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Genetics and Epigenetics

Thyroid hormone receptor alpha gene variants increase the risk of developing obesity and show gene–diet interactions



Thyroid hormone receptor-beta resistance has been associated with metabolic traits. THRA gene sequencing of an obese woman (index case) who presented as empirical thyroid hormone receptor-α (THRA) resistance, disclosed a polymorphism (rs12939700) in a critical region involved in TRα alternative processing.

Design and subjects:

THRA gene variants were evaluated in three independent europid populations (i) in two population cohorts at baseline (n=3417 and n=2265), 6 years later (n=2139) and (ii) in 4734 high cardiovascular risk subjects (HCVR, PREDIMED trial).


The minor allele of the index case polymorphism (rs12939700), despite having a very low frequency (4%), was significantly associated with higher body mass index (BMI) (P=0.042) in HCVR subjects. A more frequent THRA polymorphism (rs1568400) was associated with higher BMI in subjects from the population (P=0.00008 and P=0.05) after adjusting for several confounders. Rs1568400 was also strongly associated with fasting triglycerides (P dominant=3.99 × 10−5). In the same sample, 6 years later, age and sex-adjusted risk of developing obesity was significantly increased in GG homozygotes (odds ratio 2.93 (95% confidence interval, 1.05–6.95)). In contrast, no association between rs1568400 and BMI was observed in HCVR subjects, in whom obesity was highly prevalent. This might be explained by the presence of an interaction (P <0.001) among the rs1568400 variant, BMI and saturated fat intake. Only when saturated fat intake was high (>24.5 g d−1), GG carriers showed a significantly higher BMI than A carriers after controlling for energy intake and physical activity.


THRA gene polymorphisms are associated with obesity development. This is a novel observation linking the THRA locus to metabolic phenotypes.

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We greatly appreciate the technical assistance of Gerard Pardo and Oscar Rovira (Unit of Diabetes, Endocrinology and Nutrition. Institut d’Investigació Biomèdica de Girona, Hospital Universitari de Girona Dr Josep Trueta). JMM was supported by Sara Borrell fellowship from the Instituto de Salud Carlos III. This work was supported by research grants from the Ministerio de Educación y Ciencia (MEC) (SAF2008-02073 and PI070954), the Instituto de Salud Carlos III (CIBERobn) and Consejería de Salud Junta de Andalucía (PI-0327-2010). JMM was supported by Sara Borrell Fellowship from the Instituto Carlos III. CIBERobn de Fisiopatología de la Obesidad y Nutrición and CIBER de Diabetes y Enfermedades Metabólicas Asociadas are ISCIII projects. Funding was also obtained from the Commission’s Sixth Framework Program (CRESCENDO consortium, integrated project LSHM-CT-2005-018652), ANR GENOPAT (2008-P006850) and INSERM. The French arm of the World Health Organization-MONICA population study was funded by grants from the Conseil Régional du Nord-Pas de Calais, the Caisse Primaire d’Assurance Maladie de Sélestat, the Association Régionale de Cardiologie d’Alsace, ONIVINS, Parke-Davis, the Mutuelle Générale de l’Education Nationale (MGEN), the Réseau National de Santé Publique, the Direction Générale de la Santé, the INSERM, the Institut Pasteur de Lille and the Unité d’Evaluation du Center Hospitalier et Universitaire de Lille, and to the THRA study group for their help in recruitment of subjects (Enrique Gómez-Gracia (University of Málaga, Málaga, Spain), Miguel Fiol (University Institute for Health Sciences Investigation, Palma de Mallorca, Spain), Fernando Arós (Hospital Txagorritxu, Vitoria, Spain), José Lapetra (San Pablo Health Center, Sevilla, Spain), Luis Serra-Majem (Las Palmas University, Las Palmas, Spain, Xavier Pintó (Hospital de Bellvitge, Hospitales de Llobregat, Spain), Carolina Ortega-Azorín and María Arregui (Genetic and Molecular Epidemiology Unit. Department of Preventive Medicine. University of Valencia, Valencia, Spain)).

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Correspondence to J M Fernández-Real.

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RE researched data and contributed to discussion; DC, LG, JMM, SV, GRM, FO, JMG-Z, JS-S, MIC, ER, MS-R, FS researched data; M-TM-L, MAMG, PB, ED, DC, JF, PA, WR, AM: contributed to discussion and JMF-R: researched data and wrote the manuscript.

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Fernández-Real, J., Corella, D., Goumidi, L. et al. Thyroid hormone receptor alpha gene variants increase the risk of developing obesity and show gene–diet interactions. Int J Obes 37, 1499–1505 (2013).

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  • Thyroid hormone receptors
  • genetics
  • polymorphisms.

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