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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Hypertension. Author manuscript; available in PMC 2011 January 3.
Published in final edited form as:
PMCID: PMC3014057

Lack of Association between the Type 2 Deiodinase Thr92Ala Polymorphism and Hypertensive Traits: the Framingham Heart Study

To the editor

Thyroxine (T4) activation to T3 via the iodothyronine deiodinase type 2 (D2) allows for changes in intracellular thyroid status in a tissue specific manner independent of serum T3. A single nucleotide polymorphism in Type 2 deodinase (Dio2) gene (A/G) in humans, in which a threonine (Thr) changes to alanine (Ala) at codon 92, has been associated with a lower glucose disposal rate and higher insulin resistance in type 2 diabetes (DM2) patients (1, 2). Nevertheless, these findings were not replicated in a larger studies (3, 4). Recently, Gumieniak et al. (5) reported that the Ala allele doubles the risk for development of hypertension in euthyroid subjects. Pituitary and hypothalamic D2 plays a critical role in feedback regulation of TSH secretion (6) and higher serum TSH concentrations have been previously demonstrated in euthyroid hypertensive compared with normotensive control subjects (7). In this context, we thought it would be of interest to evaluate whether the previous reported association of Thr92Ala polymorphism and hypertension is also present in a large unselected community-based population.

The current sample size consists of 1557 individuals who had complete phenotype and genotype information available drawn from a subset of unrelated individuals from the Framingham Heart Study offspring cohort who had DNA collected between 1995–1998 (n=2933). This study was approved by the Boston University and Brigham & Women’s Institutional Review Boards and written informed consent was obtained from each subject. At each examination, blood pressure was measured twice in the left arm by an examining physician using a mercury column sphygmomanometer (Korotkoff phases I and V) after the subject had been at rest in the seated position for 5 minutes. Hypertension was defined as a systolic blood pressure (SBP) of ≥ 140 mm Hg or a diastolic blood pressure (DBP) of ≥ 90 mm Hg, or those who were receiving antihypertensive therapy at the time of the examination. Body mass index (BMI) was defined as weight (kilograms) divided by the square of height (meters). Smoking status was defined as smoking 1 or more cigarettes per day in the year preceding the examination. Mean SBP and DBP over time was computed by averaging all available measurements together. Analysis of covariance models to assess the association between hypertensive traits with A/G SNP of the DIO2 gene were used, assuming a general genetic model. Models were adjusted for age, sex, cigarette smoking, and body mass index. The genotyping of the DIO2 A/G SNP (rs225014) was performed at the Harvard Partners Genotyping Facility (3).

The characteristics of study participants (n=1557, 51.7% women) are presented in Table 1. SBP, DBP, and hypertension status were assessed at 1st and 7th examination cycles and long-term average SBP and DBP were calculated over offspring exams 1–7. Two hundred individuals (12.9%) were homozygous for the Ala allele (Ala/Ala), 749 (48.1%) were heterozygous (Ala/Thr), and 608 (39.1%) were homozygous for the Thr allele (Thr/Thr). The genotypes were in Hardy-Weinberg equilibrium and the frequency of the minor allele (0.37) similar to that previously described (2, 5). There were no significant associations (Table 1; all p>0.38) for SBP, DBP, or hypertension status, either at the 1st or 7th examination cycles. The long-term average SBP and DBP were also similar among the genotypes (p=0.84 and p=0.98, respectively).

Table 1
Characteristics of individuals who had complete phenotype and DIO2 genotype information and P-values for blood pressure-related traits derived from a general genetic model, adjusted for age, sex, cigarette smoking, and body mass index.

