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Birthweight, Type 2 Diabetes and Cardiovascular Disease: Addressing the Barker Hypothesis with Mendelian randomization

By Daniela Zanetti, Emmi Tikkanen, Stefan Gustafsson, James Rush Priest, Stephen Burgess, Erik Ingelsson

Posted 25 Oct 2017
bioRxiv DOI: 10.1101/208629 (published DOI: 10.1161/CIRCGEN.117.002054)

Background: Low birthweight (BW) has been associated with a higher risk of hypertension, type 2 diabetes (T2D) and cardiovascular disease (CVD) in epidemiological studies. The Barker hypothesis posits that intrauterine growth restriction resulting in lower BW is causal for these diseases, but causality and mechanisms are difficult to infer from observational studies. Mendelian randomization (MR) is a new tool to address this important question. Methods: We performed regression analyses to assess associations of self-reported BW with CVD and T2D in 237,631 individuals from the UK Biobank, a large population-based cohort study aged 40-69 years recruited across UK in 2006-2010. Further, we assessed the causal relationship of such associations using the two-sample MR approach, estimating the causal effect by contrasting the SNP effects on the exposure with the SNP effects on the outcome using independent publicly available genome-wide association datasets. Results: In the observational analyses, BW showed strong inverse associations with systolic and diastolic blood pressure (β, -0.83 and -0.26; per raw unit in outcomes and SD change in BW; 95% CI, -0.90, -0.75 and -0.31, -0.22, respectively), T2D (odds ratio [OR], 0.83; 95% CI, 0.79, 0.87), lipid-lowering treatment (OR, 0.84; 95% CI, 0.81, 0.86) and CAD (hazard ratio [HR] 0.85; 95% CI, 0.78, 0.94); while the associations with adult body mass index (BMI) and body fat (β, 0.04 and 0.02; per SD change in outcomes and BW; 95% CI, 0.03, 0.04 and 0.01, 0.02, respectively) were positive. The MR analyses indicated inverse causal associations of BW with low density lipoprotein cholesterol, 2-hour glucose, CAD and T2D, and positive causal association with BMI; but no associations with blood pressure. Sensitivity analyses and robust MR methods provided consistent results and indicated no horizontal pleiotropy. Conclusion: Our study indicates that lower BW is causally and directly related with increased susceptibility to CAD and T2D in adulthood. This causal relationship is not mediated by adult obesity or hypertension.

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