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Lack of Association Between the Type 2 Deiodinase A/G Polymorphism and Hypertensive Traits: The Framingham Heart Study
2008; Lippincott Williams & Wilkins; Volume: 51; Issue: 4 Linguagem: Inglês
10.1161/hypertensionaha.107.109454
ISSN1524-4563
AutoresAna Luiza Maia, Shih‐Jen Hwang, Daniel Levy, Martin G. Larson, P. Reed Larsen, Caroline S. Fox,
Tópico(s)Diet, Metabolism, and Disease
ResumoHomeHypertensionVol. 51, No. 4Lack of Association Between the Type 2 Deiodinase A/G Polymorphism and Hypertensive Traits: The Framingham Heart Study Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLack of Association Between the Type 2 Deiodinase A/G Polymorphism and Hypertensive Traits: The Framingham Heart Study Ana Luiza Maia Shih-Jen Hwang and Daniel Levy Martin G. Larson P. Reed Larsen Caroline S. Fox Ana Luiza MaiaAna Luiza Maia Thyroid Section, Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil Shih-Jen HwangShih-Jen Hwang National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, Mass, and the National Heart, Lung, and Blood Institute Center for Population Studies, Bethesda, Md and Daniel LevyDaniel Levy National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, Mass, and the National Heart, Lung, and Blood Institute Center for Population Studies, Bethesda, Md Martin G. LarsonMartin G. Larson Boston University School of Medicine, Boston, Mass P. Reed LarsenP. Reed Larsen Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass Caroline S. FoxCaroline S. Fox National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, Mass, and the National Heart, Lung, and Blood Institute Center for Population Studies, Bethesda, Md, and the Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass Originally published19 Feb 2008https://doi.org/10.1161/HYPERTENSIONAHA.107.109454Hypertension. 2008;51:e22–e23Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: February 19, 2008: Previous Version 1 To the Editor:Thyroxine (T4) activation to T3 via the iodothyronine deiodinase type 2 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 changes to alanine at codon 92, has been associated with decreased enzyme activity and higher insulin resistance in type 2 diabetes patients.1 Nevertheless, these findings were not replicated in larger studies.2 Recently, Gumieniak et al3 reported that the alanine allele doubles the risk for development of hypertension in euthyroid subjects. Pituitary and hypothalamic type 2 deiodinase play a critical role in feedback regulation of thyroid-stimulating hormone (TSH) secretion, and higher serum TSH concentrations have been demonstrated in euthyroid hypertensive compared with normotensive control subjects.4 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 present 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 and 1998 (n=2933). This study was approved by the institutional review boards of Boston University and Brigham & Women's Hospital, 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 was defined as weight (kilograms) divided by the square of height (meters). Smoking status was defined as smoking ≥1 cigarette per day in the year preceding the examination. Mean SBP and DBP over time were computed by averaging all of the available measurements together. Analysis of covariance models to assess the association between hypertensive traits with A/G single nucleotide polymorphism of the DIO2 gene were used, assuming a general genetic model. A logistic regression model was used to assess the risk of incidental hypertension cases between exams 1 to 7. Models were adjusted for age, sex, cigarette smoking, and body mass index. The genotyping of the DIO2 A/G single nucleotide polymorphism (rs225014) was performed at the Harvard Partners Genotyping Facility.3The characteristics of study participants (n=1557; 51.7% women) are presented in the Table. SBP, DBP, and hypertension status were assessed at examination cycles 1 and 7, and long-term average SBP and DBP were calculated over offspring exams 1 to 7. Two-hundred individuals (12.9%) were homozygous for the alanine allele, 749 (48.1%) were heterozygous, and 608 (39.1%) were homozygous for the threonine allele. The genotypes were in Hardy-Weinberg equilibrium and the frequency of the minor allele (0.37) similar to that described previously.2,5,6 There were no significant associations (Table; all P>0.38) for SBP, DBP, or hypertension status, either at examination cycles 1 or 7. The long-term average SBP and DBP were similar among the genotypes (P=0.84 and P=0.98, respectively). The risk of new-onset hypertension was also similar among the genotypes (138 cases; P=0.94). Table. 