Peter N Taylor1, Rebecca Richmond1, Neil Davies1, Adrian Sayers1, Kirsty Stevenson1, Wolfram Woltersdorf1, Andrew Taylor1, Alix Groom1, Kate Northstone1, Susan Ring1, Onyebuchi Okosieme1, Aled Rees1, Dorothea Nitsch1, Graham R Williams1, George Davey Smith1, John W Gregory1, Nicholas J Timpson1, Jonathan H Tobias1, Colin M Dayan1. 1. Thyroid Research Group (P.N.T., O.O., J.W.G., C.M.D.) and Institute of Molecular and Experimental Medicine (A.R.), Cardiff University School of Medicine, Cardiff, CF14 4XN United Kingdom; Medical Research Council Integrative Epidemiology Unit (R.R., N.D., G.D.S., N.J.T.), University of Bristol, Bristol, BS8 2BN United Kingdom; Department of Social and Community Medicine (A.S., A.G., K.N., S.R.), University of Bristol, Bristol, BS8 2BN United Kingdom; Department of Biochemistry (K.S.), Bristol Royal Infirmary University Hospitals Bristol National Health Service Foundation Trust, Bristol, BS2 8HW United Kingdom; Geschäftsleiter Medizinisches Versorgungszentrum Labor Dr. Reising-Ackermann und Kollegen (W.W.), D-04289 Leipzig, Germany; Department of Biochemistry (A.T.), Royal United Hospital, Bath, BA1 3NG United Kingdom; Department of Non-Communicable Disease Epidemiology (D.N.), Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, CF14 4XN United Kingdom; Molecular Endocrinology Group (G.R.W.), Department of Medicine, Imperial College London, London, WC1E 7HT United Kingdom; and Musculoskeletal Research Unit (J.H.T.), University of Bristol, Learning and Research Southmead Hospital, Westbury on Trym, Bristol, BS10 5NB United Kingdom.
Abstract
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: 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. 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.
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: 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. 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.
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