Context: Free T3 (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: A total of 3014 children who had thyroid function measured at age 7, who also
underwent dual x-ray absorptiometry 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: -standardized
(-[std]) 0.12 (95% confidence interval [CI]: 0.08, 0.16), P 4.02 10 10; whereas FT4 was
negatively associated with BMI: -(std) 0.08 (95% CI: 0.12, 0.04), P 3.00 10 5
. These
differences persisted after adjustment for age, sex, and early life environment. Genetic analysis
indicated 1 allele change in BMI allelic score was associated with a 0.04 (95% CI: 0.03, 0.04) SD
increase in BMI (P 6.41 10 17). At age 7, a genetically determined increase in BMI of 1.89 kg/m2
was associated with a 0.22 pmol/L (95% CI: 0.07, 0.36) increase in FT3 (P .004) but no substantial
change in FT4 0.01 mmol/L, (95% CI: 0.37, 0.40), P .96.
Conclusion: Our analysis shows that children with a genetically higher BMI had higher FT3 but not
FT4 levels, indicating that 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.