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The Journal of Clinical Endocrinology & Metabolism 90(9):50375040

Copyright 2005 by The Endocrine Society
doi: 10.1210/jc.2005-0227

Association of Mitochondrial Deoxyribonucleic Acid

16189 Variant (T3C Transition) with Metabolic
Syndrome in Chinese Adults
Shao-Wen Weng, Chia-Wei Liou, Tsu-Kung Lin, Yau-Huei Wei, Cheng-Feng Lee, Hock-Liew Eng,
Shang-Der Chen, Rue-Tsuan Liu, Jung-Fu Chen, I-Ya Chen, Ming-Hong Chen, and Pei-Wen Wang
Departments of Internal Medicine (S.-W.W., R.-T.L., J.-F.C., I.-Y.C., M.-H.C., P.-W.W.), Neurology (C.-W.L., T.-K.L.,
S.-D.C.), and Pathology (H.-L.E.), Chang Gung Memorial Hospital, Kaohsiung, Taiwan 833; and Department of
Biochemistry and Center for Cellular and Molecular Biology (Y.-H.W., C.-F.L.), National Yang-Ming University,
Taipei, Taiwan 112
Objective: A common variant in mitochondrial DNA (mtDNA) at bp
16189 (T3 C transition) has been associated with small birth size,
adulthood hyperglycemia, and insulin resistance in Caucasians. In
this study, we investigated whether mtDNA 16189 variant is associated with metabolic syndrome in Chinese subjects.
Methods: Six hundred fifteen Chinese adults, aged 40 yr or older,
were recruited in this study. The 16189 variant of mtDNA was detected using PCR and restriction enzyme digestion. Metabolic syndrome was diagnosed on modified National Cholesterol Education
Program Adult Treatment Panel III guidelines, using body mass
index (BMI) instead of waist circumference. An association study was
performed with 2 test and logistic regression analysis.
Results: The prevalence of the 16189 variant was higher in patients
with metabolic syndrome than in those without: 44% (125 of 284) vs.
33.2% (110 of 331) (P 0.006). The association between this 16189
variant of mtDNA and metabolic syndrome (P 0.021) remained
significant even after correcting for age and BMI. As to the individual

N 1988, REAVEN (1) noted that several risk factors for

cardiovascular diseases, including dyslipidemia, hypertension, and hyperglycemia, commonly cluster together.
This clustering, which he named syndrome X, was later
called metabolic syndrome and is the result of a combined
effect of genetic and environmental factors. Insulin resistance
has been recognized as the fundamental underlying metabolic defect of this syndrome (2, 3), although the underlying
cause of insulin resistance itself remains largely unknown.
Recently, an association between diabetes and mitochondrial
genetic defects, both qualitative and quantitative, has been
documented (4 11). A common variant in mitochondrial
DNA (mtDNA) at bp 16189 (T3 C transition) has been suggested to be related to both thinness at birth and adulthood
impaired glucose tolerance/type 2 diabetes mellitus (DM) in
men born in Hertfordshire between 1920 and 1930 (7, 10).
This 16189 variant of mtDNA was later confirmed to be

First Published Online June 21, 2005

Abbreviations: BMI, Body mass index; CI, confidence interval; DM,
diabetes mellitus; HDL, high-density lipoprotein; IFG, impaired fasting
glucose; mtDNA, mitochondrial DNA; OR, odds ratio.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.

traits, the prevalence of fasting plasma glucose of at least 110 mg/dl

(6.1 mmol/liter) [(51.5% (121 of 235) vs. 42.1% (160 of 380); P
0.023], type 2 diabetes mellitus [48.1% (113 of 235) vs. 39.2% (149 of
380); P 0.031], and hypertriglyceridemia [44.3% (104 of 235) vs.
35.8% (136 of 380); P 0.037] were significantly higher in subjects
harboring the 16189 variant of mtDNA than those with the wild type.
However, the prevalence of hypertension [53.2% (125 of 235) vs. 47.6%
(181 of 380); P 0.180], BMI greater than 25 kg/m2 [48.5% (114 of 235)
vs. 43.9% (167 of 380); P 0.270], and low high-density lipoprotein
cholesterol [61.3% (144 of 235) vs. 54.7% (208 of 380); P 0.111] did
not reach a significant difference between the two groups. Furthermore, there was a trend of increasing frequency of occurrence of the
16189 variant in individuals having an increasing number of components of metabolic syndrome (Ptrend 0.005).
Conclusion: Our data strongly suggest that mtDNA 16189 variant
underlies susceptibility to metabolic syndrome in the Chinese
population. (J Clin Endocrinol Metab 90: 50375040, 2005)

