Context: Thyroid status is hypothesized to be causally related with the risk of diabetes mellitus (DM), but previous results were conflicting possibly because of a complex interaction between... Show moreContext: Thyroid status is hypothesized to be causally related with the risk of diabetes mellitus (DM), but previous results were conflicting possibly because of a complex interaction between thyrotropin (TSH), body mass index (BMI) and DM.Objective: This work aims to investigate the causal association between thyroid status with DM and glucose homeostasis and to what extent this association is dependent on BMI.Methods: A mendelian randomization study was conducted of European-ancestry participants from the UK Biobank population. The present study involved 408895 individuals (mean age 57.4 years [SD 8.0], 45.9% men), of whom 19773 had DM. Genetic variants for circulatory TSH, free thyroxine (fT4) concentrations and BMI to calculate weighted genetic risk scores. The main outcome measures included self-reported DM-stratified analyses by BMI. Analyses were repeated for nonfasting glucose and glycated hemoglobin A(1c) (HbA(1c)) 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% CI, 0.85-0.98 in low BMI; P value for interaction = .06). Similar results were observed for glucose and HbA(1c) among individuals without DM.Conclusion: 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. Show less
Cardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the... Show moreCardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the interplay between genetic factors and lifestyle factors (eg sleep, nutrition, physical activity) with diseases such as cardiovascular disease and risk factors for cardiovascular disease (diabetes). For example, 12 blood biomarkers associated with insulin resistance have been identified, 5 of which are specifically much higher in subjects with diabetes. In addition, it appeared that a short sleep duration and poor sleep quality are associated with poorer lipids in the blood (eg cholesterol and LDL) and more insulin resistance. With regard to sleep, 59 new genetic variants have also been identified with regard to blood lipids (HDL, LDL, triglycerides). In addition, the results indicate that a better lifestyle can also help reduce the development of new cardiovascular diseases in people with an increased genetic risk. This is particularly interesting to prevent diseases in persons at high risk. All in all, this thesis has provided new insights into the various factors that are potentially important in the development of cardiovascular disease and diabetes. Show less
Ganeff, I.M.M.; Bos, M.M.; Heemst, D. van; Noordam, R. 2019