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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 4 1885-1890
Copyright © 2004 by The Endocrine Society

COMMENT

Body Mass Index and C-174G Interleukin-6 Promoter Polymorphism Interact in Predicting Type 2 Diabetes

Matthias Möhlig, Heiner Boeing, Joachim Spranger, Martin Osterhoff, Anja Kroke, Eva Fisher, Manuela M. Bergmann, Michael Ristow, Kurt Hoffmann and Andreas F. H. Pfeiffer

Departments of Clinical Nutrition (M.M., J.S., M.O., M.R., A.F.H.P.) and Epidemiology (H.B., A.K., E.F., M.M.B., K.H.), German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany; and Department of Endocrinology (M.M., J.S., M.O., M.R., A.F.H.P.), Diabetes and Nutrition, Charité-University Medicine Berlin, Campus Benjamin Franklin, 12200 Berlin, Germany; and Research Institute of Child Nutrition (A.K.), D-44225 Dortmund, Germany

Address all correspondence and requests for reprints to: Matthias Möhlig, M.D., Department of Clinical Nutrition, German Institute of Human Nutrition, Arthur-Scheunert-Allee 114-116, 14558 Bergholz-Rehbrücke, Germany. E-mail: mmoehlig{at}mail.dife.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Increased levels of IL-6 add further risk to the impact of obesity in respect to the development of type 2 diabetes mellitus (T2DM). A C-174G polymorphism within the IL-6 promoter region was shown to influence transcription rate of IL-6. We made use of a nested case-control study within the European Prospective Investigation into Cancer and Nutrition-Potsdam cohort of 27,548 individuals, selecting 188 T2DM cases and 376 controls to investigate this polymorphism in respect to development of T2DM. This polymorphism was found to modify the correlation between body mass index (BMI) and IL-6 by showing a much stronger increase of IL-6 at increased BMI for CC genotypes compared with GG genotypes. Interestingly, C-174G polymorphism was found to be an effect modifier for the impact of BMI regarding T2DM. Whereas BMI greater than or equal to 28 kg/m2 increased the risk of T2DM 3.44-fold [95% confidence interval (CI), 1.34- to 8.24-fold] for GG genotypes and 2.94-fold (95% CI, 1.56- to 5.56-fold) for GC genotypes, we found a 17.68-fold (95% CI, 3.57- to 87.66-fold) increase in risk for CC genotypes. In conclusion, obese individuals with BMI greater than or equal to 28 kg/m2 carrying the CC genotype showed a more than 5-fold increased risk of developing T2DM compared with the remaining genotypes and, hence, might profit most from weight reduction.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SEVERAL PROSPECTIVE STUDIES have recently found increased levels of inflammatory markers, such as C-reactive protein and IL-6, a central stimulus for acute-phase responses, being associated with increased risk of type 2 diabetes mellitus (T2DM) (1, 2, 3, 4, 5, 6). These data support the hypothesis that T2DM is a manifestation of a persistent subclinical inflammatory process. Serum levels of IL-6 were further positively correlated with body fat (7) and negatively correlated with insulin resistance (8) and were shown to decrease during weight loss in women (9, 10). IL-6 might deteriorate glucose homeostasis by increasing insulin resistance as shown in hepatocytes (11), even if short-term administration in healthy humans did not impair whole-body glucose disposal (12). IL-6 gene transcription was found to be influenced in vitro by the C-174G polymorphism within the IL-6 promoter (13). However, data about the effects of this polymorphism on IL-6 levels in humans are contradictory. Subjects with CC genotype were described as having lower IL-6 levels in a cohort suffering from Sjögren's syndrome (14), whereas in a cohort of humans with abdominal aneurysms, CC genotype was associated with higher IL-6 values (15). In contrast to Fishman et al. (13) who described IL-6 levels in 102 healthy subjects as being lower in case of CC genotype, Hulkkonen et al. (14) found IL-6 not significantly different among the genotypes of their 400 controls. Furthermore, the IL-6 C-174G polymorphism was found to be associated with insulin resistance (16, 17) and energy expenditure (17); again, the results of these two groups were partially contradictory.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

A nested case-control study was designed within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, which is part of the European multicenter, population-based EPIC study (18) including 27,548 subjects from the area around Potsdam, Germany (women aged 35–65 yr and men aged 40–65 yr). Informed consent was obtained from all study participants. Baseline examination and blood sampling were conducted between 1994 and 1998. Data presented here are based on the first follow-up questionnaires sent to the study participants on average 2.3 yr after baseline examination (19). Cases were free of T2DM at baseline and developed T2DM during the follow-up. Potential cases of incident diabetes were identified from self-reports of incident disease, or current medications, or current dietary treatment for diabetes (n = 399). Diagnosis for each potentially incident subject was confirmed by sending a special questionnaire to the individual’s primary care physician. Two hundred one cases of incident diabetes were identified. Nine were excluded because of positive diabetes-related antibodies indicating type 1 diabetes. The 192 remaining cases were matched with two control subjects each by age and sex (n = 384). Individuals with missing values in one of the variables used were not considered (cases, n = 4; controls, n = 8), thus leaving 188 cases and 376 controls for the final analysis. Further details of recruitment are published elsewhere (5, 20).

