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Am J Physiol Endocrinol Metab 294: E987-E992, 2008. First published March 18, 2008; doi:10.1152/ajpendo.90234.2008
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Polymorphisms in metallothionein-1 and -2 genes associated with the risk of type 2 diabetes mellitus and its complications

Lina Yang,1,* Hongyan Li,1,* Ting Yu,1 Haijun Zhao,1 M. George Cherian,1,2 Lu Cai,1,3 and Ya Liu1

1School of Public Health, Jilin University, Changchun, China; 2Department of Pathology, University of Western Ontario, London, Canada; and 3Departments of Medicine and Radiation Oncology, the University of Louisville, Louisville, Kentucky

Submitted 13 February 2008 ; accepted in final form 14 March 2008


   ABSTRACT
TOP
 ABSTRACT
RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Metallothionein (MT) as a potent antioxidant can affect energy metabolism. The present study was undertaken to investigate the association between MT gene polymorphism and type 2 diabetes mellitus. Using the PCR-based restriction fragment length polymorphism method, seven single nucleotide polymorphisms (SNPs) in MT genes (rs8052394 and rs11076161 in MT1A gene, rs8052334, rs964372, and rs7191779 in MT1B gene, rs708274 in MT1E gene, and rs10636 in MT2A gene) were detected in 851 Chinese people of Han descent (397 diabetes and 454 controls). Several serum measurements were also examined randomly for 43 diabetic patients and 41 controls. The frequency distributions of the G allele in SNP rs8052394 of MT1A gene were significantly associated with the incidence of type 2 diabetes. There was no difference between patients and controls for the rest of six SNPs. Serum levels of interleukin-6 and tumor necrosis factor-{alpha} were higher, and serum superoxide dismutase activity was significantly lower in the diabetic group than those in the control group. For diabetic patients, serum superoxide dismutase activity was significantly lower in GG or GA carriers than those of AA carriers of rs8052394 SNP. Increased serum levels in diabetic patients were positively associated with rs964372 SNP, and type 2 diabetes with neuropathy was positively associated with rs10636 and rs11076161. These results suggest that multiple SNPs in MT genes are associated with diabetes and its clinical symptoms. Furthermore, MT1A gene in rs8052394 SNP is most likely the predisposition gene locus for diabetes or changes of serum superoxide dismutase activity.

single nucleotide polymorphism; superoxide dismutase; diabetic complications

THE INCIDENCE OF DIABETES MELLITUS has increased rapidly worldwide, among which type 2 diabetes mellitus (T2DM) accounts for ~90% (19). Although unclear, the etiology of T2DM includes both genetic predisposition and environmental risk factors. If people with the genetic predisposition is exposed to environmental risk factors, the diabetic risk will be increased significantly (11, 15). Therefore, it is helpful to identify the population with genetic predisposition and to protect them from exposure to environmental risks (11).

Genomic scanning has suggested a number of chromosomal regions possibly containing T2DM susceptibility genes. These chromosomal regions include 1q, 2p, 8p, 9q, 12q, and 20q (16, 18, 26, 28). Ras-associated with diabetes is related to T2DM and is located on chromosome 16q22 (10, 22), while some members of metallothionein (MT) genes are also located on 16q22 (17). Therefore, any changes in MT genes may be associated with T2DM predisposition.

MTs are a family of proteins with low molecular mass and high affinity to certain metal ions. MTs exist in multiple organs with several molecular forms, including isoforms of MT1, MT2, MT3, and MT4 (2, 19). A multigene family with at least 14 closely related and pseudo genes encodes MT proteins, and the most MT genes, including the functional MT genes (MT1A, MT1B, MT2A), lie on human chromosome 16 (17). MTs can function on the regulation of zinc and copper homeostasis and also act as potent antioxidants against various oxidative damages.

Because the major cause of diabetes and diabetic complications is related to the induction of oxidative stress, we and others have demonstrated protection by increased MT expression in the pancreas (5, 29) and in the heart (3, 4, 9, 12) against initiation of diabetes and diabetic cardiomyopathy, respectively. Furthermore, MT was found also to play a critical role in energy metabolism (1, 20). Although few clinical investigations have indicated the association of polymorphisms in MT genes with human health problems (6, 14, 23), only one study was undertaken to explore the association of one single nucleotide polymorphism (SNP) in the MT gene with diabetes and diabetic complications in one ethnic population using a small number of patients (13).

