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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 1 363-366
Copyright © 2007 by The Endocrine Society

BRIEF REPORT

Studies of the Common DIO2 Thr92Ala Polymorphism and Metabolic Phenotypes in 7342 Danish White Subjects

Niels Grarup, Mette K. Andersen, Camilla H. Andreasen, Anders Albrechtsen, Knut Borch-Johnsen, Torben Jørgensen, Johan Auwerx, Ole Schmitz, Torben Hansen and Oluf Pedersen

Steno Diabetes Center (N.G., M.K.A., C.H.A., A.A., K.B.-J., T.H., O.P.), 2820 Gentofte, Copenhagen, Denmark; Faculty of Health Sciences (N.G., K.B.-J., O.P.), University of Aarhus, 8000 Aarhus C, Denmark; Research Centre for Prevention and Health (K.B.-J., T.J.), Glostrup University Hospital, 2600 Glostrup, Denmark; Institut de Génétique et Biologie Moléculaire et Cellulaire (J.A.), Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur Strasbourg, 67404 Illkirch Cedex, France; Institut Clinique de la Souris (J.A.), 67404 Illkirch Cedex, France; Department of Endocrinology and Diabetes M (O.S.), Aarhus University Hospital, Aarhus Sygehus, 8000 Aarhus C, Denmark; and Department of Clinical Pharmacology (O.S.), University of Aarhus, 8000 Aarhus C, Denmark

Address all correspondence and requests for reprints to: Niels Grarup, Steno Diabetes Center, Niels Steensens Vej 2, 2820 Gentofte, Denmark. E-mail: ngrp{at}steno.dk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The type 2 iodothyronine deiodinase (D2) catalyzes the conversion of T4 to the active form of thyroid hormone, which is a critical regulator of thermogenesis and glucose metabolism. A Thr92Ala polymorphism in the gene encoding D2 (DIO2) has been reported to associate with insulin resistance.

Objective: The aim of the present study was to assess the impact of the DIO2 Thr92Ala variant on type 2 diabetes (T2D), obesity, and related quantitative metabolic traits including measures of insulin resistance. Because DIO2 is activated through a ß-adrenergic receptor-dependent pathway, we further hypothesized that variation in the ADRB genes interacts with DIO2 Thr92Ala variant to influence metabolic traits.

Design and Patients: The DIO2 polymorphism was genotyped in a total of 7342 white subjects including 1405 T2D patients.

Results: We detected no significant association of the DIO2 Thr92Ala polymorphism with T2D or obesity. We observed nominal significant associations of genotype with increased area under the serum insulin curve during an oral glucose tolerance test (P = 0.03) and elevated fasting plasma glucose (P = 0.02) in homozygous Ala92 allele carriers, the latter strengthened by epistasis with the ADRB2 Gly16Arg variant in a double recessive model (P = 0.004). However, after permutation procedure, performed to correct for multiple hypothesis testing, the associations did not reach study-wide significance.

Conclusions: The DIO2 Thr92Ala variant does not confer an increased risk of T2D, obesity, or insulin resistance.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE TYPE 2 IODOTHYRONINE deiodinase (D2) catalyzes intracellular conversion of T4 to the active form of T3, allowing for tissue-specific control of T3 action independent of serum levels (reviewed in Ref. 1). In rodents, D2 is mainly expressed in brown adipose tissue (BAT). Mice with a targeted disruption of the Dio2 gene have an impaired cold-induced BAT adaptive thermogenesis and only survive by a major increase in activity of the sympathetic nervous system and induction of mechanical thermogenesis (2, 3). Furthermore, stimulation of ß-adrenergic receptors (ß-ARs) up-regulates Dio2 expression (4). These findings indicate a synergistic effect of sympathetic nervous stimulation of ß-ARs and thyroid hormone action, mediated by peripheral conversion of T4 to T3 catalyzed by D2, in regulating BAT metabolism (5).

The involvement of D2 in regulation of energy expenditure is further supported by a recent study demonstrating a novel bile acid and D2-dependent pathway, mediating high-fat diet-induced adaptive thermogenesis in rodent BAT in vivo and human skeletal muscle in vitro (6).