Despite prior data from the studies suggesting an association, we failed to demonstrate any significant association between hypertensive traits with the variant allele. Association studies offer a potentially powerful approach to identify genetic variants that influence susceptibility to common diseases (8). Nevertheless, caution is recommended in the interpretation of positive associations, especially those performed in relatively small or selected population samples. In fact, Gumieniak et al mention the small number of individuals as a specific limitation of the earlier study (5). To minimize such effect, it has been proposed that genetic association studies should include a large number of unselected participants, such as the present study. Another potential explanation for these apparently discrepant results refers to the definition of hypertension. Our definition of hypertension coincides with the definitions used in the JNC7 guidelines and all subjects were evaluated on their regular medications. In Gumieniak’s study (5), patients with severe forms of hypertension were excluded, the cut-offs for hypertension were different from the usual, and antihypertensive medications were suspended for 2 to 4 weeks. Of note, another study performed in a sample of 315 type 2 diabetes patients also failed to detect an association between this DIO2 polymorphism and hypertension (9). The present study has several strengths. We had adequate power to detect modest differences between genotypes. All subjects were Caucasians, thus reducing the risk of false positive or negative associations due to stratification bias. However, we only tested the association of one SNP in the DIO2 gene. It is possible that additional untested variants in this gene are associated with hypertension traits. Therefore, this study cannot rule out the DIO2 gene as a susceptibility gene for hypertension. In conclusion, the Dio2 Thr92Ala polymorphism is not associated with hypertensive traits in an unselected community-based population.


Grant support: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil.


1. Mentuccia D, Proietti-Pannunzi L, Tanner K, Bacci V, Pollin TI, Poehlman ET, Shuldiner AR, Celi FS. Association between a novel variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance: evidence of interaction with the Trp64Arg variant of the beta-3-adrenergic receptor. Diabetes. 2002;51:880–3. [PubMed]
2. Canani LH, Capp C, Dora JM, Meyer EL, Wagner MS, Harney JW, Larsen PR, Gross JL, Bianco AC, Maia AL. The Type 2 Deiodinase A/G (Thr92Ala) Polymorphism is associated with Decreased Enzyme Velocity and Increased Insulin Resistance in Patients with Type 2 Diabetes Mellitus. Journal of Clinical Endocrinology and Metabolism. 2005;90:3472–8. [PubMed]
3. Maia AL, Dupuis J, Manning A, Liu C, Meigs JB, Cupples LA, Larsen PR, Fox CS. The type 2 deiodinase (DIO2) A/G polymorphism is not associated with glycemic traits: the Framingham Heart Study. Thyroid. 2007;17:199–202. [PubMed]
4. Grarup N, Andersen MK, Andreasen CH, Albrechtsen A, Borch-Johnsen K, Jorgensen T, Auwerx J, Schmitz O, Hansen T, Pedersen O. Studies of the common DIO2 Thr92Ala polymorphism and metabolic phenotypes in 7342 Danish white subjects. J Clin Endocrinol Metab. 2007;92:363–6. [PubMed]
5. Gumieniak O, Perlstein TS, Williams JS, Hopkins PN, Brown NJ, Raby BA, Williams GH. Ala92 type 2 deiodinase allele increases risk for the development of hypertension. Hypertension. 2007;49:461–6. [PubMed]
6. Christoffolete MA, Ribeiro R, Singru P, Fekete C, da Silva WS, Gordon DF, Huang SA, Crescenzi A, Harney JW, Ridgway EC, Larsen PR, Lechan RM, Bianco AC. Atypical expression of type 2 iodothyronine deiodinase in thyrotrophs explains the thyroxine-mediated pituitary thyrotropin feedback mechanism. Endocrinology. 2006;147:1735–43. [PubMed]
7. Gumieniak O, Hurwitz S, Perlstein TS, Ngumezi UC, Hopkins PN, Jeunemaitre X, Williams GH. Aggregation of high-normal thyroid-stimulating hormone in hypertensive families. J Clin Endocrinol Metab. 2005;90:5985–90. [PubMed]
8. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003;33:177–82. [PubMed]
9. Canani LH, Leie MA, Machado WE, Capp C, Maia AL. Type 2 deiodinase Thr92Ala polymorphism is not associated with arterial hypertension in type 2 diabetes mellitus patients. Hypertension. 2007;49:e47. author reply e48. [PubMed]