Paradoxical Relationship Between Body Mass Index and Thyroid Hormone Levels: A Study Using Mendelian Randomization

Context: Free T-3 (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: beta-standardized (beta-[std]) = 0.12 (95% confidence interval [CI]: 0.08, 0.16), P = 4.02 x 10(-10); whereas FT4 was negatively associated with BMI: beta-(std) = -0.08 (95% CI: -0.12, -0.04), P = 3.00 x 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 x 10(-17)). At age 7, a genetically determined increase in BMI of 1.89 kg/m(2) 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.