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Circ Genom Precis Med. 2018 Jun;11(6):e002054. doi: 10.1161/CIRCGEN.117.002054.

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

Author information

1
Division of Cardiovascular Medicine, Department of Medicine (D.Z., E.T., E.I.).
2
Division of Cardiology, Department of Pediatrics (J.R.P.).
3
Stanford University School of Medicine, CA. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Sweden (S.G., E.I.).
4
MRC Biostatistics Unit and Department of Public Health and Primary Care, University of Cambridge, United Kingdom (S.B.).
5
Division of Cardiovascular Medicine, Department of Medicine (D.Z., E.T., E.I.), eriking@stanford.edu.
6
and Stanford Cardiovascular Institute (D.Z., E.I.).

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

Comment in

PMID:
29875125
PMCID:
PMC6447084
DOI:
10.1161/CIRCGEN.117.002054
[Indexed for MEDLINE]
Free PMC Article

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