associated with insulin resistance (5) and type 2 DM (11) in

Caucasians. Believing that these findings make the 16189
variant of mtDNA a good candidate gene for metabolic syndrome, we investigated the association between the 16189
variant of mtDNA and metabolic syndrome in Chinese
subjects.
Subjects and Methods
Six hundred fifteen people volunteered to participate in the study.
The study group included 374 patients from the Meta/Endo clinic and
241 subjects from our health screening center. Subjects included in this
study were more than 40 yr old, of Han Chinese origin, and from the
same region in Taiwan at the time of study. The exclusion criteria were
type 1 diabetes, maturity-onset diabetes in youth, and secondary diabetes or hypertension caused by endocrinopathy or drug use. The 615
participants were categorized into two groups: those who had metabolic
syndrome (n 284) and those who did not (n 331). Diagnosis was
based on a modified version of the definition of metabolic syndrome by
the National Cholesterol Education Program Adult Treatment Panel III.
In the modification, the waist circumference is replaced with body mass
index (BMI), as was done in the West of Scotland Coronary Prevention
Study (12) and Womens Health Study (13). Based on recent recognition
of a need to revise BMI criteria for Asian populations (14, 15) and
Taiwanese (16), we set the cutoff point for obesity at BMI greater than
25 kg/m2 rather than the 30 kg/m2 cutoff point that was used for
Caucasians. Participants were defined as having metabolic syndrome if
they had three or more of the five components of metabolic syndrome:

5037

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J Clin Endocrinol Metab, September 2005, 90(9):50375040

1) BMI greater than 25 kg/m2, 2) triglycerides at least 150 mg/dl (1.69

mmol/liter), 3) high-density lipoprotein (HDL) cholesterol less than 40
mg/dl (1.03 mmol/liter) in men and less than 50 mg/dl (1.29 mmol/
liter) in women, 4) blood pressure at least 130/85 mm Hg or taking
antihypertension medication, and 5) fasting plasma glucose at least 110
mg/dl (6.1 mmol/liter) or taking hypoglycemic medication. These
include subjects with impaired fasting glucose (IFG), whose fasting
plasma glucose levels were between 110 and 125 mg/dl (6.1 6.9 mmol/
liter) and overt diabetes with a plasma glucose at least 126 mg/dl (7
mmol/liter). The definition of dyslipidemia in patients with type 2 DM
was used only when triglycerides or HDL cholesterol were at abnormal
levels after control of blood glucose for more than 3 months and before
the use of lipid-lowering agents. The study plan was reviewed and
approved by our institutional review committee, and informed consent
was given by the patients and control subjects.

Detection of the 16189 variant of mtDNA

mtDNA was extracted from peripheral leukocytes and amplified
using an adaptation of the PCR and restrictive enzyme digestion (17, 18).
The forward PCR primer was L15911 (1591115930), 5-ACC AGT CTT
GTA AAC CGG AG-3, and the reverse primer was H16540 (16540
16521), 5-GTG GGC TAT TTA GGC TTT AT-3. Each 50-l PCR contained 20 m of each primer, 200 m of each dNTP 200 ng DNA, and
1 U Taq DNA polymerase. Samples of total cellular DNA were subjected
to 30 cycles of PCR, and the presence of the 16189 variant of mtDNA was
determined using the PCR-restriction fragment length polymorphism
analysis with the enzyme Mn1I. PCR products were digested with 1 U
of the enzyme for at least 1 h at 37 C and electrophoresed with both
positive and negative controls on a 3% agarose gel for 60 min at 80 V.
Duplicate samples were assessed for every subject without knowing the
metabolic state. In rare cases of ambiguous reading, direct sequencing
of the PCR product was conducted.

Statistical analysis
All statistical analyses were performed using the Statistical Package
for Social Science program (SPSS for Windows, version 11.5; SPSS,
Chicago, IL). Continuous variables were expressed as means sd and
compared using the Students t test. The statistical difference in the
frequency of occurrence of the 16189 variant of mtDNA between different subgroups was assessed by the Pearsons 2 test. Logistic regression analysis was used to analyze the association of the 16189 variant of
mtDNA with metabolic syndrome traits after correction for age and BMI.
P 0.05 was considered statistically significant.

