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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0227
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 9 5037-5040
Copyright © 2005 by The Endocrine Society

Association of Mitochondrial Deoxyribonucleic Acid 16189 Variant (T->C 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

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{at}adm.cgmh.org.tw.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Objective: A common variant in mitochondrial DNA (mtDNA) at bp 16189 (T->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 {chi}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 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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IN 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, 5, 6, 7, 8, 9, 10, 11). A common variant in mitochondrial DNA (mtDNA) at bp 16189 (T->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 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
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
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 Women’s 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: 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 (15911–15930), 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-µl PCR contained 20 µM of each primer, 200 µM 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 Student’s t test. The statistical difference in the frequency of occurrence of the 16189 variant of mtDNA between different subgroups was assessed by the Pearson’s {chi}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
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
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 1Go. 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).


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  		TABLE 1. Comparison of subjects with and without metabolic syndrome

 
The association between the 16189 variant of mtDNA and the individual components of metabolic syndrome is shown in Table 2Go. 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 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), 1.07–2.23; 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, 0.97–1.91; 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). Moreover, 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. 1Go). The difference was statistically significant ({chi}2 = 8.91; Ptrend < 0.005).


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  		TABLE 2. Comparison of subjects harboring the wild type and the 16189 variant of mtDNA

 


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  		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 ({chi}2 = 8.91; Ptrend < 0.005).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
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 1Go and 2Go). 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 2Go). 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 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 insulin-resistant 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 A->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 T->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 (C->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 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, 30, 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.


   Footnotes
 
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.

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.

Received February 2, 2005.

Accepted June 14, 2005.


   References
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 Introduction
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 Results
 Discussion
 References
 

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