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Promoter Polymorphisms of the TNF- (G-308A) and IL-6 (C-174G) Genes Predict the Conversion From Impaired Glucose Tolerance to Type 2 Diabetes

The Finnish Diabetes Prevention Study

¹ Department of Medicine, University of Kuopio, Kuopio, Finland
² Department of Clinical Nutrition, University of Kuopio, Kuopio, Finland
³ Department of Epidemiology and Health Promotion, Diabetes and Genetic Epidemiology Unit, National Public Health Institute, Helsinki, Finland
⁴ Research and Development Centre, Social Insurance Institution, Turku, Finland
⁵ Department of Medicine, Finnish Diabetes Association and University of Tampere, Tampere, Finland
⁶ Department of Public Health Science and General Practice, University of Oulu, Oulu University Hospital and Department of Sport Medicine, Oulu Deaconess Institute, Oulu, Finland
⁷ Department of Public Health, University of Helsinki, Helsinki, Finland

	ABSTRACT

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High levels of cytokines are risk factors for type 2 diabetes. Therefore, we investigated whether the promoter polymorphisms of the tumor necrosis factor- (TNF-; G-308A) and interleukin 6 (IL-6; C-174G) genes predict the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in the Finnish Diabetes Prevention Study. Altogether, 490 overweight subjects with IGT whose DNA was available were randomly divided into one of the two treatment assignments: the control group and the intensive, individualized diet and exercise intervention group. The -308A allele of the TNF- gene was associated with an approximate twofold higher risk for type 2 diabetes compared with the G-308G genotype (odds ratio 1.80, 95% CI 1.05–3.09; P = 0.034). Subjects with both the A allele of the TNF- gene and the C-174C genotype of the IL-6 gene had a 2.2-fold (CI 1.02–4.85, P = 0.045) higher risk of developing type 2 diabetes than subjects without the risk genotypes. We conclude that the -308A allele of the promoter polymorphism (G-308A) of the TNF- gene is a predictor for the conversion from IGT to type 2 diabetes. Furthermore, this polymorphism seems to have a gene-gene interaction with the C-174C genotype of the IL-6 gene.

In this study, we investigated whether two polymorphisms in the promoter region of the TNF- and IL-6 genes predict the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in participants from the Finnish Diabetes Prevention Study (DPS) (11). To this aim, we genotyped 490 participants of the DPS for the G-308A promoter polymorphism of the TNF- gene and the C-174G promoter polymorphism of the IL-6 gene.

In all study subjects, the frequencies of the genotypes were 74% G-308G, 25% G-308A, and 1% A-308A for the TNF- gene promoter polymorphism and 32% C-174C, 46% C-174G, and 22% G-174G for the IL-6 gene promoter polymorphism. The frequencies did not differ between the intervention and control groups, and they were in Hardy-Weinberg equilibrium. As only six subjects had the A-308A genotype of the TNF- gene, they were combined with subjects who had the G-308A genotype. There were no differences in clinical characteristics, fasting and 2-h levels of glucose and insulin in the oral glucose tolerance test, or homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and insulin secretion (HOMA-IS) at baseline according to the G-308A promoter polymorphism of the TNF- gene or the C-174G promoter polymorphism of the IL-6 gene (data not shown).

During the 3-year follow-up 69 genotyped subjects (19 subjects in the intervention group and 50 subjects in the control group) developed type 2 diabetes. We found that the -308A allele (G-308A and A-308A genotypes) of the TNF- gene was associated with a high incidence of type 2 diabetes in all subjects in the DPS (P = 0.032) because 12.6% of subjects (44 of 348) with the G-308G genotype and 20.7% of subjects (25 of 121) with the -308A allele converted from IGT to type 2 diabetes. The IL-6 polymorphism was not associated with the progression to type 2 diabetes (14.1% of C-174C genotype subjects, 15.3% of C-174G genotype subjects, and 14.3% of G-174G genotype subjects developed diabetes; P = 0.796). When the intervention and control groups were analyzed separately, the presence of the -308A allele of the TNF- gene was a predictor of type 2 diabetes only in the intervention group (P = 0.011) (Fig. 1B). No significant difference in weight loss between subjects with the G-308G genotype and -308A allele carriers of the TNF- gene was found in either the intervention or control group (Fig. 1A).

