Birthweight, Type 2 Diabetes Mellitus, and Cardiovascular Disease: Addressing the Barker Hypothesis With Mendelian Randomization

Abstract

Background: Low birthweight has been associated with a higher risk of hypertension, type 2 diabetes mellitus (T2D), and cardiovascular disease. The Barker hypothesis posits that intrauterine growth restriction resulting in lower birthweight is causal for these diseases, but causality is difficult to infer from observational studies.

Methods: We performed regression analyses to assess associations of birthweight with cardiovascular disease and T2D in 237 631 individuals from the UK Biobank. Further, we assessed the causal relationship of such associations using Mendelian randomization.

Results: In the observational analyses, birthweight showed inverse associations with systolic and diastolic blood pressure (β, -0.83 and -0.26; per raw unit in outcomes and SD change in birthweight; 95% confidence interval [CI], -0.90 to -0.75 and -0.31 to -0.22, respectively), T2D (odds ratio, 0.83; 95% CI, 0.79-0.87), lipid-lowering treatment (odds ratio, 0.84; 95% CI, 0.81-0.86), and coronary artery disease (hazard ratio, 0.85; 95% CI, 0.78-0.94), whereas the associations with adult body mass index and body fat (β, 0.04 and 0.02; per SD change in outcomes and birthweight; 95% CI, 0.03-0.04 and 0.01-0.02, respectively) were positive. The Mendelian randomization analyses indicated inverse causal associations of birthweight with low-density lipoprotein cholesterol, 2-hour glucose, coronary artery disease, and T2D and positive causal association with body mass index but no associations with blood pressure.

Conclusions: Our study indicates that lower birthweight, used as a proxy for intrauterine growth retardation, is causally related with increased susceptibility to coronary artery disease and T2D. This causal relationship is not mediated by adult obesity or hypertension.

Keywords: cardiovascular disease; diabetes mellitus, type 2; genetics; hypertension; obesity.

Figure.

Inverse-variance weighted (IVW) estimates from Mendelian randomization (MR) analyses and association results (BETA/ hazard ratio [HR]/odds ratio [OR]) from observational analyses of birth weight (BW) with cardiovascular outcomes in UK Biobank (UKB) using multivariable-adjusted linear and logistic regression, and multivariable-adjusted Cox proportional hazards models. A, Continuous outcomes: systolic blood pressure (SBP) and diastolic blood pressure (DBP) in UKB, body mass index (BMI), waist-to-hip ratio (WHR), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), body fat percentage (BF), 2-h glucose, fasting glucose, and fasting insulin. B, Binary outcomes: coronary artery disease (CAD), atrial fibrillation (AF), ischemic stroke (IS), hemorrhagic stroke (HS), heart failure (HF), type 2 diabetes mellitus (T2D), and lipid medications (LIP). The β values from linear regression represent SD change in outcome variable per SD change in BW, except for SBP and DBP where they represent the outcome in raw unit (mm Hg) per SD change in BW. MR analyses were based on the 46 variants included in the instrument variable 2 using data sources listed in the Table. All effects for the IVW (β or OR) are given in original units as provided by the consortia. Model adjustment: age, sex, region of the UKB assessment center, ethnicity, maternal smoking, and Townsend index. CI indicates confidence interval; and N, number of variants included in the instrument variable.