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Right arrow Thyroid
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 2 636-640
Copyright © 2007 by The Endocrine Society

The Association of Polymorphisms in the Type 1 and 2 Deiodinase Genes with Circulating Thyroid Hormone Parameters and Atrophy of the Medial Temporal Lobe

Frank Jan de Jong, Robin P. Peeters, Tom den Heijer, Wendy M. van der Deure, Albert Hofman, André G. Uitterlinden, Theo J. Visser and Monique M. B. Breteler

Departments of Epidemiology and Biostatistics (F.J.d.J., T.d.H., A.H., A.G.U., M.M.B.B.), Neurology (F.J.d.J., T.d.H.), Internal Medicine (R.P.P., W.M.v.d.D., A.G.U., T.J.V.), and Clinical Chemistry (A.G.U.), Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. Monique M. B. Breteler, Department of Epidemiology, Biostatistics, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands. E-mail: m.breteler{at}erasmusmc.nl.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Thyroid function has been related to Alzheimer disease (AD) and neuroimaging markers thereof. Whether thyroid dysfunction contributes to or results from developing AD remains unclear. Variations in the deiodinase type 1 (DIO1) and type 2 (DIO2) genes that potentially alter thyroid hormone bioactivity may help in elucidating the role of thyroid function in AD.

Objective: We investigated the association of recently identified polymorphisms in the DIO1 (D1a-C/T, D1b-A/G) and DIO2 (D2-ORFa-Gly3Asp, D2-Thr92Ala) genes with circulating thyroid parameters and early neuroimaging markers of AD.

Design and Participants: The Rotterdam Scan Study is a population-based cohort study among 1,077 elderly individuals aged 60–90 yr.

Main Outcome Measures: DIO1 and DIO2 polymorphisms and serum TSH, free T4, T3, and reverse T3 (rT3) levels were determined in 995 nondemented elderly, including 473 persons with assessments of hippocampal and amygdalar volume on brain magnetic resonance imaging.

Results: Carriers of the D1a-T allele had higher serum free T4 and rT3, lower T3, and lower T3/rT3. The D1b-G allele was associated with higher serum T3 and T3/rT3. The DIO2 variants were not associated with serum thyroid parameters. No associations were found with hippocampal or amygdalar volume.

Conclusion: This is the first study to report an association of D1a-C/T and D1b-A/G polymorphisms with iodothyronine levels in the elderly. Polymorphisms in the DIO1 and DIO2 genes are not associated with early magnetic resonance imaging markers of AD. This suggests that the previously reported association between iodothyronine levels and brain atrophy reflects comorbidity or nonthyroidal illness rather than thyroid hormones being involved in developing AD.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THYROID DISORDERS ARE associated with cognitive impairment and dementia (1). Whether thyroid dysfunction also contributes to developing Alzheimer disease (AD) remains unclear. Within the Rotterdam Study we found subclinical hyperthyroidism to increase the risk of dementia and AD over 3-fold in a 2-yr period (2). Recently, we reported higher serum free T4 (fT4) levels within the normal range to be associated with hippocampal and amygdalar atrophy, putative early markers of AD (3), on brain magnetic resonance imaging (MRI) of nondemented elderly (4). This suggests that hyperthyroidism contributes to the development of AD. Alternatively, thyroid dysfunction may result from AD because both rT3 and T3/rT3, indicators of nonthyroidal illness (5), were also associated with brain atrophy on MRI (4).

Genetic factors could determine up to 65% of the variation in serum thyroid hormone levels in healthy subjects (6). Therefore, genetic variation in thyroid hormone pathway genes may help to elucidate the role of thyroid hormone bioactivity in AD. The peripheral metabolism of thyroid hormone is regulated by three different deiodinases (D1–D3) (7). D1 is present in the thyroid, liver, and kidneys and is involved in serum T3 production and rT3 clearance. D2 catalyzes local T3 production in several tissues. In the brain, D2 is expressed mainly in astrocytes in various structures including the cerebral cortex, hippocampus, and amygdala (8). D3 regulates T3 and T4 clearance. Variants in both the deiodinase type 1 (DIO1) and type 2 (DIO2) genes were recently reported to alter thyroid hormone levels in healthy blood donors (9, 10). Carriers of the T allele of the D1a-C/T polymorphism had higher serum rT3 levels and lower T3/rT3, whereas the G allele of the D1b-A/G polymorphism was associated with higher T3/rT3 (9). Carriers of the D2-ORFa-Asp3 allele had lower T4, fT4, and rT3 levels and a higher T3 to T4 ratio (10). The D2-Thr92Ala polymorphism has been associated with insulin resistance in different populations (11, 12), but not with serum thyroid levels (10).