Results

In the 615 cases, the prevalence rates of metabolic syndrome in different subgroups were as follows: 71.2% (200 of
281) in subjects with IFG/type 2 DM, 42.1% (8 of 19) in
subjects with IFG, 73.3% (192 of 262) in subjects with type 2
DM, 65.4% (200 of 306) in hypertension, 82.5% (198 of 240)
in hypertriglyceridemia, 66.2% (233 of 352) in low HDL cholesterol, and 73% (205 of 281) in obesity groups. A comparison of clinical characteristics in subjects with and without
metabolic syndrome is shown in Table 1. The difference in
the frequency of occurrence of this variant between subjects
who had metabolic syndrome (44%, 125 of 284) and those
who did not (33.2%, 110 of 331) was statistically significant
(P 0.006).
The association between the 16189 variant of mtDNA and
the individual components of metabolic syndrome is shown
in Table 2. The prevalence of IFG/type 2 DM (51.5 vs. 42.1%;
P 0.023), type 2 DM (48.1 vs. 39.2%; P 0.031), and hypertriglyceridemia (44.3 vs. 35.8%; P 0.037) were significantly higher in subjects harboring the 16189 variant of
mtDNA than those with the wild type. However, the prevalence of hypertension (53.2 vs. 47.6%; P 0.180), BMI greater

Weng et al. mtDNA 16189 Variant and Metabolic Syndrome

TABLE 1. Comparison of subjects with and without

metabolic syndrome
Metabolic syndrome
Absent

No.
331
Age (yr)
58.2 10.9
Sex (male/female)
177/154
BMI
23.7 2.6
Triglyceride (mg/dl)
109.8 48.0
HDL cholesterol (mg/dl)
47.8 13.6
IFG/type 2 DM
81/331 (24.5%)
IFG
11/331 (3.3%)
Type 2 DM
70/331 (21.1%)
Hypertension
106/331 (32%)
mtDNA16189 variant
110/331 (33.2%)

Present

P value

284
61.2 9.7
146/138
26.6 3.3
202.5 118.6
38.2 8.6
200/284 (70.4%)
8/284 (2.8%)
192/284 (67.6%)
200/284 (70.4%)
125/284 (44%)

0.01
NS
0.001
0.001
0.001
0.001
NS
0.001
0.001
0.006

Subjects with IFG had fasting blood glucose of 110 125 mg/dl
(6.1 6.9 mmol/liter); type 2 DM subjects were taking antidiabetic
agents or had a fasting blood glucose of at least 126 mg/dl (7 mmol/
liter); and hypertension subjects were taking antihypertension medication or their blood pressure was at least 130/85 mm Hg. NS, not
significant.

than 25 kg/m2 (48.5 vs. 43.9%; P 0.270), and low HDL

cholesterol (61.3 vs. 54.7%; P 0.111) did not reach a significant difference between the two groups. We further analyzed the association after correcting for the environmental
factors of age and BMI. We found that the results were still
highly significant for metabolic syndrome [odds ratio (OR)
1.55; 95% confidence interval (CI), 1.072.23; P 0.021]. It
remained marginally significant for IFG/type 2 DM (OR
1.38; 95% CI, 0.99 1.93; P 0.056) and hypertriglyceridemia
(OR 1.36; 95% CI, 0.971.91; P 0.074). Finally, multivariate stepwise regression analysis for the independent determinant of the 16189 variant of mtDNA, including hypertension, hypertriglyceridemia, low HDL cholesterol, BMI
greater than 25 kg/m2, diabetes, and metabolic syndrome
revealed that metabolic syndrome was the only independent
determinant (OR 1.58; 95% CI, 1.14 2.19; P 0.006). MoreTABLE 2. Comparison of subjects harboring the wild type and
the 16189 variant of mtDNA

No.
Age (yr)
BMI
Triglyceride (mg/dl)
HDL cholesterol (mg/dl)
Sex (male/female)
IFG/type 2 DM
IFG
Type 2 DM
Hypertriglyceridemia
Hypertension
BMI 25 kg/m2
Low HDL cholesterol
Metabolic syndrome

