Paradoxical relationship between body mass index and thyroid hormone levels: a study using Mendelian Randomization

CONTEXT: Free tri-iodothyronine (FT3) has been positively associated with body mass index (BMI) in cross-sectional studies in healthy individuals. This is difficult to reconcile with clinical findings in pathological thyroid dysfunction.

OBJECTIVE: We aimed to investigate whether childhood adiposity influences FT3 levels.

DESIGN: Mendelian randomization using genetic variants robustly associated with BMI.

SETTING: Avon Longitudinal Study of Parents and Children, a population-based birth cohort.

PARTICIPANTS: 3,014 children who had thyroid function measured at age 7, who also underwent DXA scans at ages 9.9 and 15.5 years and have genetic data available.

MAIN OUTCOME MEASURES: FT3.

RESULTS: Observationally at age 7 years, BMI was positively associated with FT3: β standardized (std)=0.12 (95%CI: 0.08, 0.16) p=4.02x10(-10) whereas FT4 was negatively associated with BMI: β (std)=-0.08 (95%CI: -0.12, -0.04) p=3.00x10(-5). These differences persisted after adjustment for age, sex and early life environment. Genetic analysis indicated a one allele change in BMI allelic score was associated with a 0.04 (95%CI: 0.03, 0.04) standard deviation increase in BMI (p=6.41×10(-17)). At age 7 a genetically determined increase in BMI of 1.89kg/m(2) was associated with a 0.22 pmol/liter (95%CI 0.07, 0.36) increase in FT3 (p=0.004) but no substantial change in FT4 0.01 mmol/liter, (95%CI -0.37, 0.40) p=0.96.

CONCLUSION: Our analysis shows that children with a genetically higher BMI had higher FT3 but not FT4 levels indicating higher BMI/fat mass has a causal role in increasing FT3 levels. This may explain the paradoxical associations observed in observational analyses. Given rising childhood obesity levels, this relationship merits closer scrutiny.