View larger version (18K): [in this window] [in a new window]   FIG. 1. Three-year weight change (%) (mean ± SE) (A) and 3-year incidence (%) (B) of type 2 diabetes in the intervention and control groups according to the G-308A polymorphism of the TNF- gene.

View this table: [in this window] [in a new window]   TABLE 1 TNF- promoter polymorphism (G-308A) as a predictor for the development of type 2 diabetes by the study group (logistic regression analysis)

Subjects simultaneously having the -308A allele of the TNF- gene and the C-174C genotype of the IL-6 gene had the highest incidence of type 2 diabetes (26.8%) compared with subjects without these risk genotypes (14.2%, P = 0.041). In univariate logistic regression analysis (Table 2), subjects having both the -308A allele of the TNF- gene and the C-174C genotype of the IL-6 gene had a 2.22-fold (CI 1.02–4.85, P = 0.045) higher risk of developing type 2 diabetes than subjects having neither of these risk genotypes (model 1). This risk was not, however, significantly higher than that for the -308 A allele of the TNF- gene alone. In the intervention group the subjects with both risk genotypes had an approximate sixfold higher incidence of diabetes (OR 6.19, 95% CI 2.06–18.6). This association did not essentially change, even after the inclusion of baseline weight and weight change into the model.

View this table: [in this window] [in a new window]   TABLE 2 TNF- promoter (-308 A allele) and IL-6 promoter (C-174C genotype) risk genotypes as predictors for the development of type 2 diabetes in 41 subjects with both risk alleles and 240 subjects without any risk allele by the study group (logistic regression analysis)

View larger version (22K): [in this window] [in a new window]   FIG. 2. Three-year change (mean ± SE) in HOMA-IR (A) and HOMA-IS (B) according to the G-308A polymorphism of the TNF- gene in subjects who converted and who did not convert to type 2 diabetes. Three-year change (mean ± SE) in HOMA-IR index (C) and HOMA-IS index (D) according to the presence or absence of risk genotypes of the TNF- gene (-308A allele) and the IL-6 gene (C-174C genotype) in subjects who converted and who did not convert to type 2 diabetes.

There is substantial evidence that TNF- contributes to insulin resistance and thus to type 2 diabetes. Long-term exposure of cultured cells to TNF- induces insulin resistance (12). TNF- inhibits insulin receptor signaling by decreasing autophosphorylation of insulin receptor and promoting serine phosphorylation of insulin receptor substrate proteins (7,13). The evidence that TNF- impairs insulin secretion is much more limited. However, in pancreatic ß-cell lines TNF- decreased glucose-stimulated insulin secretion (8).

The -308A allele of the TNF- gene has been found to increase TNF- transcription (5,6) and secretion (14). Thus, high incidence of type 2 diabetes, particularly in obese subjects, may be due to increased production of TNF- in subjects with the -308A allele. The C-174C genotype has been shown to be associated with insulin resistance (9); therefore, the IL-6 polymorphism could influence the conversion from IGT to type 2 diabetes. However, in our study the C-174C genotype did not increase the risk of type 2 diabetes, but we found a gene-gene interaction between the TNF- and IL-6 promoter polymorphisms (P = 0.05). Subjects with the C-174C genotype of the IL-6 gene and the -308A allele of the TNF- gene had about a two times higher incidence of type 2 diabetes than subjects without these genotypes.

There are several possibilities how TNF- and IL-6 polymorphisms could interact with each other. The synthesis of IL-6 is tightly regulated, and a multiple response element of the IL-6 gene promoter (-173 to 145) is also controlled by TNF-. TNF- stimulates transcription of the IL-6 gene (15,16) and induces the production of IL-6 and its receptor (17). On the other hand, IL-6 has been suggested to negatively control TNF- production (18).

