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

Int J Obes (Lond). 2013 Nov;37(11):1499-505. doi: 10.1038/ijo.2013.11. Epub 2013 Feb 12.


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 <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.

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

Publication types

  • Case Reports
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Body Mass Index
  • Cardiovascular Diseases / genetics
  • Cross-Sectional Studies
  • Dietary Fats
  • Energy Intake
  • Female
  • France
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Hypothyroidism / genetics*
  • Hypothyroidism / metabolism
  • Insulin Resistance / genetics*
  • Male
  • Middle Aged
  • Obesity / etiology
  • Obesity / genetics*
  • Obesity / metabolism
  • Polymorphism, Single Nucleotide*
  • Risk Factors
  • Spain
  • Thyroid Hormone Receptors alpha / genetics*
  • Thyroid Hormone Receptors alpha / metabolism


  • Dietary Fats
  • Thyroid Hormone Receptors alpha