on hypertension. Russo et
al (18) have reported that the
-344C>T polymorphism of the CYP11B2 is associated with
MetS in European populations including Italy, the United Kingdom
and Belgium. The C allele of the variant was associated with MetS
in men but not in women. Although our data were not associated with
the C allele, a significant association with MetS was observed only
in the recessive (TT+TC vs. CC) genotype of the men included in the
study. By contrast, Bellili et al (5) did not find any association of the
-344T>C polymorphism with MetS in a French population.
Therefore, the results of the -344T>C polymorphism on MetS
remain inconclusive. In previous studies (19–22),
the -344T>C and K173R polymorphisms were found strong in LD.
Polymorphisms CYP11B2, K173R and -344T>C of this study
exhibited a moderate level of LD. Therefore, further prospective
and cross-sectional studies with larger sample sizes of various
populations are required to evaluate the exact role of
CYP11B2 -344T>C polymorphism in MetS patients.
As the results of the haplotype analysis from three
diallelic RFLPs (-344T>C, K173R and IC) of this study reveal,
the C-R-W haplotype was associated with higher MetS susceptibility
in the total number of subjects and men. By contrast, the T-R-W,
C-K-W and C-R-C haplotypes of the total number of subjects, the
C-K-W haplotype in men and the T-K-C haplotype in women showed a
significantly lower association with the risk of MetS. Therefore
these haplotypes may be in LD with other functionally important
polymorphisms in CYP11B2 or CYP11B1. However, Bellili
et al (5) studied the
-344T/C and 3097G>A polymorphisms of CYP11B2 gene in a
French MetS population. The AA genotype of the 3097G>A
polymorphism was associated with a lower incidence of the MetS in
men but not in women. The -344T>C polymorphism was, however, not
associated with MetS. In the haplotype analysis from the -344T>C
and 3097G>A polymorphisms, the T-A and C-A haplotypes were
associated with a lower incidence of the total MetS and men MetS,
respectively. From these results, haplotype analysis using multiple
polymorphic loci than single nucleotide polymorphism may be
beneficial in defining more specific genotypes associated with MetS
risk.
MetS is defined by a cluster of factors such as
obesity, lipid metabolic disorders, diabetes and hypertension.
However, the exact definition and pathophysiology of MetS remains
to be elucidated. MetS is a multifactorial disorder in which still
largely unknown genetic determinants and environmental factors,
including lifestyle and dietary habits, are involved. Therefore
more genetic markers should be identified for MetS.
In conclusion, although CYP11B2 polymorphisms
studied in this study were not associated with an increased risk of
MetS, the -344T>C polymorphism in men and haplotypes were
associated with MetS susceptibility. Based on these results, the
associations between CYP11B2 polymorphisms and patients with
MetS in various populations using a larger sample size remain to be
verified.
Acknowledgements
This research was supported by Basic Science
Research Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and Technology
(NRF-2012R1A1A4A01012216).
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