The association of variants in the DIO1 and DIO2 genes with serum thyroid hormone levels has not been replicated thus far. Neither the DIO1 nor the DIO2 polymorphisms have been studied with respect to hippocampal and amygdalar volume on MRI. The aim of this study was to investigate the association of the D1a-C/T, D1b-A/G, D2-ORFA-Gly3Asp, and D2-Thr92Ala polymorphisms with serum thyroid parameters, and putative early MRI markers of AD in a population of nondemented elderly of Caucasian origin.


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

This study was based on the Rotterdam Scan Study, an ongoing prospective population-based cohort study designed to study causes and consequences of age-related brain changes on MRI (13). In 1995 and 1996, subjects were randomly selected in strata of age (5 yr, 60–90 yr) and sex from the population-based Zoetermeer and Rotterdam studies (14, 15). As part of the eligibility criteria, subjects who were demented, blind, or had MRI contraindications at time of selection were excluded. Complete information, including MRI of the brain, was obtained in 1077 subjects (overall response 63%). Participants originating from the Rotterdam Study underwent an additional three-dimensional (3D) MRI sequence during the scanning protocol, which allowed volumetric assessment of the hippocampus and amygdala (n = 511). The Rotterdam Scan Study was conducted in accordance with the tenets of the Declaration of Helsinki. The Medical Ethics Committee of the Erasmus University approved the study and written informed consent was obtained from all participants.

Thyroid hormone assessments

Nonfasting blood samples were collected at time of MRI, and within 30 min, serum was separated and stored at –80 C. TSH, fT4, and T3 were measured by chemoluminescence assays (Vitros ECI Immunodiagnostic System, Ortho-clinical Diagnostics; Amersham, Rochester, NY). rT3 was measured with an in-house RIA (16). Reference ranges were 0.4–4.3 µU/dl for TSH, 0.85–1.94 ng/dl for fT4, 92.8–162.9 ng/dl for T3, and 9.1–22.1 ng/dl for rT3. Complete thyroid hormone assessments were available for 1047 persons.

Hippocampal and amygdalar volume

In the 511 participants with a volumetric MRI sequence, coronal brain slices (contiguous 1.5-mm slices) were reformatted from the 3D MRI sequence and aligned to be perpendicular to the long axis of the hippocampus. The procedure of segmenting the hippocampus and amygdala has been described (17). The left and right hippocampus and amygdala were manually outlined on each slice with a mouse-driven pointer. The areas on each side were multiplied with slice thickness, and left and right side were summed to yield estimates of absolute volume (milliliters). As a proxy for head size, we measured midsagittal area (square centimeters) by tracing the inner skull on a reformatted middle sagittal area MRI slice. Head size differences across individuals were corrected for by dividing the uncorrected volumes by the calculated head size area of the subject and subsequently multiplying this ratio by the average head size area (men and women separately) (18). Hippocampal and amygdalar volume in this nondemented population ranged from 4.21–9.29 ml for hippocampal volume and from 2.17–6.77 ml for amygdalar volume.

