Abstract
Background
The Renin-Angiotensin Aldosterone system (RAAS) is the major player in the long-term blood pressure (BP) regulation. Following cleavage of angiotensinogen by renin, the resulting angiotensin I peptide is further converted to angiotensin II by the Angiotensin Converting Enzyme (ACE). Angiotensin II can then bind to its type 1 receptor, stimulating the production of aldosterone, a steroid hormone inducing sodium and water retention, thus raising BP. The RAAS is targeted by commonly used anti-hypertensive drugs, but despite its importance, little is still known about its genetics, partially due to the technical difficulties in the quantification of the involved biomarkers.
Methods
Using mass-spectrometry, we simultaneously quantified in serum equilibrium angiotensin I (eqAngI), angiotensin II (eqAngII) and aldosterone (Aldo) on 2105 participants to the Cooperative Health Research In South Tyrol study (CHRIS), who were either normotensive or under documented anti-hypertensive drug (AHD) treatment. We derived proxies of renin activity (PRA-S=eqAngI+eqAngII), angiotensin-converting enzyme activity (ACE-S=eqAngII/eqAngI) and adrenal gland function (AA2-ratio=Aldo/eqAngII). We tested association of these biomarkers with 1,085,897 SNPs imputed against a population specific whole-exome-sequencing-based panel, adjusting for age, sex, AHD, and assuming an additive genetic model, using Regenie v 3.1.1.
Results
ACE activity (ACE-S) was associated with variants spanning the ACE gene. The top association was seen at rs4363 (p=2.8E-18), already associated with serum ACE level, and we replicated the association with rs4343 (p=6.7E-18) and ACE activity described in an Asian population. We found strong evidence of association of eqAngII and adrenal function (AA2-ratio) with the missense/stop gained rs27044 in the ubiquitous endoplasmic reticulum aminopeptidase 1 (ERAP1, p=8.2E-10), involved in angiotensin II degradation. We observed a bordeline association between aldosterone and the synonymous/non-coding transcript exon rs7275 at SMARCA4/LDLR (p=5.9E-8), previously related to lipid metabolism and coronary artery disease.
Conclusions
While some results await replication in an independent cohort, findings are consistent with known physiology, and shed light on undescribed mechanisms possibly involved in RAAS biology.