Genetically-determined higher TSH is associated with lower risk of diabetes mellitus in individuals with low BMI.

CONTEXT Thyroid status is hypothesized to be causally related with the risk of diabetes mellitus (DM), but previous results were conflicting possibly due to a complex interaction between TSH, body mass index (BMI) and DM. OBJECTIVE To investigate the causal association between thyroid status with DM and glucose homeostasis and to what extent this association is dependent on BMI. DESIGN Mendelian Randomization study. SETTING European-ancestry participants from the UK Biobank population. PARTICIPANTS The present study was performed in 408,895 individuals (mean age 57.4 years (standard deviation 8.0), 45.9% men), of which 19,773 DM cases. INTERVENTIONS Genetic variants for circulatory thyroid stimulating hormone (TSH), free thyroxine (fT4) concentrations and BMI to calculate weighted genetic risk scores. MAIN OUTCOME MEASURES(S) self-reported DM, stratified analyses by BMI. Analyses were repeated for non-fasting glucose and Hb1Ac among individuals without DM. RESULTS Genetically-determined TSH and fT4 levels were not associated with risk of DM in the total UK Biobank population. However, in analyses stratified on genetically-determined BMI, genetically-determined higher TSH, and not fT4, was associated with a lower risk for DM only in the low BMI group (odds ratio 0.91; 95% confidence interval 0.85,0.98 in low BMI; p-value for interaction = 0.06). Similar results were observed for glucose and Hb1Ac among individuals without DM. CONCLUSIONS TSH, but not fT4, is a potential causal risk factor for DM in individuals with genetically determined low BMI highlighting potential protective effects of TSH only in low-risk populations.