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

Abstract

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. We aimed to investigate whether childhood adiposity influences FT3 levels. Mendelian randomization using genetic variants robustly associated with BMI. Avon Longitudinal Study of Parents and Children, a population-based birth cohort. 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. FT3. Observationally at age 7 years, BMI was positively associated with FT3: β-standardized (β-[std]) = 0.12 (95% confidence interval [CI]: 0.08, 0.16), P = 4.02 × 10(-10); whereas FT4 was negatively associated with BMI: β-(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/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. 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.