Wild type

16189 variant

P value

380
58.9 10.6
24.9 3.4
149.5 98.2
43.6 11.6
201/179
160/380 (42.1%)
11/380 (2.9%)
149/380 (39.2%)
136/380 (35.8%)
181/380 (47.6%)
167/380 (43.9%)
208/380 (54.7%)
159/380 (41.8%)

235
60.7 10.2
25.2 3.0
157.6 101
43.0 13.9
122/113
121/235 (51.5%)
8/235 (3.4%)
113/235 (48.1%)
104/235 (44.3%)
125/235 (53.2%)
114/235 (48.5%)
144/235 (61.3%)
125/235 (53.2%)

NS
NS
NS
NS
NS
0.023
NS
0.031
0.037
NS
NS
NS
0.006

Subjects with IFG had fasting blood glucose of 110 125 mg/dl
(6.1 6.9 mmol/liter); type 2 DM subjects were taking antidiabetic
agents or had a fasting blood glucose of at least 126 mg/dl (7 mmol/
liter); hypertriglyceridemia subjects had triglyceride at least 150
mg/dl (1.69 mmol/liter); low HDL-cholesterol means HDL cholesterol less than 40 mg/dl (1.03 mmol/liter) in men and less than 50
mg/dl (1.29 mmol/liter) in women; and hypertension subjects were
taking antihypertension medication or their blood pressure was at
least 130/85 mm Hg. NS, not significant.

Weng et al. mtDNA 16189 Variant and Metabolic Syndrome

over, we found that the greater the number of the components of metabolic syndrome an individual has, the higher
the frequency of occurrence of the mtDNA 16189 variant is
(Fig. 1). The difference was statistically significant (2 8.91;
Ptrend 0.005).
Discussion

We found in this study a high prevalence rate (71.2%) of

metabolic syndrome in subjects with IFG/type 2 DM, as has
been found in previous reports for Chinese (75.1%) (19) and
Scandinavian patients with diabetes (20). The prevalence rate
of metabolic syndrome in the hypertensive group (65.4%),
the low-HDL cholesterol group (66.2%), the obesity group
(73%), and the hypertriglyceridemia group (82.5%) were
quite similar to that of the diabetes group in general. This
finding suggests that the presence of each component in an
individual may represent the possibility of the same underlying metabolic defect.
Furthermore, we found a clear association between the
16189 variant of mtDNA and metabolic syndrome (Tables 1
and 2). As to the individual traits of metabolic syndrome, the
16189 variant of mtDNA was significantly associated with
hyperglycemia (51.5 vs. 42.1%; P 0.023) and hypertriglyceridemia (44.3 vs. 35.8%; P 0.037), respectively (Table 2).
Because environmental factors contribute to the development of metabolic syndrome, we further tested this association after correction for age and BMI, and the results showed
that this association remained significant (P 0.021) after
correcting for the environmental factors. Finally, the independent association between the 16189 variant and the metabolic syndrome was confirmed by the multivariate analysis.
In this study we also found that the greater the number of the
components of metabolic syndrome an individual has, the
greater the frequency of occurrence of the 16189 variant of
mtDNA is, implying that this common 16189 polymorphism
of mtDNA underlies susceptibility to metabolic syndrome in
the Chinese adult, probably, for the most part, through the
development of the phenotype of hyperglycemia and
hypertriglyceridemia.
Recently, Wilson et al. (4) described a large kindred with
a syndrome including hypertension, hypercholesterolemia,
and hypomagnesemia. The affected subjects are on maternal
linkage and have a mutation substituting cytidine for uridine

FIG. 1. The frequency of occurrence of the 16189 variant of mtDNA

in individuals with different numbers of the components of metabolic
syndrome (MS): zero (28.6%), one (32.1%), two (36.1%), three (43.1%),
four (41.2%), and five components (52.3%). The difference was statistically significant (2 8.91; Ptrend 0.005).

