Abstract
Background and aims
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 (AngI) is further converted to angiotensin II (AngII) by the Angiotensin Converting Enzyme (ACE). Angiotensin II (AngII) can bind to its type 1 receptor, stimulating the production of aldosterone, a steroid hormone inducing sodium and water retention, raising BP. The RAAS is targeted by common anti-hypertensive drugs, but little is still known about its genetics. We therefore investigated genetic variants associated with RAAS biomarkers.
Methods
We simultaneously quantified serum equilibrium AngI (eqAngI), AngII (eqAngII) and aldosterone on 2105 participants to the Cooperative Health Research In South Tyrol (CHRIS) study, who were either normotensive or under documented anti-hypertensive drug (AHD) treatment. We derived proxies of the renin activity (PRA-S=eqAngI+eqAngII), ACE activity (ACE-S=eqAngII/eqAngI) and the aldosterone-to-AngII ratio (AA2-ratio=aldosterone/eqAngII). We conducted a genome-wide association study of the six biomarkers on 1,085,897 single nucleotide polymorphisms (SNPs) imputed against a population specific whole-exome-sequencing panel, adjusting for age, sex, AHD treatment, and assuming an additive genetic model, using Regenie v3.1.1.
Results
ACE-S was associated with variants in the ACE gene. The top associations were observed at rs4363 (p=2.8E-18), already associated with serum ACE level, and rs4343 (p=6.7E-18) previously associated with ACE activity in an Asian sample. eqAngII and AA2-ratio were associated 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), related to lipid metabolism and coronary artery disease.
Conclusions
While some results await replication in an independent study, findings are consistent with known physiology, and shed light on undescribed mechanisms involved in RAAS biology.