Genotyping

Genomic DNA was extracted from peripheral leukocytes according to standard procedures. One to 2 ng genomic DNA was dispensed into 384-well plates using a Caliper Sciclone ALH3000 pipetting robot (Caliper LS, Mountain View, CA). Genotypes were determined using the TaqMan allelic discrimination assay. The Assay-by-Design service (Applied Biosystems) was used to set up a TaqMan allelic discrimination assay for the the D1a-C/T (rs11206244) and D1b-G/T (rs12095080) polymorphisms in the DIO1 gene (9) and the ORFa-Gly3Asp (rs12885300) (10) and Thr92Ala (rs2250114) polymorphisms in the DIO2 gene. The PCR mixture included 2 ng of genomic DNA in a 2-µl volume and the following reagents: FAM and VIC probes (200 nM), primers (0.9 µM), 2x TaqMan PCR master mix (ABgene, Epsom, UK). Reagents were dispensed in a 384-well plate using the Deerac Equator NS808 (Deerac Fluidics, Dublin, Ireland). PCR cycling reactions were performed in 384-well PCR plates in an ABI 9700 PCR system (Applied Biosystems Inc., Foster City, CA) and consisted of initial denaturation for 15 min at 95 C and 40 cycles with denaturation of 15 sec at 95 C and annealing and extension for 60 sec at 60 C. Results were analyzed by the ABI TaqMan 7900HT using the sequence detection system 2.22 software (Applied Biosystems Inc.). Genotyping of the four DIO1 and DIO2 polymorphisms succeeded in 1018 persons in whom also thyroid hormone assessments were available.

Covariates

Several variables may confound an association of DIO1 and DIO2 polymorphisms with either thyroid hormone levels or measures of brain atrophy, such as age at time of thyroid assessment, sex, educational level, depressive symptoms, smoking habits, medication use, atrial fibrillation, diabetes mellitus, body mass index (calculated as weight in kilograms divided by height in meters squared), cholesterol, creatinine, and homocysteine levels. Educational status was defined as the highest education according to the United Nations Educational, Scientific, and Cultural Organization and dichotomized into primary education only, and more than primary education (19). Depressive symptoms were assessed with a validated Dutch version of the Center for Epidemiologic Studies Depression scale (20). Smoking status was categorized into current, former, and never smoking. We included reported use of cardiac medication (including amiodarone), ß-blocking agents, and systemic use of corticosteroids (Anatomical Therapeutical Chemical codes c01, c07, and h02). Presence of atrial fibrillation was based on analysis of digitally stored standard 12-lead electrocardiograms using the Modular Electrocardiogram Analysis System (21). Diabetes mellitus was defined as reported use of oral antidiabetic treatment or insulin, or a random serum glucose concentration greater than or equal to 202 ng/dl. Serum total and high-density lipoprotein cholesterol, creatinine, and glucose levels were determined using an automated enzymatic procedure. Homocysteine levels were determined by a fluorescence polarization immunoassay (22).

Statistical analysis

Deviation from Hardy-Weinberg proportions was analyzed using a {chi}2 test. Analysis of covariance was used to compute age- and sex-adjusted means of serum TSH and iodothyronine levels within the D1 and D2 genotype groups. In the subset with MRI measures of brain atrophy, analyses of covariance were used to compute age- and sex-adjusted means of hippocampal and amygdalar volumes on MRI within genotype. In addition, the genotype was entered as a linear term in the models to yield P values of the allele-dose trend. All analyses were performed with exclusion of persons who used thyromimetic or thyrostatic medication: n = 23 in the overall analyses and n = 10 in the analyses on brain volume, leaving 995 persons for the overall analyses and 473 persons for the analyses on brain volume. All models were additionally adjusted for the other covariates. All statistical analyses were performed using SPSS statistical software version 11 (SPSS Inc., Chicago, IL). Linkage disequilibrium for the polymorphisms was quantified by r2 values calculated with the Haploview Program (23).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Genotype distributions were similar in the overall study population and the subset with measures of brain atrophy on MRI (Table 1Go) and were all in Hardy Weinberg equilibrium. Baseline characteristics for the overall study sample and the subset with measures of brain atrophy on MRI are shown in Table 2Go.


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  		TABLE 1. Polymorphisms in the DIO1 and DIO2 genes in the study sample in total and in the subset with hippocampal and amygdalar volumes

 

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  		TABLE 2. Characteristics of the study sample in total and of the subset with hippocampal and amygdalar volumes

 
Table 3Go presents the associations of the DIO1 polymorphisms with serum TSH and iodothyronine levels. The D1a-T allele was associated with higher rT3 and lower T3 levels and a lower T3 to rT3 ratio. fT4 levels were also higher in carriers of the D1a-T allele. The D1b-G allele of the D1b-A/G variant was related to higher T3 levels and a higher T3 to rT3 ratio. No effect of the D2-ORFa-Gly3Asp and D2-Thr92Ala polymorphisms was seen on serum thyroid hormone levels (Table 4Go). Additional adjustment for potential other confounders did not change the associations between the DIO1 and DIO2 polymorphisms and TSH or iodothyronine levels. The associations were similar in the subset with measures of brain atrophy on MRI when compared with the overall study sample.