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 IndexCharacteristic or TraitExam 1PExam 7PAge, mean±SD, y36.6±8.9662.9±8.79Body mass index, mean±SD, kg/m225.5±4.3428.1±5.12Smokers, n (%)645 (41.5)197 (12.7)Systolic blood pressure, mean±SD, mm Hg121.1±14.70.61128.4±18.630.76Diastolic blood pressure, mean±SD, mm Hg77.9±9.970.9773.7±9.780.89Hypertension, n (%)264 (16.7)0.61402 (25.8)0.38Despite previous 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. Nevertheless, caution is recommended in the interpretation of positive associations, especially those performed in relatively small or selected population samples. In fact, Gumieniak et al3 mention the small number of individuals as a specific limitation of the earlier study. 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 Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, and all of the subjects were evaluated on their regular medications. In the study by Gumieniak et al,3 patients with severe forms of hypertension were excluded, the cutoffs 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 patients with type 2 diabetes also failed to detect an association between this DIO2 polymorphism and hypertension.5,6 The present study has several strengths. We had a 96% and 100% power to detect a 5- or 10-mm Hg difference of SBP between genotypes, respectively. All of the subjects were white, thus reducing the risk of false-positive or -negative associations because of stratification bias. However, we only tested the association of 1 single nucleotide polymorphism 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.Sources of FundingThis work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brazil) and also by the National Heart, Lung, and Blood Institute Framingham Heart Study (N01-HC-25195) and National Institutes of Health grants DK 36256 and FIC TW007559.DisclosuresNone.1 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. J Clin Endocrinol Metab. 2005; 90: 3472–3478.CrossrefMedlineGoogle Scholar2 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.CrossrefMedlineGoogle Scholar3 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: 461–466.LinkGoogle Scholar4 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: 5985–5990.CrossrefMedlineGoogle Scholar5 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.LinkGoogle Scholar6 Gumieniak O, Williams GH. Response to type 2 deiodinase Thr92Ala polymorphism is not associated with arterial hypertension in type 2 diabetes mellitus patients. Hypertension. 2007; 49: e48LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Kang Y, Koo B, Yi H, Kim J, Park B, Lee J, Shong M and Kang Y (2023) Association between DIO2 Thr92Ala polymorphism and hypertension in patients with hypothyroidism: Korean Genome and Epidemiology Study, The Korean Journal of Internal Medicine, 10.3904/kjim.2022.292, 38:2, (226-237), Online publication date: 1-Mar-2023. Luongo C, De Stefano M, Ambrosio R, Volpe F, Porcelli T, Golia V, Bellevicine C, Troncone G, Masone S, Damiano V, Matano E, Klain M, Schlumberger M and Salvatore D (2023) Type 2 Deiodinase Thr92Ala Polymorphism and Aging Are Associated with a Decreased Pituitary Sensitivity to Thyroid Hormone, Thyroid, 10.1089/thy.2022.0472 Zyara M, Hoshi B and Jubair S (2022) The impact of deiodinase type II gene on the therapeutic response to levothyroxine in a sample of Iraqi hypothyroidism patients, Gene Reports, 10.1016/j.genrep.2022.101661, 28, (101661), Online publication date: 1-Sep-2022. Kuś A, Teumer A, Chaker L and Medici M (2020) Thyroid Genetics and the Cardiovascular System Thyroid and Heart, 10.1007/978-3-030-36871-5_15, (187-202), . 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St. Germain D (2010) Thyroid Hormone Metabolism Endocrinology, 10.1016/B978-1-4160-5583-9.00075-7, (1409-1422), . Kim B and Bianco A (2009) For Some, l-Thyroxine Replacement Might Not Be Enough: A Genetic Rationale, The Journal of Clinical Endocrinology & Metabolism, 10.1210/jc.2009-0410, 94:5, (1521-1523), Online publication date: 1-May-2009. Gereben B, Zavacki A, Ribich S, Kim B, Huang S, Simonides W, Zeöld A and Bianco A (2008) Cellular and Molecular Basis of Deiodinase-Regulated Thyroid Hormone Signaling1, Endocrine Reviews, 10.1210/er.2008-0019, 29:7, (898-938), Online publication date: 1-Dec-2008. April 2008Vol 51, Issue 4 Advertisement Article InformationMetrics https://doi.org/10.1161/HYPERTENSIONAHA.107.109454PMID: 18285610 Originally publishedFebruary 19, 2008 PDF download Advertisement SubjectsGenetics
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