The present study recruited a relatively large case number of T2DM patients and appropriate healthy controls from Han Chinese in North China. Seven SNPs in MT genes were examined using the PCR-restriction fragment length polymorphism (PCR-RFLP) method for both differences of allelic gene and genotype distributions between T2DM and control groups. In addition, we also investigated the relationship of the SNPs in MT genes with a few serum measurements, including interleukin-6 (IL-6), tumor necrosis factor-{alpha} (TNF-{alpha}), superoxide dismutase (SOD), and hexokinase II (HK II), and diabetic complications.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Subjects and protocol. A total of 397 T2DM patients (202 males and 195 females) and 454 age-matched controls (199 males and 255 females) of Chinese Han descents were recruited for the genetic analysis at the Jilin University Research Center for Genomic Medicine (Changchun, China). These subjects originally came from the Northeast area of China with an average age of 54.94 ± 11.55 yr for patients and 55.71 ± 10.72 yr for controls. The patients were admitted to Jilin University-Affiliated Hospitals, and Daqing Oil Field-Affiliated Hospitals during the period between 2001 and 2005. They were diagnosed as T2DM based on the World Health Organization 1999 guideline that was adopted from the American Diabetes Association 1997 standard. All subjects gave written informed consent for the genetic analysis as approved by the ethics committee of the Jilin University.

SNP selection and RFLP analysis. We detected seven SNPs using PCR-RFLP analysis based on the SNP map of the genes for MT1 and MT2 (http://www.ncbi.nlm.nih.gov/; http://snp.cshl.org/; http://www.ncbi.nlm.nih.gov/SNP). These SNPs included rs8052394 and rs11076161 in the MT1A gene, rs8052334, rs964372, and rs7191779 in the MT1B gene, rs708274 in the MT1E gene, and rs10636 in the MT2A gene. Only those showing heterozygosity of >10% were used as a genetic marker. Genomic information of polymorphic SNPs and the primers are given in Table 1.


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  		Table 1. The primer sequence for PCR-RFLP in a Chinese population

 
Genomic DNA used for PCR amplification was extracted from the whole blood sample using a DNA extraction kit (Promega, Beijing, China). The PCR amplification was performed in a 25-µl reaction mixture with each primer, for which the conditions included an initial denaturation at 94°C for 5 min, followed by 35–40 cycles of 94°C for 45 s, 55–60°C for 1 min and 72°C for 1 min, and a final elongation at 72°C for 10 min. A 15-µl aliquot of the PCR products was completely digested with 7–10 units of restriction enzymes (Table 2).


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  		Table 2. Genotypes and allele of the SNPs

 
Serum measurements. Activities of serum HK II and SOD and serum levels of TNF-{alpha} and IL-6 were measured using commercial available kits based on the instructions provided in the kits. Kits for the measurement of HK II and SOD activities by the colorimetric method were purchased from Nanjing Jiancheng BioEngineering (Nanjing, China). Kits for the measurement of TNF-{alpha} and IL-6 levels by enzyme-linked immunosorbent assay method were purchased from Beijing Chemclin Biotech (Beijing, China).

Statistic analysis. The Hardy-Weinberg equilibrium for genotypic distributions was examined using the {chi}2 goodness-of-fit test. The {chi}2 values and the degree of freedom were summed over all SNPs genotyped to estimate a global significance level. Analysis for the genotype incidence and distribution was performed with {chi}2 test using statistical software (SPSS12.0). The conditional test was used to examine the combined effect of distinct loci on the disease by conditioning on allele or by conditioning on genotype. Data for the biochemical measurements were analyzed by one-way ANOVA and Student's t-test post hoc comparisons and are presented as means ± SD. Differences were considered to be significant at P < 0.05.


   RESULTS
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 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Genotyping analysis for the association with T2DM. All seven SNPs detected in this study were highly polymorphic. The {chi}2 goodness-of-fit test showed that the genotypic distributions of all seven SNPs were not deviated from the Hardy-Weinberg equilibrium (P > 0.05), suggesting the suitability of this sample pool for genetic analysis. The {chi}2 analysis showed a significant difference in the frequency distributions of the allelic gene for MT1A gene rs8052394 between the T2DM group and control group (P < 0.05, Table 3). Although there was no significant difference in the frequency distributions of the genotype for MT1A gene rs8052394 between T2DM and control groups (P > 0.05, Table 3), if we combined GG and GA together (for GG there was only 2.3% in all subjects), there was a significant difference between the T2DM group and the control group [P ' 0.036, odds ratio = 1.300, 95% confidence interval (1.011~1.672)]. The details of genotyping distribution of this SNP in the control and T2DM are summarized in Fig. 1, indicating that the point mutation of the G allele increased significantly in the T2DM group (Fig. 1C).


