Search

Context: Obesity, glucose, insulin resistance [homeostatic model assessment, version 2, for insulin resistance (HOMA2-IR)], and insulin secretion (HOMA2-β) have been associated with type 2 diabetes (T2D) observationally. However, the causal, genetic contribution of each parameter to this risk is largely unknown and important to study because observational data are prone to confounding but genetic, causal data are free of confounding and reverse causation., Objective: We examined the causal, genetic contribution of body mass index (BMI), glucose level, C-peptide level, HOMA2-IR, and HOMA2-β to the risk of T2D in 95,540 individuals from the Copenhagen General Population Study and estimated the absolute 10-year risks., Methods: Cox regression analysis, instrumental variable analysis, and Poisson regression analysis were performed to estimate the observational hazard ratios, causal, genetic ORs, and absolute 10-year risks of T2D., Results: For 1-SD greater level, BMI was associated with an observational 66% (95% CI, 62% to 72%) and causal, genetic 121% (95% CI, 25% to 291%) greater risk of T2D; glucose with an observational 44% (95% CI, 41% to 46%) and causal, genetic 183% (95% CI, 56% to 416%) greater risk of T2D; and HOMA2-IR with an observational 30% (95% CI, 18% to 44%) and causal, genetic 12% (95% CI, 2% to 22%) greater risk of T2D. In contrast, for 1-SD greater level, HOMA2-β was associated with an observational 14% (95% CI, 11% to 16%) and causal, genetic 21% (95% CI, 8% to 32%) lower risk of T2D. The upper tertiles of HOMA2-IR were associated with absolute 10-year diabetes risks of 31% and 37% in obese women and men, age >60 years, and a glucose level of 6.1 to 11.0 mmol/L., Conclusions: BMI, glucose level, HOMA2-IR, and HOMA2-β are causally associated with T2D., (Copyright © 2019 Endocrine Society.)

Aims Whether high body mass index (BMI) causally influences development and prognosis of heart failure has implications for clinical practice. We tested the hypotheses that high BMI causally influences heart failure incidence and mortality. Methods and results Using observational and Mendelian randomization causal, genetic analyses, we studied 106 121 individuals from the Copenhagen General Population Study, 18 407 from the Copenhagen City Heart Study, and 977 323 from publicly available databases. In observational analyses in the Copenhagen studies with 10 years of median follow-up, multivariable adjusted hazard ratios per 1 kg/m2 increment of BMI were 1.06 (95% confidence interval: 1.05–1.07; P < 0.001; n = 124 528; events = 6589) for heart failure incidence, 1.04 (1.03–1.06; P < 0.001; n = 124 528; events = 1237) for heart failure mortality, and 1.01 (1.00–1.01; P < 0.001; n = 124 528; events = 24 144) for all-cause mortality. In genetic analyses in the Copenhagen studies, the age and sex adjusted causal risk ratios per 1 kg/m2 increment of BMI were 1.19 (1.05–1.36; P = 0.008; n = 118 200; events = 6541) for heart failure incidence, 1.27 (0.82–1.98; P = 0.28; n = 118 200; events = 889) for heart failure mortality, and 1.11 (1.02–1.22; P = 0.022; n = 118 200; events = 16 814) for all-cause mortality. Finally, combining genetic data from the Copenhagen studies, the Genetic Investigation of ANthropometric Traits, the Heart Failure Molecular Epidemiology for Therapeutic Targets, and the UK Biobank, the unadjusted causal risk ratios per 1 kg/m2 increment of BMI were 1.39 (1.27–1.52; P < 0.001; n = 1 095 523; events = 53 850) for heart failure incidence, 1.18 (1.00–1.38; P = 0.05; n = 576 853; events = 2373) for heart failure mortality, and 1.02 (1.00–1.04; P = 0.03; n = 576 853; events = 44 734) for all-cause mortality. Conclusion High BMI causally increases the risk of both heart failure incidence and mortality. [ABSTRACT FROM AUTHOR]