In humans, DIO2 is expressed in skeletal muscle (7) in which thyroid hormone is known to up-regulate the expression of the primary glucose transporter GLUT4 and thereby to increase basal and insulin-stimulated glucose uptake (8). These insights point to a role for thyroid hormone in regulation of glucose metabolism in humans (9).

A common DIO2 Thr92Ala polymorphism has been associated with a 20% lower glucose disposal rate in nondiabetic subjects and a more pronounced insulin resistance in type 2 diabetes (T2D) patients (10, 11); yet, a recent study found no association with insulin resistance or T2D (12). Additionally, association with a small, but statistically significant, increase in body mass index (BMI) in carriers of both the ADRB3 Trp64Arg and the DIO2 variants has been reported (10). Results of functional studies investigating the effect of the DIO2 Thr92Ala polymorphism on gene expression and D2 enzymatic activity have, however, been conflicting (11, 13).

Thus, given the emerging essential physiological importance of D2, the objective of this study was to investigate the DIO2 Thr92Ala polymorphism in relation to T2D, obesity, and related quantitative metabolic traits in a relatively large population-based cohort of whites. Furthermore, we hypothesized, that possible gene-gene interactions with common variation in the genes encoding ß-ARs influence quantitative metabolic traits.


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

The DIO2 Thr92Ala polymorphism was successfully genotyped in 7342 white Danish subjects comprising three study groups. The first was a population-based, randomized, nonpharmacological intervention study of middle-aged subjects for the prevention of ischemic heart disease (Inter99), conducted at the Research Centre for Prevention and Health, Glostrup (ClinicalTrials.gov; identifier: NCT00289237) (14). Of the 5942 participants (50% men), 4428 had normal glucose tolerance, 489 had impaired fasting glycemia, 678 had impaired glucose tolerance, 248 had screen-detected and treatment-naïve T2D, and 99 had previously diagnosed T2D. The second group comprised 342 unrelated and elderly subjects with normal glucose tolerance recruited at random from Copenhagen County. The third group included 1058 unrelated patients with T2D recruited at the outpatient clinic at the Steno Diabetes Center, Copenhagen. All subjects of the first and second study group underwent a standard 75-g oral glucose tolerance test (OGTT).

All T2D patients and subjects with normal glucose tolerance were included in the association study of T2D, involving a total of 1405 (60% men) cases and 4770 (46% men) control subjects. The phenotypic characteristics of the cases were: mean ± SD age at entry to the examination, 56.8 ± 10.6 yr; age at clinical diagnosis, 51.3 ± 11.2 yr; BMI, 29.6 ± 5.3 kg/m2; and HbA1C, 7.8 ± 1.7%. Diabetes was diagnosed according to the World Health Organization 1999 criteria (15). Exclusion of distinct T2D cases was performed as previously described (16). The phenotypic characteristics of the control subjects were: mean±SD age, 46.4 ± 8.8 yr; BMI, 25.5 ± 4.1 kg/m2.

The association studies of overweight and obesity, the study of quantitative metabolic traits, and the gene-gene interaction studies of metabolic traits were performed in the Inter99 cohort (study group 1), excluding patients treated for T2D.

All study participants were Danish white subjects by self-report. Informed written consent was obtained from all study participants. The studies were conducted in accordance with the Declaration of Helsinki II and were approved by the local Ethical Committee of Copenhagen.

Biochemical measures

Blood samples were drawn after a 12-h overnight fast. The HbA1C (normal range, 4.1–6.4%), plasma glucose, serum insulin, serum triglyceride, and cholesterol were measured as previously described (16).

Genotyping

Genotyping of the DIO2 Thr92Ala (rs225014), ADRB1 Gly389Arg (rs1801253), ADRB2 Gly16Arg (rs1042713), ADRB2 Gln27Glu (rs1042714), and ADRB3 Trp64Arg (rs4994) variants was conducted using chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (Sequenom, San Diego, CA) of PCR-generated primer extension products (17). The genotyping success rate was more than 97%. 451 samples were genotyped in duplicates, with a mismatch rate less than 0.4%. The distributions of genotypes for all variants were in Hardy-Weinberg equilibrium.