J Clin Endocrinol Metab, September 2005, 90(9):50375040

5039

immediately 5 to the mitochondrial transfer RNAIle anticodon. The authors suggested that all the features of metabolic
syndrome can be result from pleiotropic effects of impaired
mitochondrial function. In this kindred, the prevalence of
hypertension showed a marked age dependence, indicating
that the loss of mitochondrial function with aging might
commonly contribute to all components of the metabolic
syndrome. Supporting their hypothesis, Peterson et al. (21)
have demonstrated insulin resistance in the skeletal muscle
of offspring of patients with type 2 diabetes. The insulinresistant offspring had an increased intramyocellular lipid
content measured by proton magnetic resonance spectroscopy. Their dysregulation of intramyocellular fatty acid metabolism was attributable to an inherited defect in mitochondrial oxidative phosphorylation assessed by 31P magnetic
resonance spectroscopy. Their findings also indicated the
mitochondrial origin of this metabolic disorder. This common mtDNA 16189 variant we studied was initially reported
to be associated with the development of diabetogenic A3 G
mutation at bp 3243 (22). It was then documented to be
associated with insulin resistance in Caucasians in 1998 (5)
and, in a more recent study of 932 subjects from Cambridgeshire, significantly associated with type 2 diabetes
(11). Another study of nondiabetic adults in Korea, although
not finding a difference in fasting insulin and insulin resistance, did find an association between the 16189 variant of
mtDNA and higher fasting glucose and BMI (23). In our
series, the association between the 16189 variant of mtDNA
and type 2 diabetes was replicated in the Chinese population,
suggesting the association is probably not a chance finding.
In our other study with 165 type 2 diabetes and 168 controls,
patients with type 2 diabetes harboring the 16189 mtDNA
variant showed impaired ability to respond properly to oxidative stress and oxidative damage (24). However, we have
to emphasize that this 16189 variant occurs in a noncoding
region, and the mechanism underlying any effect is far from
clear. It was suggested that the T3 C substitution at bp 16189
results in a polycytosine tract that in turn can lead to heteroplasmic length variation in the control region of mtDNA.
The heteroplasmic length variation in the regulatory D-loop
may predispose the mtDNA to errors of replication (22). This
does not occur if a second transition (C3 T) occurs further
down the polycytosine tract. Sequencing showed that heteroplasmic length variation was a feature of the 16189 variant, but only if there were no other mutation in the region
that interrupted the resultant polycytosine tract (22, 25). Because our PCR/restriction fragment length polymorphism
methodology does not distinguish these two variants, it is not
possible from our results to work out whether the association
is stronger for subjects with the heteroplasmic length
variation.
In our series, the prevalence rate of the 16189 variant of
mtDNA in Taiwan Chinese adults was 34.6% in nondiabetic
and 43.1% in diabetic subjects, a finding similar to those
reported for Koreans (28.8%) (23), Japanese (34.4%) (26), and
Mainland Chinese (nondiabetes, 20%; type 2 diabetes, 33%)
(27) but higher than those reported for Anglo-Saxon Caucasians (nondiabetes, 6.4%; type 2 diabetes, 9.9%) (11) and
Indians (12.2%) (28). Before our study, evidence of a direct
correlation of metabolic syndrome with the16189 variant of

5040

J Clin Endocrinol Metab, September 2005, 90(9):50375040

mtDNA was still lacking. Our sample (n 615) was large

enough to represent the people of the Asia-Pacific region,
and the mean BMI (25.0 3.3 kg/m2) was typical of people
from this area. Therefore, the high prevalence of the 16189
variant of mtDNA in Asians, as shown in our series and
others (23, 26, 27), indicates that it might play a more important role in development of metabolic syndrome in
Asians than it does in Caucasians. The rapid, almost epidemic, increase of type 2 diabetes in this area (29 31) under
the influence of Western civilization may partly be explained
by the high prevalence of this mtDNA variant in the people
living in this region.
Acknowledgments
We thank Ms. Tzu-Ling Chen and Ms. Fong-Mei Huang for technical
support and Ms. Bih-Ru Hsueh for preparation of this manuscript.
Received February 2, 2005. Accepted June 14, 2005.
Address all correspondence and requests for reprints to: Pei-Wen
Wang, M.D., Department of Internal Medicine, Chang Gung Memorial
Hospital, 123 Ta-Pei Road, Niao-sung Hsiang, Kaohsiung Hsien, Taiwan
833. E-mail: wangpw@adm.cgmh.org.tw.
This work was supported by the National Science Council (Republic
of China) Research Grants NSC 91-2314-B-182A-132 and NSC
92-2314-B-182A-119.

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JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the
endocrine community.