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  		Table 3. Distribution of allelic and genotypic frequency of SNPs

 

Figure 1
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  		Fig. 1. Association of single nucleotide polymorphism (SNP) rs8052394 with type 2 diabetes mellitus (T2DM). A significant difference in the frequency distributions of the allele A and G for SNP rs8052394 in the MT1A gene between the T2DM (397 cases) and control (454 cases) groups was found by {chi}2 analysis (A). There was no significant difference in the frequency distributions of the genotype between T2DM and control groups (B), but, if combining GG and GA carriers together, there is a significant difference between the T2DM group and control group (C). *P < 0.05 vs. control.

 
There was no significant difference between the T2DM group and control group for the rest of six SNPs (P > 0.05, Table 3).

Association of SNPs with obesity and other clinic biochemical measurements. A proportion of obese individuals (body mass index ≥ 25) in the T2DM group [66.8% (265/397)] was significantly higher than that in the control group [51.3% (233/454), P < 0.01]. Taking diabetic and control groups together, there was a significant association of the frequency of obesity with an allelic change of SNP rs8052334 (P < 0.05, Table 4), with a positive association of the C allele with the increased risk of obesity (data not shown). The distribution of phenotype or allelic gene for the rest of the six SNPs was not associated with the incidence of obesity (Table 4).


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  		Table 4. Results of association between SNPs and BMI

 
We also randomly selected 256 T2DM patients to investigate the associations of the allele or genotype of SNPs with clinical manifestations or laboratory measurements. There were several positive associations of SNPs with either clinical manifestations or laboratory measurements (Table 5): rs8052334 and rs10636 SNPs were significantly associated with hyperlipidemia, and rs964372 SNP was significantly associated with the increased serum triglyceride. In addition, both SNPs rs11076161 and rs10636 were found to be significantly associated with the incidence of T2DM with neuropathy.


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  		Table 5. Associations of SNPs with clinical parameters

 
Because G mutation at SNP rs8052394 was significantly associated with T2DM (Table 3), we further examined its association with several inflammation cytokines (Table 6) and antioxidant SOD (Fig. 2) in blood plasma randomly collected from the 43 T2DM patients and 41 control subjects. No significant difference for IL-6, TNF-{alpha}, and SOD levels among AA, AG, and GG carriers in the control group was found. There were slight increases in the serum IL-6, TNF-{alpha}, and HK levels in the T2DM group compared with that in the control group, without any significant difference among phenotypes of T2DM patients (Table 6). However, there was a significant decrease in serum SOD activity in the T2DM group compared with the control group, and, within diabetic groups, there was also a significant decrease in serum SOD activity in both GG carriers and G/A carriers compared with AA carriers (Fig. 2).


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  		Table 6. Association of plasma IL-6, TNF-{alpha}, and HK levels with rs8052394 genotypes in cases and controls

 

Figure 2
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  		Fig. 2. Association of SNP rs8052394 polymorphisms with the decreased serum SOD activity in T2DM patients. P < 0.05 vs. control (*) and vs. AA carriers (#).

 

   DISCUSSION
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The present study revealed an association of MT genes with T2DM. Significant associations of MT1A rs8052394 (G alteration) with T2DM and decreased serum SOD activity were established. The other six SNPs were not significantly associated with T2DM. However, SNPs rs964372 and rs10636 were found to be significantly associated with increased serum triglyceride and neuropathy among T2DM individuals.

In the MT-null mouse model, examination of gene profiles has indicated a potential role of MT in energy metabolism since 29 of 8,737 genes analyzed were altered in the liver of MT-null mice compared with their wild type: 19 and 10 genes were upregulated and downregulated, respectively. Among these 29 genes, 14 genes were related to energy metabolism (20). In fact, MT-null mice indeed became significantly heavier at age 5–6 wk and were obese at 39 wk old after birth (1). In addition, cardiac overexpression of MT can significantly prevent the cardiac damage from high-fat feeding-induced hyperlipidemia, probably through an increase in protein kinase B-dependent fatty acid utilization (8, 12).

In support of the above experimental findings, we demonstrated that multiple MT gene polymorphisms (SNPs: rs8052334, rs10636, and rs964372) are significantly associated with a decreased utilization of fatty acid as shown by hyperlipidemia and increased serum triglyceride (Table 5). In a preliminary study, Giacconi et al. (13) presented clinical data from 91 Italian T2DM patients and 188 Italian healthy controls, showing a significantly different distribution of 209 MT2A genotypes between diabetic patients and controls with an increased frequency of AA genotype in the patients compared with the control group. In support of this Italian pilot study, we have demonstrated in the present study from Chinese people of Han descent (397 T2DM and 454 controls) that there was a significantly different distribution of MT1A gene rs8052394 for both genotypes and allelic frequencies between T2DM patients and controls with a significant increased frequency of GA or GG carriers in T2DM groups compared with the control (Table 3 and Fig. 1). However, we did not find any significant association of the remaining six SNPs screened in the present study with T2DM.