Body mass index (BMI) was calculated as body weight (kilograms) divided by body height (meters) squared. Physical activity level was calculated from the self-administrated physical activity using the EPIC core questions on physical activity (21) taking into account the metabolic equivalents of Ainsworth et al. (22) as described in detail for the EPIC cohort elsewhere (23). Dietary intake was assessed by a self-administered, validated food-frequency questionnaire (24, 25). The questionnaire consisted of 148 food items. Macronutrient intake was calculated using the data of the German food code (26). Information on drug use was obtained during the interview at baseline and comprised all medications being taken during the previous 4 wk in detail on the level of medication name.

Laboratory procedures

Peripheral venous citrate blood samples were taken, and plasma was stored immediately after centrifugation at –80 C until assaying. IL-6 was measured by ELISA (R&D Systems, Minneapolis, MN), and diabetes-associated antibodies GAD65 and IA-2 were analyzed by RIA (Medipan Diagnostica, Selchow, Germany). Hemoglobin A1c (HbA1c) was determined using enzyme immunoassay (Dako Diagnostika, Hamburg, Germany). DNA was extracted from blood cells using Magnasep magnetic beads, following the manufacturer’s instruction (Agowa, Berlin, Germany). PCR was performed with the upper primer 5'-TAGCCTGTTAATCTGGTCACTG and the lower primer 5'-TAAATCTTTGTTGGAGGGTG at 64 C annealing temperature and with 2.5 mM MgCl2 concentration. The single-nucleotide polymorphism diagnostic was performed by elongating the primer 5'-AATGTGACGTCCTTTAGCAT using SNuPE and following the instructions and recommendations for purification of the manufacturer (Amersham, Piscataway, NJ). Detection was performed on a MegaBACE 1000 (Molecular Dynamics, Sunnyvale, CA) using single-nucleotide polymorphism profiler 1.0 software.

Statistical analyses

SPSS software 8.0 (SPSS, Inc., Chicago, IL) and SAS software 8.0 (SAS Institute, Cary, NC) were used. All significances are two sided. Values of IL-6 below the limit of quantification were set at 0.7 times the detection limit (27). BMI was dichotomized at 28 kg/m2. Nonparametric tests were used for testing significant differences (Mann-Whitney U test if two groups were compared, otherwise Kruskal-Wallis test). Differences in frequencies were tested by the Pearson {chi}2 test. Unconditional logistic regression analysis was used to estimate odds ratios and 95% confidence intervals (CI; likelihood). Odds ratios and 95% CIs for the BMI effects of the different genotypes on development of T2DM were calculated by taking into account the effects of BMI, the genotype present, and the interaction term between BMI and the genotype (28). Odds ratios were used to approximate the relative risk (29). Risk estimates in the fully adjusted model were obtained after adjustment for sex, age, alcohol consumption (grams per day, continuous), carbohydrate consumption (grams per day, continuous), fat consumption (grams per day, continuous), protein consumption (grams per day, continuous), physical activity level (continuous), use of angiotensin-converting enzyme (ACE) inhibitors (dichotomized), use of antihypertensive drugs other than ACE inhibitors (dichotomized), use of statins (dichotomized), use of lipid-lowering drugs other than statins (dichotomized), use of corticoid drugs (dichotomized), use of antiphlogistic drugs (dichotomized), sporting activities (continuous), smoking status (current smoker, nonsmoker), educational attainment (basic training, technical school, or university), and HbA1c (continuous).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
To evaluate the predictive value of the IL-6 C-174G polymorphism with respect to T2DM, we made use of a nested case-control study within the EPIC-Potsdam study cohort (27,548 individuals) consisting of 188 case subjects identified in a 2.3-yr follow-up period. Cases were defined as being disease-free at baseline and having developed T2DM during follow-up. Three hundred seventy-six disease-free controls were matched for age and sex to case subjects. Characteristics of cases and controls were previously described (5, 20) and are summarized in Table 1Go. Cases showed a higher BMI and less sporting activity, and a higher percentage of cases were on antihypertensive drug and fibrate therapy. These variables were not different between the C-174G genotypes (Table 2Go). Furthermore, IL-6 concentrations were not significantly different between the genotypes. Age was the only deviating parameter across the genotypes due to age differences in the control group. Age was controlled for in all subsequent statistical models. The frequencies of the different genotypes at C-174G in the study population were as follows: 18% CC, 55% GC, and 27% GG. The genotype distributions were not different between the case and the control groups. However, interesting results were revealed regarding the relationship between BMI and IL-6 levels dependent on the C-174G polymorphism. The correlation between BMI and IL-6 levels among subjects with the CC genotype was higher (0.52; 95 CI, 0.366–0.650; n = 103) than among subjects with the GG genotype (0.2; 95% CI, 0.036–0.344; n = 150). In case of the GC genotype, the correlation was in between (0.31; 95% CI, 0.209–0.410; n = 311). Such correlation-modifying properties of the C-174G genotype might also influence the risk estimates for BMI in respect to the development of T2DM. Therefore, we first applied a risk model for T2DM that included interaction terms of continuous BMI and C-174G genotypes. In this model, the interaction term of BMI and CC genotype was of borderline significance after adjustment for age and sex (P = 0.08). There was no interaction between BMI and IL-6 with respect to T2DM risk.