Statistical analysis

In case-control studies, Fisher’s exact test was used to examine differences in allele frequencies and logistic regression was used to examine differences in genotypes assuming an additive, dominant or recessive model with adjustment for sex, age, and BMI, when appropriate. A general linear model was used for testing quantitative traits in relation to genotype adjusting for the effect of sex, age, and BMI. The gene-gene interaction analyses were done using a general linear model comparing the full genetic model including interaction terms with the null model (global effect) or with a model lacking the interaction terms (epistatic effect), with adjustment for the effect of sex, age, and BMI. P < 0.05 was considered significant. Permutation testing of individual traits to obtain an empirical P value (100,000 permutations of each trait) was performed using Blossom, version 2005.08.26 (Fort Collins Science Center, Fort Collins, CO; available at http://www.fort.usgs.gov/products/software/blossom/) (18). All other analyses were performed using RGui, version 2.2.0 (The R Foundation for Statistical Computing, Vienna, Austria; available at http://www.r-project.org). To correct for multiple hypothesis testing, we used a permutation procedure for all the performed tests in which the genotypes were permuted together in each iteration. The best P value from each iteration was saved and used as an empirical null distribution to evaluate the study-wide significance (18).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
In a case-control study we found no association of DIO2 Thr92Ala genotype with T2D (Table 1Go). Likewise, assuming a dominant or a recessive model for the penetrance of Ala92 allele, no association was demonstrated (data not shown).


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  		TABLE 1. Association studies of the DIO2 Thr92Ala polymorphism with T2D and obesity in Danish white subjects

 
In an association study of obesity we observed a borderline significant difference in allele frequencies (Table 1Go). When analyzing data assuming a dominant or a recessive model for the penetrance of Ala92 allele no association with obesity was detected (data not shown).

In a study of quantitative metabolic traits including 5843 subjects we observed a significant association of the DIO2 Thr92Ala variant with elevated fasting plasma glucose and increased incremental area under the serum insulin curve during an OGTT in subjects homozygous for the Ala92 allele (Table 2Go). To ensure the robustness of the tests we performed permutation testing to obtain an empirical P value of each single trait and found permutated P values of 0.01 and 0.08, respectively. After permutation procedure, performed to correct for multiple hypothesis testing, both associations were not statistically significant at the study-wide level.


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  		TABLE 2. Quantitative metabolic traits of 5843 white Danish middle-aged subjects with normal glucose tolerance, impaired fasting glycemia, impaired glucose tolerance, or screen-detected and treatment-naïve T2D stratified according to DIO2 Thr92Ala genotype

 
As a part of our working hypothesis, we examined for a gene-gene interaction of the DIO2 Thr92Ala genotype with the ADRB1 Gly389Arg, ADRB2 Gly16Arg, ADRB2 Gln27Glu, and ADRB3 Trp64Arg variants on selected quantitative metabolic traits [fasting plasma glucose and serum insulin, incremental area under the plasma glucose and serum insulin curves during OGTT, homeostasis model assessment of insulin resistance (HOMA-IR), and BMI] in 5843 subjects. We found no significant interaction of DIO2 genotype with variants in the ADRB1 and ADRB3 genes. However, we found a putative epistatic effect of the DIO2 Thr92Ala and ADRB2 Gly16Arg variants, showing elevated fasting glycemia in DIO2 Ala92/ADRB2 Arg16 double homozygous carriers (n = 100, mean ± SE, 5.75 mmol/liter ± 0.08 vs. all other, 5.53 mmol/liter ± 0.01; P = 0.001, epistatic model: P = 0.004; global model: P = 0.005). Permutation testing of this single trait did not change the results (P < 0.005); however, after permutation procedure, which included both the single locus tests and the all tests for epistasis, the epistatic effect did not reach study-wide statistical significance (P = 0.16).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In vivo and in vitro studies give evidence of a function for the peripherally T4 to T3 converting enzyme, D2, in both cold- and diet-induced adaptive thermogenesis in rodent BAT and human skeletal muscle tissue making DIO2 a biological candidate gene for insulin resistance and disorders of energy metabolism.

