ORIGINAL

PAPER

Public Health Focus

Adiponectin Genotype, Blood Pressures, and Arterial Stiffness: The

Cardiometabolic Risk in Chinese (CRC) Study
Jun Liang, MD, PhD;1,2,* Qinqin Qiu, MS;3,* Ying Gong, MS;1,2,* Xuekui Liu, BS;1,2 Lianjun Dou, MS;1,2 Caiyan Zou, MS;1,2
Yu Wang, MS;1,2 Lu Qi, MD, PhD4,5
From the Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, The Affiliated XuZhou Hospital of
Medical College of Southeast University, Jiangsu, China;1 Xuzhou Institute of Medical Sciences, Xuzhou Institute of Diabetes, Xuzhou, Jiangsu,
China;2 Xuzhou Medical College, Xuzhou, Jiangsu, China;3 Department of Nutrition, Harvard School of Public Health, Boston, MA;4 and Department
of Medicine, Channing Laboratory, Brigham and Womens Hospital and Harvard Medical School, Boston, MA5

The authors examined whether the adiponectin gene (ADIPOQ) variant was associated with blood pressure and
arterial stiffness in Chinese adults. A genome-wide association study of the adiponectin variant rs864265 in the
ADIPOQ gene was genotyped in a total of 2364 participants.
After adjustment for sex, age, body mass index (BMI),
fasting glucose, and lipids, participants carrying the T allele
of rs864265 showed a greater increase in carotid-femoral
pulse wave velocity (cfPWV) and systolic blood pressure
(SBP). Further adjustment for blood pressure did not

appreciably change the association with cfPWV. The

authors found significant interactions between rs864265
and BMI, waist circumference, body fat percentage, and
SBP in relation to cfPWV (P for interaction = .035, .001,
.003, .013, respectively). The T allele of rs864265 was
associated with high blood pressure and arterial stiffness.
BMI, body fat percentage, waist circumference, and SBP
might modify the effects of genetic polymorphism on
arterial stiffness. J Clin Hypertens (Greenwich). 2015;
17:395400. 2015 Wiley Periodicals, Inc.

Adiponectin is a hormone produced predominantly by

adipocytes, which exerts antiatherogenic effects via
action on endothelium, inhibition of lipid accumulation,
and vascular smooth muscle cell proliferation and antiinflammatory effects.13 Indeed, emerging evidence has
shown that hypoadiponectinemia may play an important role in the pathogenesis of cardiovascular diseases.47 Recent genome-wide association studies
identified genetic variants in the adiponectin gene
(ADIPOQ) associated with blood levels of adiponectin.812 The ADIPOQ variants have also been related to
other metabolic disorders such as diabetes and insulin
resistance.1315 Among these genetic variants, one SNP
rs864265, located 5 kb upstream of the widely discussed ADIPOQ promoter region and 16 kb upstream
of the translation start site (chr3: 188 036 986), showed
the strongest association with plasma adiponectin, also
associated with insulin resistance and diabetes-related
metabolic traits.11,12 However, data are scarce on the
relationship between ADIPOQ variants and markers of
early-stage atherosclerosis.16
In the present study, we examined the associations of
ADIPOQ polymorphism rs864265 with measure of
early-stage atherosclerosis (arterial stiffness) in Chinese

adults. Since adiponectin level is determined by

adiposity and correlated with blood pressure
(BP),17,18 a factor closely related to arterial stiffness,19,20 we particularly assessed the interactions
between rs864265 and these factors in relation to
arterial stiffness.

*These authors contributed equally to this work.

Address for correspondence: Jun Liang, MD, PhD, Department of
Endocrinology, Xuzhou Central Hospital, 199# South Jiefang Road,
Xuzhou, Jiangsu 221009, China
E-mail: mwlj521@163.com
Manuscript received: November 23, 2014; revised: January 14, 2015;
accepted: January 17, 2015
DOI: 10.1111/jch.12516