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  		TABLE 1. Baseline characteristics of cases and controls

 

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  		TABLE 2. Characteristics of the genotypes at the C-174G polymorphism within the IL-6 promoter

 
Subsequently, we applied models with dichotomized BMI at 28 kg/m2 because we assumed a threshold value of BMI for the modifying effect of the genotype. The interaction term of dichotomized BMI and C-174G was significantly associated with the risk of T2DM for the CC genotype after adjustment for sex and age (P = 0.016, Table 3Go), and this interaction regarding the risk of T2DM remained significant both in a model further adjusting for HbA1c, alcohol consumption, sporting activity, education, and smoking status (P = 0.033, Table 3Go) and in the fully adjusted model, as described in Subjects and Methods (P = 0.042, Table 3Go). Within the group with a BMI greater than or equal to 28 kg/m2, there were 122 controls and 135 cases. For all models calculated, the interaction terms between BMI and the GC and GG genotypes were not significantly associated with the risk of T2DM, and for these genotypes, the BMI effect was largely determined by the main effect of BMI (Table 3Go). From the statistical model, we calculated the T2DM risk of BMI greater than or equal to 28 kg/m2 compared with BMI less than 28 kg/m2 for the genotypes, considering the respective main and interaction terms. For the CC genotype, an increase in risk of T2DM for a BMI greater than or equal to 28 kg/m2 was estimated to be 17.68 (95% CI, 3.57–87.66) in the fully adjusted model. In contrast, for the GG genotype, a BMI greater than or equal to 28 kg/m2 increased the risk only by 3.44 (95% CI, 1.34–8.24), and for the GC genotype, the risk increased only by 2.94 (95% CI, 1.56–5.56; Fig. 1Go). Thus, a BMI greater than or equal to 28 kg/m2 was associated with a more than 5-fold higher increase in risk of T2DM in subjects carrying the CC genotype than in subjects with the GC or GG genotypes. Further inclusion of multiplicative interaction terms between genotype and statin use, use of ACE inhibitors, and protein, carbohydrate, and fat intake revealed no significant interactions, and these interaction terms were, therefore, not included in the full model. Even in the larger model including the just mentioned further interaction terms, the interaction between CC genotype and BMI greater than or equal to 28 kg/m2 remained significantly associated with the development of T2DM (P = 0.022). Among the confounders, HbA1c was found to be most strongly associated with T2DM risk in all models applied.


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  		TABLE 3. Results of unconditional regression analysis

 


