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

• Published in: International Journal of Obesity 2013-11, Vol.37 (11), p.1499-1505
• Main Authors: Fernández-Real, J M, Corella, D, Goumidi, L, Mercader, J M, Valdés, S, Rojo Martínez, G, Ortega, F, Martinez-Larrad, M-T, Gómez-Zumaquero, J M, Salas-Salvadó, J, Martinez González, M A, Covas, M I, Botas, P, Delgado, E, Cottel, D, Ferrieres, J, Amouyel, P, Ricart, W, Ros, E, Meirhaeghe, A, Serrano-Rios, M, Soriguer, F, Estruch, R
• Format: Article
• Language: English
• Subjects: 631/208/2489/144; 631/80/86/2363; 692/699/2743/393; Adult; Biological and medical sciences; Body Mass Index; Cardiovascular Diseases - genetics; Cross-Sectional Studies; Development and progression; Diabetes; Dietary Fats; Endocrinology; Energy; Energy Intake; Epidemiology; Exercise; Female; France; Genetic aspects; Genetic Predisposition to Disease; Genetic variation; Health aspects; Health care; Health Promotion and Disease Prevention; Health risks; Heterozygote; Humans; Hypothyroidism - genetics; Hypothyroidism - metabolism; Insulin Resistance - genetics; Internal Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Middle Aged; Nutrition research; Obesity; Obesity - etiology; Obesity - genetics; Obesity - metabolism; original-article; Physiological aspects; Polymorphism; Polymorphism, Single Nucleotide; Preventive medicine; Public Health; Risk Factors; Spain; Thermogenesis; Thyroid; Thyroid gland; Thyroid Hormone Receptors alpha - genetics; Thyroid Hormone Receptors alpha - metabolism; Thyroid hormones
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2013.11

Objective: 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). Results: 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 24.5 g d −1 ), GG carriers showed a significantly higher BMI than A carriers after controlling for energy intake and physical activity. Conclusions: THRA gene polymorphisms are associated with obesity development. This is a novel observation linking the THRA locus to metabolic phenotypes.