Circulating cardiovascular proteomic associations with genetics and disease
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Background
The analysis of the circulating proteome can identify translational modifiers and biomarkers of disease expressivity and severity at a given time point. Here we explore the relationships between protein measures implicated in cardiovascular disease and whether they mediate causal relationships between cardiovascular risk factors and disease development.
Methods
To understand the relationships between circulating biomarkers and genetic variants, medications, anthropometric traits, lifestyle factors, imaging-derived measures, and diagnoses of cardiovascular disease, we analysed measures of nine plasma proteins with a priori roles in genetic and structural cardiovascular disease or treatment pathways (ACE2, ACTA2, ACTN4, BAG3, BNP, CDKN1A, NOTCH1, NT-proBNP, and TNNI3) from the Pharma Proteomics Project of the UK Biobank cohort (over 45,000 participants sampled at recruitment).
Results
We identified significant variability in circulating proteins with age, sex, ancestry, alcohol intake, smoking, and medication intake. Phenome-wide association studies highlighted the range of cardiovascular clinical features with relationships to protein levels. Genome-wide genetic association studies identified variants near GCKR , APOE , and SERPINA1 , that modified multiple circulating protein levels (BAG3, CDKN1A, and/or NOTCH1). NT-proBNP and BNP levels associated with variants in BAG3 . ACE2 levels were increased with a diagnosis of hypertension or diabetes and were influenced by variants in genes associated with diabetes ( HNF1A, HNF4A ). Two-sample Mendelian randomisation identified ACE2 as protective for systolic blood pressure and Type-2 diabetes.
Conclusions
From a panel of circulating proteins, the results from this observational study provide evidence that ACE2 is causally associated with hypertension and diabetes. This suggests that ACE2 stimulation may provide additional protection from these cardiovascular diseases. This study provides an improved understanding of the circulating pathways depicting cardiovascular disease dynamics.