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  		TABLE 3. Association of serum TSH and iodothyronine levels with the D1a-C/T and D1b-A/G variants (n = 995)

 

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  		TABLE 4. Association of serum TSH and iodothyronine levels with the D2-ORFa-Gly3Asp and D2-Thr92Ala variants (n = 995)

 
Neither the D1a-C/T, nor the D1b-A/G polymorphism was associated with hippocampal or amygdalar volume on MRI (Table 5Go). Nor did we find a relation of the D2-ORFa-Gly3Asp and D2-Thr92Ala polymorphisms with brain volume on MRI (Table 6Go). Additional adjustments did not change the results.


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  		TABLE 5. Association of the D1a-C/T and D1b-A/G variants with brain volume on MRI (n = 473)

 

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  		TABLE 6. Association of the D2-ORFa-Gly3Asp and D2-Thr92Ala variants with brain volume on MRI (n = 473)

 
Linkage analysis for the D1a-C/T and the D1b-A/G polymorphisms using the Haploview program showed a r2 value of 0.06, which is low. In a similar manner, we found a r2 value of 0.22 for linkage between the D2-ORFa-Gly3Asp and the D2-Thr92Ala polymorphism. Haplotype analyses are not meaningful when the r2 is this low and, therefore, were not performed.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We found, in a population-based study among elderly Caucasian individuals, that the D1a-C/T polymorphism was associated with both serum iodothyronine levels and the T3 to rT3 ratio. The D1b-A/G variant was related to serum T3 and the T3 to rT3 ratio. The D2-ORFa-Gly3Asp and D2-Thr92Ala polymorphisms were not related to circulating thyroid parameters. Both the polymorphisms in the DIO1 and those in the DIO2 gene were not associated with early MRI markers of Alzheimer pathology.

Strengths of this study are its population-based setting and large number of volumetric assessments on MRI. Potential limitations of genetic association studies are related to population stratification or heterogeneity, which is of particular importance in case-control studies and in persons of mixed racial origin. In our study, this has played no role because all subjects were of Dutch Caucasian origin and can be considered ethnically homogeneous. In addition, allele frequencies of the polymorphisms were in agreement with those reported in other Caucasian subjects (9, 10). Although the polymorphisms were associated with thyroid hormone levels, no association was found with hippocampal and amygdalar volume. Because volumetric measures were only available in half of our sample, this has limited our power to find an association. The 3D sequence necessary to obtain volumetric measures of the hippocampus and amygdala could only be added in participants originating from the Rotterdam Study. Because this was due to logistic reasons and not related to clinical characteristics of the participants, this makes selection bias unlikely. However, larger series with more power are needed to verify and replicate our findings. The relatively small number of subjects that developed dementia during follow-up of the study (n = 62, follow-up until January 2005) limited our abilities to investigate the association of variants in the DIO1 and DIO2 genes with risk of dementia.

Previous reports suggest that the D1a-T and D1b-G variants in the DIO1 gene are associated with altered D1 activity (9, 10, 11, 12). Because liver D1 plays an important role in the production of serum T3 from T4 and in the breakdown of the metabolite rT3, functionally relevant variants in the DIO1 gene are expected to affect serum iodothyronine levels, in particular rT3 and ratios between serum iodothyronines (7). Peeters et al. (9) analyzed 156 healthy blood donors and reported higher serum levels of rT3 and a lower T3 to rT3 ratio in those carrying the D1a-T allele. Both associations were confirmed in this elderly population. In agreement with these findings, we found carriers of the D1a-T allele to have lower serum levels of T3 altogether, suggesting a negative effect of the D1a-T variant on total D1 activity. The higher fT4 levels in carriers of the D1a-T allele may reflect a lower conversion to T3 by D1 in these subjects.