METHODS
Participants
This study was designed as part of the Cardiometabolic
Risk in Chinese (CRC) study, in which 2364 Chinese
participants with genotype data available at baseline
were sequentially recruited. All participants (aged 29
79 years) were randomly selected from residents living
in central China who completed a community-based
health examination survey. All participants completed
the baseline assessments, which included age, body
weight, body mass index (BMI), body fat percentage
(BFP), neck circumference, waist circumference, pulse
wave velocity (PWV), BP, and other metabolic markers.
The exclusion criteria included a history of diabetes
mellitus, vascular disease, hyperlipidemia, and treatment
with medication. Individuals who had a serum creatinine
level >1.5 mg/dL were also excluded. There was no
significant difference between the basic characteristics of
the participants with and without genotype data.
The study was reviewed and approved by the ethics
committee of the Central Hospital of Xuzhou, Affiliated
Hospital of Medical School of Southeast University,
China, and participants provided written informed
consent for participation, including consent for genetic
analysis.
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The Cardiometabolic Risk in Chinese Study | Liang et al.

Assessment of Biomarkers and Covariates

Biomarkers were measured for all participants. Venous
blood sampling from all participants was performed after
fasting overnight (812 hours). After blood was drawn,
samples were allowed to clot at room temperature for 1 to
3 hours. Following clotting, serum was immediately
separated by centrifugation for 15 minutes at
3000 rpm. The blood samples were collected for measurement of serum uric acid, fasting blood glucose, serum
insulin, total cholesterol, total triglyceride, high-density
lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels using an autoanalyzer
(Type 7600; Hitachi Ltd, Tokyo, Japan). Glycosylated
hemoglobin (HbA1c) was measured using high-performance liquid chromatography (HPLC; HLC-723G7
hemoglobin HPLC analyzer; Tosoh Corp, Minato,
Tokyo) according to the standardized method. Participants underwent a 75-g oral glucose tolerance test. Blood
samples were drawn at 120 minutes after glucose or
carbohydrate load. Urinary microalbumin level was
measured by the Bromcresol green photometric method
(IatroFine ALB II).
Body weight was recorded to the nearest 0.1 kg with
the participants wearing light indoor clothing and no
shoes. Height was recorded to the nearest 0.5 cm
without shoes using a standardized wall-mounted height
board. BMI was calculated as weight (in kilograms)
divided by height (in meters) squared. Waist circumference, an index of total abdominal fat, was measured at
the mid-point between the lowest rib margin and the
iliac crest.21 Neck circumference, an index of upperbody fat, was measured with a flexible tape in a
standardized manner horizontally above the cricothyroid cartilage to 1-mm accuracy.22 BP was measured by
trained doctors using a mercury sphygmomanometer on
the dominant arm after a resting period of at least
5 minutes in the supine position.23,24 The participants
arm was placed at the heart level, and BP values were
taken as the mean of three measurements. Individuals
who had a sitting BP 140/90 mm Hg or who were
taking antihypertensive drugs regularly were defined as
hypertensive.25
Assessment of PWVs
Carotid-femoral PWV (cfPWV), a marker for central
aortic stiffness, was measured using an automatic
waveform analyzer (Complior System; Artech Medical
Corp, Pantin, Franc). Following 5 minutes of rest in a
supine position, occlusion and BP monitoring cuffs were
placed around both arms and ankles of the participant.
Carotid and femoral artery pressure wave forms were
recorded with multi-array tonometry sensors at the left
femoral artery and the left carotid arteries. Electrocardiography was monitored by electrodes on both wrists.
Carotid artery dorsalis pedis PWV (cdPWV) and
carotid-radial PWV (crPWV), the markers for peripheral arterial stiffness, were obtained in a similar manner,
with the pulse wave measured simultaneously in the
right radial dorsum of the foot and right carotid arteries.
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Sixteen PWVs were measured for each participant, and

the average PWV was calculated after removing the
three highest and three lowest measurements. PWV was
based on the distance/time ratio (meters/second), and
was calculated as the path length between arterial sites
of interest divided by the time delay between the foot of
the respective waveforms.26,27
Genotype Determination
Genomic DNA was extracted from the buffy coat
fraction of centrifuged blood by using a QIAamp Blood
Mini Kit (Qiagen, Chatsworth, CA). We selected the
SNP rs864265 in the ADIPOQ gene that is associated
with plasma adiponectin levels.5 The rs864265 genotypes were determined by TaqMan SNP allelic discrimination with an ABI 7900HT (Applied Biosystems,
Foster City, CA) and the genotype success rate was
99%. Replicate quality-control samples (10%) were
included and genotyped with greater than 99% concordance.
Statistical Analysis
Data management and statistical analysis were performed using SAS statistical software (version 9.1; SAS
Institute, Inc, Cary, NC). The Hardy-Weinberg equilibrium of rs864265 genotypes was examined by chisquare test. Differences in continuous variables at
baseline were tested using one-way analysis of variance.
Data are presented as meansstandard deviations
(SDs). The relationship between rs864265 and PWVs
or BPs were examined using multivariate linear regression models. We adjusted for multiple potential confounding variables in the models. Multivariate linear
regression models were used to test the potential
interactions of genetic variation with BMI, BFP, waist
circumference, and systolic BP (SBP) in relation to
arterial stiffness. All reported P values are two-tailed.
Variables with P<.05 were considered statistically
significant.

RESULTS
Baseline Characteristics of the Study Participants
The risk allele frequency of rs864265 (T allele) was
13.9% in all participants. Table I shows the baseline
characteristics of the participants according to rs864265
genotype. There was significant difference in adiposity
measures including body weight, BMI, neck circumference, and waist circumference across the genotypes of
rs864265. In addition, the genotypes were correlated
with systolic BP (P<.05). We also did not observe
significant differences between rs864265 genotypes and
other metabolic markers.
Associations Between rs864265 and PWVs
Table II displays the associations between PWVs and
genotypes of rs864265. After adjustment for sex and
age, participants with the T allele were associated with
higher cfPWV values than those without this allele

The Cardiometabolic Risk in Chinese Study | Liang et al.

TABLE I. Baseline Characteristics of the Study Participants According to rs864265 Genotypes

rs864265
GG(0)

GT(1)

P Value

No.

1789

Age, y
Male, No. (%)

46.59.35
961 (53.7)

46.09.61
274 (55.7)

48.411.38
46 (55.4)

.092
.720

Weight, kg
BMI, kg/m2

70.911.48
24.73.06

71.611.49
25.03.15

75.110.34
26.13.02

.003
<.001

NC, cm
WC, cm

36.63.59
87.09.49

37.04.13
87.89.80

37.83.03
91.48.44

.01
<.001

26.845.00
5.281.27

26.764.99
5.281.19

26.441.78
5.371.20

.749
.817

FINS, l/L
HbA1c, %

9.626.90
5.860.86

10.28.05
5.820.81

9.75.79
5.90.88

.234
.666

OGTT2 hours, mmol/L

U-mALB, mg/L

7.63.16
31.739.4

7.52.92
32.542.06

7.83.47
40.348.71

.813
.164

TC, mmol/L
TG, mmol/L

5.070.91
1.781.80

5.120.95
1.951.84

5.060.86
1.981.64

.613
.113

HDL-C, mmol/L
LDL-C, mmol/L

1.230.30
3.020.78

1.210.30
3.010.82

1.170.27
2.980.78

.147
.869

123.5116.16
80.2911.81

125.9714.8
79.2410.43

126.3618.05
79.1811.78

.024
.167

BFP, %
FBG, mmol/L

SBP, mm Hg
DBP, mm Hg

492

TT(2)
83

Abbreviations: BFP, body fat percentage; BMI, body mass index; DBP, diastolic blood pressure; FBG, fasting blood glucose; FINS, fasting insulin;
HbA1c, glycosylated hemoglobin; HDL-C, high density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NC, neck circumference;
OGTT2 hours, 2 hours blood glucose of oral glucose tolerance test; SBP, systolic blood pressure; SUA, serum uric acid; TC, total cholesterol; TG,
triglycerides; U-mALB, urinary microalbumin; WC, waist circumference. Data are presented as meanstandard deviations or number (percentage).

TABLE II. Associations of rs864265 With Arterial

Stiffness
GG(0)

GT(1)

TT(2)

P for Trend

Model 1
Model 2

10.71.78
10.61.78

11.01.95
11.01.95

11.32.53
11.32.58

.001
.002

cfPWV, m/s

Model 3

10.81.79

11.11.95

11.32.58

.012

crPWV, m/s
Model 1

10.51.55

10.61.58

10.61.56

.604

Model 2
Model 3

10.41.55
10.51.55

10.61.58
10.81.54

10.61.51
10.61.56

.641
.796

cdPWV, m/s
Model 1

9.71.51

10.01.43

9.81.27

.070

Model 2
Model 3

9.81.51
9.71.52

10.01.45
10.01.43

9.81.23
9.91.27

.126
.342

Abbreviations: cdPWV, carotid artery dorsalis pedis pulse wave

velocity; cfPWV, carotid-femoral pulse wave velocity; crPWV, carotidradial pulse wave velocity. Data are presented as meansstandard
deviations. Model 1: adjusted for sex and age. Model 2: adjusted for
sex, age, and body mass index. Model 3: adjusted for sex, age, body
mass index, blood pressure, fasting glucose, total cholesterol,
triglycerides, high-density lipoprotein cholesterol, and low-density
lipoprotein cholesterol, when they were not the strata variables.

(P for trend = .001), while no significant associations

were found between rs864265 and crPWV or cdPWV.
Further adjustment for BMI did not significantly change
the associations. Additional adjustment for SBP and

other biomarkers did not appreciably change the results

(P=.012).
Interaction Between rs864265 and Metabolic Risk
Factors on Central Arterial Stiffness and SBP
We further examined the interactions between the
rs864265 genotypes and other metabolic risk factors in
relation to cfPWV (Table III). Considering the study
power for the stratified analyses, we grouped the strata
factors (BMI, BFP, waist circumference, SBP, and
diastolic BP) into three categories (tertiles): low, median,
and high. We found significant interaction between
rs864265 and all the adiposity measures in relation to
cfPWV. Participants with the T allele showed a greater
increase in cfPWV in the groups with median and high
adiposity measures (BMI, BFP, and waist circumference)
than in those with low levels of these measures.
In addition, we found that SBP significantly interacted
with rs864265 (P=.013) and these two markers showed
an additive effect on cfPWV (Figure). Compared with
the group with the G allele and lowest SBP, individuals
in the group with the T allele and highest SBP had nearly
3 m/s higher cfPWV. We did not find an interaction
between rs864265 and diastolic BP on cfPWV.

DISCUSSION
In the present study of Chinese adults, ADIPOQ
polymorphism rs864265 was found to be significantly
related to arterial stiffness, independent of other cardiovascular risk factors. Furthermore, the deleterious
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TABLE III. Interactions Between rs864265 Polymorphism and Adiposity in Relation to cfPWV
GG(0)

GT(1)

TT(2)

P for Trend

P for Interaction

10.61.96

10.61.85

10.73.03

.505

.035

10.71.77
10.91.58

10.91.56
11.32.28

11.32.72
11.42.36

.018
.009

10.71.64

10.81.56

10.61.21

.377

10.81.78
10.71.93

10.81.53
11.12.57

10.81.72
12.13.68

.700
.001

10.41.71

10.31.51

9.60.99

.191

10.81.78
11.11.84

11.11.76
11.42.24

10.81.80
11.82.78

.005
.012

cfPWV
BMI, kg/m2
Low (<23.5)
Median (23.526.1)
High (>26.1)
BFP (%)
Low (<24.8)
Median (24.828.7)
High (>28.7)
WC, cm
Low (<84)
Median (8491)
High (>91)

.001

.003

Abbreviations: BFP, body fat percentage; BMI, body mass index; cfPWV, carotid-femoral pulse wave velocity; WC, waist circumference. Data are
expressed as meansstandard deviations.

FIGURE. The joint effect of rs864265 genotypes and systolic blood

pressure (SBP; low, median, and high levels) on the risk of arterial
stiffness. The mean values of carotid femoral pulse wave velocity
(cfPWV) are presented.

effect of the T allele in rs864265 polymorphism was

modified by body adiposity and SBP.
Several previous studies have shown that hypoadiponectinemia is associated with hypertension.5,28 Recent
genome-wide association studies identified genetic variants in the adiponectin gene (ADIPOQ) associated with
blood levels of adiponectin. Our results indicate that the
adiponectin-associated ADIPOQ SNP rs864265 was
related to arterial stiffness, a subclinical measure of
early-stage atherosclerosis. Because genetic markers are
less likely affected by confounding and free of reverse
causation, the genetic association may provide evidence
supporting the potential causal relationship between
adiponectin and arterial stiffness.29 In a recent cohort
study, adiponectin was found to be independently
related to brachial-ankle PWV,16 which is an index of
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both central and peripheral arterial stiffness index.

However, it is not clear whether adiponectin levels
specifically affect central or peripheral arterial stiffness.
Intriguingly, we found that the association between
the rs864265 polymorphism and cfPWV was stronger
among adults with higher BMI, BFP, and waist circumference, which are markers of obesity. Recent studies
demonstrate that obesity represents a major independent risk factor for cardiovascular diseases, including
arterial stiffness.30,31 In adults, a previous study
reported a positive relationship between obesity and
PWV.32 Adiponectin, a 244-amino acid protein, is
secreted by adipocytes.33 Genome-wide association
studies reported that the T allele of ADIPOQ SNP
rs864265 was associated with lower adiponectin
level.11,12 Evidence has also shown that BMI,31 BFP,34
and waist circumference31 are significantly positively
correlated with arterial stiffness. These findings as well
as our results suggest that rs864265 and obesity
synergistically affect central arterial stiffness. The T
allele of rs864265 was associated with significantly
higher arterial stiffness risk in obese patients.
Another interesting finding of our study was that the
adverse effects of the T allele of rs864265 on central
arterial stiffness appeared more evident in participants
with higher SBP. Arterial stiffness is strongly associated
with BP. A recent study demonstrated that PWV was
positively related to peripheral or central SBP and that
for 1 standard deviation of peripheral SBP, PWV
increases 0.329 m/s.32 Samar and colleagues also found
that lower levels of adiponectin and higher levels and
annual changes of SBP were associated with greater
progression in aortic stiffness.35 The mechanisms underlying such an additive effect between rs864265 and BP
remain unclear; however, some studies have shown that
PWV reflects functional or even structural changes in
the vascular wall structure as part of the evolving
hypertension process and is therefore a harbinger of
further BP elevation in the future.32 Therefore, one

The Cardiometabolic Risk in Chinese Study | Liang et al.

possibility is that the T allele of rs864265 affects arterial

stiffness through an increase in BP. Further investigations are needed to examine this postulation.

6.

STUDY LIMITATIONS

7.

Several limitations of this study warrant consideration.

First, we did not measure plasma adiponectin levels in
the study participants. This prevented the potential
analysis of the relationship of genetic variants and
plasma adiponectin levels and the roles of plasma
adiponectin levels in the observed associations. However, according to the Mendelian randomization principle, a genetic marker could be a surrogate for the
biomarker in yielding a causal relationship.36,37 Still, we
acknowledge that measuring the plasma adiponectin
levels would provide additional evidence and strengthen
our conclusion. Second, only the ADIPOQ rs864265
polymorphism was genotyped in the study. A more
comprehensive coverage of SNPs in and around this
region would provide more information regarding the
role of ADIPOQ genetic polymorphisms in arterial
stiffness risk. Third, we did not collect information on
dietary habits and all lifestyle information. Therefore, it
is possible that residual confounding of these unmeasured variables might influence the associations. Last, as
all participants were Chinese, the results may not be
generalized to other ethnic groups. Further studies in
other populations of different ethnicities are warranted
to verify our findings.

8.
9.

10.
11.

12.

13.

14.
15.

16.

17.

CONCLUSIONS
We demonstrated that the T allele of rs864265 was
associated with increased arterial stiffness, independent
of conventional cardiovascular risk factors, in Chinese
adults. Body adiposity and SBP might modify these
genetic effects.
Acknowledgments: The authors would like to thank Huaidong Song for
excellent technical support and Ben Wang and Fei Teng for critically reviewing
the manuscript.
Sources of Funding: This work was sponsored by Jiangsu Provincial Bureau of
Health Foundation (H201356), the International Exchange Program, and the
Jiangsu Six Talent Peaks Program (2013-WSN-013). It was also supported by
the Xuzhou Outstanding Medical Academic Leader project and a Xuzhou
Science and Technology Grant (XM13B066).

18.
19.

20.
21.
22.

23.

Conflict of Interest: None declared.

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