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.
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.
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.
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.
Causal associations of circulating biomarkers with cardiovascular disease
The overall goal of this project is to study the causal roles of the 36 biomarkers currently being assayed in UK Biobank for development of coronary heart disease, stroke and heart failure. Knowledge about causal relations of these 36 biomarkers with cardiovascular outcomes will give important insights regarding the etiological understanding of these diseases and accelerate development of new prevention strategies, including druggable targets. Hence, the proposed research does meet UK Biobank's stated purpose via improving the prevention and treatment of heart disease and stroke. First, we will study associations of 36 circulating biomarkers representing different biological systems with incidence of coronary heart disease, stroke and heart failure.
Second, by combing data from the UK Biobank gene analyses with the biomarker data, we will perform genetic studies across the whole human genome for all 36 biomarkers to establish common genetic variation associated with respective biomarker.
Third, we will perform so called Mendelian randomization analyses to study whether the biomarkers are causally related to coronary heart disease, stroke and heart failure.
Full cohort (n=502,650).
|Lead investigator:||Professor Themistocles Assimes|
|Lead institution:||Stanford University|
8 related Returns
|Return ID||App ID||Description||Archive Date|
|2167||13721||Associations of Fitness, Physical Activity, Strength, and Genetic Risk With Cardiovascular Disease||9 Apr 2020|
|2166||13721||Biological Insights Into Muscular Strength: Genetic Findings in the UK Biobank||9 Apr 2020|
|2829||13721||Body composition and atrial fibrillation: a Mendelian randomization study||18 Nov 2020|
|2794||13721||Clinical and Genetic Determinants of Varicose Veins||4 Nov 2020|
|2163||13721||Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development||8 Apr 2020|
|2793||13721||Genome-wide association study of coronary artery disease among individuals with diabetes: the UK Biobank||4 Nov 2020|
|2831||13721||Identification of 22 novel loci associated with urinary biomarkers of albumin, sodium, and potassium excretion||19 Nov 2020|
|2888||13721||Urinary Albumin, Sodium, and Potassium and Cardiovascular Outcomes in the UK Biobank||27 Nov 2020|
|2793||Birthweight, Type 2 Diabetes Mellitus, and Cardiovascular Disease: Addressing the Barker Hypothesis With Mendelian Randomization||Zanetti et al||2020||Circulation: Genomic and Precision Medicine|