Because carriers of the D1b-G allele were reported to have a higher serum T3 to rT3 ratio, the D1b-G allele was suggested to increase total D1 activity (9), which is strengthened by findings from our study showing D1b-G carriers to have both higher serum levels of T3 and a higher ratio of serum T3 to rT3.

No effect of either of the two polymorphisms in the DIO2 gene was seen on thyroid hormone levels in this elderly population. Whereas the D2-Thr92Ala variant was not associated with serum thyroid hormone levels in previous studies (9, 10, 12), the D2ORFa-Gly3Asp variant was, yet only in healthy blood bank donors and not in elderly subjects (10). Therefore, our results are in agreement with previous studies. However, an effect of these variants on local thyroid hormone bioactivity cannot be excluded because D2 is mainly involved in the conversion of T4 to T3 at the tissue level.

Recently, we reported hippocampal and amygdalar volume to be associated with higher serum levels of fT4, rT3 and a lower T3 to rT3 ratio in nondemented elderly (4). Due to the cross-sectional design of the study, it could not be determined whether higher thyroid hormone levels were involved in the development of brain atrophy or resulted from neurodegeneration. Using data from the same study population, we report in this study that both the D1a-C/T and the D1b-A/G variants were related to iodothyronine levels and the T3 to rT3 ratio. If thyroid hormone levels were causally related to hippocampal and amygdalar atrophy, one would expect an association of these polymorphisms in the DIO1 gene, altering lifetime exposure to T3 and rT3 levels, with these measures of brain atrophy on MRI. The lack of such a relation suggests that the higher serum levels of rT3 in those with more marked brain atrophy reflects comorbidity or nonthyroidal illness in the elderly, rather than thyroid function being causally involved in the development of brain atrophy related to AD. The observation that polymorphisms in the DIO2 gene also were not related to early brain markers for AD, further argues against an important role of thyroid function in the development of brain atrophy and AD, because D2 is highly expressed in the brain, especially in the hippocampus and amygdala (8).

Other mechanisms should be considered. First, thyroid hormone concentrations are tightly regulated in the brain (24). Whereas D2 is important for maintaining adequate levels of T3, D3 preserves the brain from detrimental T3 levels by converting T4 to rT3. After treating rats for 8 wk with a high dose of T4, T3 concentrations appeared unaltered in cortex, hippocampus, and amygdala (25), and were elevated only in brain areas in which D3 activity was low or absent. Although comparative data based on studies in humans is lacking, this could suggest that the potential effects of D2 polymorphisms may have been counterbalanced by increased D3 activity. Second, somatic alterations of DIO2 potentially alter the peripheral thyroid hormone milieu, which in turn could contribute to the development of AD. Finally, it is also possible that thyroid hormones contribute to the rate of progression of brain atrophy and subsequently AD, rather than being a cause.

In conclusion, this is the first study to report an association of the D1a-C/T and D1b-A/G variants in the DIO1 gene with serum iodothyronine levels in the elderly. The absence of a relation between genetically determined bioactivity of thyroid hormones and early brain imaging markers for AD suggests that the previously described association between thyroid hormones and brain atrophy on MRI reflects comorbidity or nonthyroidal illness in the elderly, rather than thyroid hormones being involved in developing AD.


   Acknowledgments
 
We thank Hans van Toor for carrying out the thyroid hormone measurements. We thank Pascal Arp for help with the polymorphism analyses. We also gratefully acknowledge the staff of the Rotterdam Study center and the cooperating general practitioners in Ommoord and Zoetermeer for their assistance in the data collection.


   Footnotes
 
This work was supported by the International Foundation of Alzheimer Research (ISAO Grant 01500) and the Netherlands Organization for Health Research and Development (ZonMW, Grant 904-61-155).

Disclosure Statement: F.J.d.J., R.P.P., T.d.H., W.M.v.d.D., A.H., A.G.U., T.J.V., and M.M.B.B. have nothing to declare.

First Published Online November 14, 2006

Abbreviations: AD, Alzheimer disease; 3D, three-dimensional; DIO1, deiodinase type 1; DIO2, deiodinase type 2; fT4, free T4; MRI, magnetic resonance imaging.

Received June 21, 2006.

Accepted November 3, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals