Background Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed... Show moreBackground Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status. Methods Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction. Results Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99-1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96-1.04; p value 0.59). Conclusions Lower thyroid status leads to an unfavorable lipid profile and a somewhat increased cardiovascular disease risk. Show less
Bos, M.M.; Vliet, N.A. van; Mooijaart, S.P.; Noordam, R.; Heemst, D. van 2021
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
Bos, M.M.; Noordam, R.; Bennett, K.; Beekman, M.; Mook-Kanamori, D.O.; Dijk, K.W. van; ... ; Heemst, D. van 2020
Introduction Several plasma metabolites have been associated with insulin resistance and type 2 diabetes mellitus. Objectives We aimed to identify plasma metabolites associated with different... Show moreIntroduction Several plasma metabolites have been associated with insulin resistance and type 2 diabetes mellitus. Objectives We aimed to identify plasma metabolites associated with different indices of early disturbances in glucose metabolism and insulin sensitivity. Methods This cross-sectional study was conducted in a subsample of the Leiden Longevity Study comprising individuals without a history of diabetes mellitus (n = 233) with a mean age of 63.3 +/- 6.7 years of which 48.1% were men. We tested for associations of fasting glucose, fasting insulin, HOMA-IR, Matsuda Index, Insulinogenic Index and glycated hemoglobin with metabolites (Swedish Metabolomics Platform) using linear regression analysis adjusted for age, sex and BMI. Results were validated internally using an independent metabolomics platform (Biocrates platform) and replicated externally in the independent Netherlands Epidemiology of Obesity (NEO) study (Metabolon platform) (n = 545, mean age of 55.8 +/- 6.0 years of which 48.6% were men). Moreover, in the NEO study, we replicated our analyses in individuals with diabetes mellitus (cases: n = 36; controls = 561). Results Out of the 34 metabolites, a total of 12 plasma metabolites were associated with different indices of disturbances in glucose metabolism and insulin sensitivity in individuals without diabetes mellitus. These findings were validated using a different metabolomics platform as well as in an independent cohort of non-diabetics. Moreover, tyrosine, alanine, valine, tryptophan and alpha-ketoglutaric acid levels were higher in individuals with diabetes mellitus. Conclusion We found several plasma metabolites that are associated with early disturbances in glucose metabolism and insulin sensitivity of which five were also higher in individuals with diabetes mellitus. Show less
Ganeff, I.M.M.; Bos, M.M.; Heemst, D. van; Noordam, R. 2019