The metal binding MT can also act as a potential antioxidant and protect cells in vitro and tissues in vivo against oxidative damage caused by a variety of oxidative stress conditions (2, 19). In the early pilot study (13), a significant different distribution of genotype for –209 A/G MT2A polymorphism between T2DM patients with and without ischemic cardiomyopathy but a significant increase in cardiomyopathy in AA carriers in the T2DM group was reported. In the present study, we found that both SNPs rs11076161 and rs10636 are significantly related to the occurrence of diabetic neuropathy in the T2DM groups. Experimental studies have shown the enhanced or reduced neuronal protection against a variety of oxidative stress-induced damages in MT-overexpressing or knockout mice (21, 24, 25). Both of these experimental findings with clinical studies strongly suggest an association of MT gene polymorphisms with the onset of diabetes and the development of diabetic complications. There were differences in the two human data showing the association of different SNPs of MT genes with T2DM, which is most likely the result of ethnic differences between these populations in the two studies.

Another novel finding of the present study is that G carriers of SNP rs8052394 are not only significantly associated to T2DM (Fig. 1) but also significantly associated with the decreased serum SOD activity (Fig. 2). There were significant differences in SOD activity among AA, AG, and GG carriers in the diabetic patients, and the order of reduced SOD activity in the diabetic patients is GG, GA, and AA carriers (Fig. 2). The enzyme SOD catalyzes the dismutation of superoxide into oxygen and hydrogen peroxide. Therefore, it is an important antioxidant defense mechanism in almost all cells exposed to oxygen. Diabetes patients were found to predominantly overproduce superoxide and systemically impair antioxidant system, resulting in oxidative damage to multiple organs that play a critical role in initiating the pathogenesis of diabetic complications (7, 27). There are two SODs activated by different metals (zinc/copper-SOD and manganese-SOD), and zinc/copper-SOD is a predominant component in cytosol. MT plays a critical role in the storage and homeostasis of zinc and copper; therefore, any abnormal expression of MT due to gene alterations may affect the supply of zinc and copper to enzymes such as zinc/copper-SOD in cells.

The abnormal expression of MT thus may be responsible for the decreased SOD levels and they may lead to systemic oxidative stress in the diabetic patients. The continued oxidative stress may further cause the production of several inflammatory cytokines (13), such as TNF-{alpha} and IL-6, observed in the current study (Table 6). Therefore, the functional changes in MT may cause uncontrolled oxidative stress and inflammatory responses and may accelerate the development of diabetic complications.

In support of these findings, an earlier study compared the +838 C/G MT2A polymorphism for 288 patients with atherosclerosis and 218 healthy controls (14) and also showed a decrease in serum levels of zinc with increased inflammatory cytokines in the patients with atherosclerosis. Furthermore, the GG carriers (C–) had a significantly higher frequency of atherosclerosis than elderly controls. C– carriers showed a significant decrease in intracellular zinc availability along with decreased serum zinc and copper levels and increased inflammatory cytokines. C– carriers also had a major incidence of soft carotid plaques (14). These results support our conclusion that MT gene polymorphisms may cause decreases in serum zinc and copper levels along with a decrease in intracellular zinc availability to form antioxidant enzymes such as zinc/copper-SOD.

In summary, in the present study, we demonstrate that G carriers of the rs8052394 locus in MT1A gene was significantly related to the prevalence of T2DM and also significantly associated with the low activity of serum SOD in T2DM. Although whether this can be used as another predictive indicator for T2DM at present remains uncertain, the changes in zinc metabolism induced by this mutation can affect insulin production and other zinc finger proteins. Further studies in different ethnic populations with a larger number of patients, similar to an earlier pilot study, may provide its usefulness as a potential new genomic indicator to screen populations for diabetes. Thus these results suggest that MT gene mutations may be an additional useful indicator to monitor and predict the risk of diabetes and its complications in certain populations.


   GRANTS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported, in part, by a grant from the National Science Research Foundation (30370669) to Y. Liu and L. Cai and by grants from the American Diabetes Association (02-07-JF-02; 05-07-CD-02) to L. Cai.


   ACKNOWLEDGMENTS
 
Present address of L. Yang: School of Public Health, Central South Unviersity, Changsha, Hunan, 410078, China.


   FOOTNOTES
 

Address for reprint requests and other correspondence: Y. Liu, Dept. of Nutrition and Toxicology, The School of Public Health at Jilin University, 1163 Ximin St., Changchun 130021, China (e-mail: liuy{at}jlu.edu.cn); and L. Cai: 511 South Floyd St., MDR 533, Louisville, KY 40202 (e-mail: L0cai001{at}louisville.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

* L. Yang and H. Li contributed equally to this work. Back


   REFERENCES
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 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
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