Previous studies have implied a role for the DIO2 Thr92Ala polymorphism in the pathology of insulin resistance based on studies finding a 20% lower glucose disposal rate and an increased HOMA-IR index in Ala92 allele carriers in 135 nondiabetic and 183 T2D white subjects, respectively (10, 11). A recent study, however, failed to replicate these findings evaluating 747 nondiabetic Amish subjects (12). In the present study we observed a nominal significant increased area under the serum insulin curve during an OGTT in subjects homozygous for the Ala92 allele; however, after permutation testing of the single traits the association was borderline significant. Furthermore, we were unable to associate the DIO2 variant with insulin sensitivity indices (19, 20). In the present study we had a considerable statistical power to detect differences in quantitative traits, yet, it is emphasized that application of a more exact measure of insulin resistance in skeletal muscle, like the hyperinsulinemic euglycemic clamp technique, may have changed the results. Moreover, it is possible that nonreplication is due to population-specific differences in linkage disequilibrium with a yet unidentified causative variant.

In association studies of obesity, we observed a borderline significant lower Ala92 allele frequency in obese subjects compared with nonobese subjects (Table 1Go). However, this association probably represents a type I error, an interpretation enforced by the fact that the Ala92 allele associated with no other level of BMI or with quantitative measures of obesity (Table 2Go). Previous studies have not associated the DIO2 Ala92 allele with measures of obesity (10, 11, 12); yet, one study established an interaction with the ADRB3 Trp64Arg variant showing a small but statistically significant increase in BMI in combined carriers of both polymorphisms in a study of 960 nondiabetic Caucasians (10). This combined effect has, so far, not been challenged, but in the present report, we investigated this interaction in 5708 subjects, finding no evidence of association. Using simulation we estimated that the statistical power in the present study to replicate this finding was 97% assuming similar effect sizes and standard errors.

We found a putative interaction of DIO2 Thr92Ala and ADRB2 Gly16Arg genotype showing a 0.22 mmol/l increase in fasting plasma glucose in Ala92 and Arg16 allele double homozygous carriers as a result of an epistatic effect. Although this interaction is biologically plausible, the effect did not, however, reach study-wide statistical significance.

Finally, we did not detect an association of the DIO2 Thr92Ala variant with the presence of T2D (Table 1Go). Assuming a relative risk of 1.3 we had a statistical power greater than 95% to detect an association of the DIO2 Thr92Ala genotype with T2D or obesity.

Based on the present investigations performed in relatively large samples of whites, we conclude that the DIO2 Thr92Ala polymorphism does not confer an increased risk of T2D, obesity, or insulin resistance in the examined populations.


   Acknowledgments
 
The authors thank A. Forman, I.-L. Wantzin, and M. Stendal for technical assistance and G. Lademann for secretarial support. The study was supported by grants from the European Union (EUGENE2, Grant no. LSHM-CT-2004-512013), the Health Faculty of Aarhus University, the Danish Clinical Intervention Research Academy, and the Sehested Hansen Foundation.


   Footnotes
 
Disclosure Statement: M.K.A., C.H.A., A.A, T.J., J.A., O.S., T.H., and O.P. have nothing to declare. N.G. holds stock in Novo Nordisk and K.B.-J. holds stock in Novo Nordisk and has received lecture fees from a commercial sponsor.

First Published Online October 31, 2006

Abbreviations: ß-AR, ß-Adrenergic receptor; BAT, brown adipose tissue; BMI, body mass index; D2, type 2 iodothyronine deiodinase; HOMA-IR, homeostasis model assessment of insulin resistance; OGTT, oral glucose tolerance test; T2D, type 2 diabetes.

Received September 6, 2006.

Accepted October 20, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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