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  		FIG. 1. Odds ratios (OR) and 95% CIs for the effect of BMI greater than or equal to 28 kg/m2 with regard to risk of T2DM dependent on IL-6 C-174G polymorphism. BMI less than 28 kg/m2 is set as reference. Data obtained from the fully adjusted model.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this prospective study, we demonstrate that the C-174G polymorphism within the IL-6 promoter affects the correlation between BMI and IL-6 levels. Increasing BMI was correlated with higher IL-6 concentrations for the CC genotype than for GG the genotype. Therefore, in respect to the risk factor IL-6, obesity is more deleterious for persons carrying the CC genotype than for those with the GG genotype. Furthermore, C-174G polymorphism modifies the association between BMI and the risk of T2DM. Being obese was associated with a higher risk of developing T2DM (>5 times higher in our study cohort) among subjects with the CC genotype than among subjects with the remaining genotypes. This conclusion was also valid in the fully adjusted model including additional environmental factors such as nutrient intake (protein intake, fat intake, carbohydrate intake, and alcohol consumption) or drug use (ACE inhibitors and other antihypertensive drugs and statins and other lipid-lowering drugs, as well as corticosteroids and antiphlogistic drugs). Statins and ACE inhibitors were independently fit into the model because there is evidence that both reduce diabetes risk (30, 31, 32). For the risk of coronary heart disease, a protective effect of statin use was shown in case of CC genotype (33). Therefore, we included further interaction terms between C-174G and statin use, ACE inhibitor use, and macronutrient intakes into the model. None of these interaction terms yielded significant impact on T2DM risk. Neither further subdividing the medications into the specific substances mentioned in Table 2Go nor the additional inclusion of a variable for acute infection (flu) at baseline substantially altered the interaction between BMI and CC genotype described here (data not shown).

Effect modification between a genotype and an environmental factor is a scientifically important concept. Here we demonstrated such a phenomenon in case of the C-174G polymorphism within the IL-6 promoter and BMI. The statistical analyses clearly indicate that, for the CC genotype, a high BMI is associated with a higher risk of T2DM compared with the remaining genotypes. However, the relatively small study population certainly limited the precise risk estimation and resulted in large CIs. Therefore, our point estimates of relative risk need confirmation in studies with larger sample sizes. Accepting the concept of an interaction between C-174G polymorphism and BMI, other reports regarding the effect of this genotype may be interpreted properly together with BMI. Otherwise, genotype-specific effects might be misinterpreted. The interaction of the C-174G polymorphism with BMI leading to an increased risk of T2DM in obese CC genotypes in our cohort might also explain the differences in the results of a recent cross-sectional study (34). This study described the GG genotype as being more common in diabetics vs. nondiabetics, and one might speculate whether this result is driven by differences in BMI between the genotypes. Berthier et al. (35) described recently the G allele at C-174G as being more common in lean subjects. This result fits well with the finding of a lower basal metabolic rate in case of CC genotype (17), possibly leading to body weight gain. However, in our study focusing on the development of T2DM, BMI was not significantly different between genotypes.

The impact of the IL-6 C-174G polymorphism on IL-6 levels in humans has been controversial (13, 14, 15). Again, one might speculate that the interaction with BMI as described here is responsible for the different results described in the literature. The different slope of correlation between BMI and IL-6 concentrations dependent on the C-174G polymorphism implies, in the case of CC genotype, a lower IL-6 concentration for lean individuals and a higher IL-6 concentration for obese persons compared with GG genotypes. BMI was not significantly different between the genotypes of the current study population, and the mean BMI was in the range of the intersection between the two fitting lines for the correlations between IL-6 and BMI for both CC and GG genotypes. Therefore, it is reasonable that we found IL-6 levels not significantly different between the genotypes. Again, it seems to be necessary to take the BMI values into account in discussing IL-6 levels in the different genotypes at the C-174G polymorphism.

Epidemiological studies, like the one performed here, in principal cannot elucidate the mechanisms responsible for the interactions described. Therefore, which factors linked to BMI differentially regulate IL-6 gene expression dependent on the C-174G polymorphism within the IL-6 promoter remain to be evaluated.


   Acknowledgments
 
We thank K. Sprengel for laboratory assistance and W. Bernigau and U. Fiddicke for managing the study data. The HbA1c analyses were conducted at the Department of Clinical Biochemistry, University of Greifswald, under the responsibility of Dr. Rose. We thank C. A. Barth for critical discussion of the project.


   Footnotes
 
This work was supported by a grant from the Gottfried-Wilhelm-Leibnitz-Gesellschaft. Further grants to the authors were from the German Diabetes Association (to M.M., J.S., and M.R.), the Fritz-Thyssen-Stiftung (Grant 10.01.2.102 to M.R.), the Deutsche Forschungsgemeinschaft (Grant RI 1076/1-1 to M.R.), the Eli Lilly International Foundation (to J.S. and A.F.H.P.), the European Union (Grant SOC 95 201408 OSF02), and the Deutsche Krebshilfe (Grant 70-2488-HAI to A.K.).

M.M., H.B., and J.S. contributed equally to this article.

Abbreviations: ACE, Angiotensin-converting enzyme; BMI, body mass index; CI, confidence interval; EPIC, European Prospective Investigation into Cancer and Nutrition; HbA1c, hemoglobin A1c; T2DM, type 2 diabetes mellitus.

Received June 26, 2003.

Accepted December 29, 2003.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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