Although the HOMA model is not a gold standard for the measurement of insulin sensitivity and insulin secretion, our results indicated that HOMA-IR was significantly higher among converters to diabetes than among nonconverters independently of the G-308A polymorphism of the TNF- gene (Fig. 2). Interestingly, in subjects with both risk genotypes of the TNF- and IL-6 genes, the reduction in insulin secretion (HOMA-IS) was clearly more pronounced than in subjects carrying only one risk genotype, suggesting that the effect on insulin secretion was additive.

In summary, we have demonstrated that the G-308A promoter polymorphism of the TNF- gene is a predictor of type 2 diabetes. Furthermore, we have shown that this promoter polymorphism of the TNF- gene has a gene-gene interaction with the IL-6 promoter polymorphism (C-174G), further increasing the risk of type 2 diabetes. Finally, the G-308A promoter polymorphism of the TNF- gene seems to have an interaction with lifestyle changes.

	RESEARCH DESIGN AND METHODS

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Subjects and research design.
The DPS is a multicenter longitudinal study carried out in five participating centers in Finland (11). Subjects with IGT according to the World Health Organization 1985 criteria (fasting glucose <7.8 mmol/l and 2-h plasma glucose 7.8–11.0 mmol/l [19]) who were at high risk for progression to type 2 diabetes were recruited. All 522 participants were overweight and had IGT. Subjects were randomly divided into one of two groups: the control group and the intensive, individualized diet and exercise intervention group (11,20). Oral glucose tolerance tests were performed annually, and a diagnosis of diabetes was confirmed in two subsequent tests. DNA was available from 490 subjects (161 men and 329 women). Their mean BMI was 31.1 ± 4.6 kg/m² and age 55.4 ± 7.1 years. All participants gave written informed consent, and the ethics committee of the National Public Health Institute in Helsinki, Finland, approved the study protocol.

Measurements.
Medical history and physical examination were done at baseline and during annual follow-up visits, as previously described (11,20). HOMA-IR was calculated using the formula fasting plasma glucose (mmol/l) x fasting serum insulin (mU/l)/22.5, and HOMA-IS was calculated as 20 x fasting serum insulin (mU/l)/(fasting plasma glucose [mmol/l] - 3.5) (21).

DNA analysis.
The G-308A polymorphism of the TNF- gene was screened by the restriction fragment-length polymorphism after digestion with NcoI restriction enzyme, as previously described (22). The genotyping of the C-174G polymorphism of the IL-6 gene was performed by PCR with published primers (23) followed by the single-strand conformation polymorphism analysis as previously reported in detail (24).

Statistical analysis.
Data were analyzed with the SPSS/Win programs (version 10.0; SPSS, Chicago, IL). Data are given as means ± SD, unless otherwise indicated. Students’ t test for independent samples was used to compare the two groups, and ANOVA was used to compare the three genotypes. ² test was used in comparison of categorical variables. Insulin concentrations were log transformed before statistical analyses to achieve a normal distribution. Logistic regression analysis was performed to evaluate if the TNF- or IL-6 polymorphisms predict the development of type 2 diabetes.

	ACKNOWLEDGMENTS

 
This study was financially supported by grants from the Academy of Finland (38387 and 46558 to J.T. and 40758 to M.U.), the EVO-fund of the Kuopio University Hospital (5106 to M.U.), the Ministry of Education, the Finnish Diabetes Research Foundation, and the European Union (QLRT-1999-00674 to M.L.).

Address correspondence and reprint requests to Markku Laakso, Professor and Chair, Department of Medicine, University of Kuopio, 70210 Kuopio, Finland. E-mail: markku.laakso{at}kuh.fi

Received for publication February 9, 2003 and accepted in revised form April 8, 2003

Abbreviations: DPS, Diabetes Prevention Study; HOMA, homeostasis model assessment; HOMA-IR, HOMA for insulin resistance; HOMA-IS, HOMA for insulin secretion; IGT, impaired glucose tolerance; IL-6, interleukin-6; TNF-, tumor necrosis factor-

	REFERENCES

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