Abstract 12625: Genome-Wide Analysis Revealed Genetic Control of the Renin-Angiotensin-Aldosterone System in the General Population

Abstract

Introduction: The Renin-Angiotensin Aldosterone system (RAAS) is the major player in the long-term blood pressure (BP) regulation. 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, angiotensin II and aldosterone 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= angiotensin I + angiotensin II), angiotensin-converting enzyme activity (ACE-S= angiotensin I / angiotensin II) and adrenal gland function (AA2-ratio =aldosterone/ angiotensin II). 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 v3.1.1. Results: Study participants were 21 to 95 years old, and 52% were females. Most participants (86%) received specific AHD treatments. 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 replicating previous findings in an Asian population sample. We found strong evidence of association of angiotensin II and AA2-ratio with the stop gained rs27044 (p=8.2E-10) in the ERAP1, involved in angiotensin II degradation. We observed a borderline association between aldosterone and the synonymous rs7275 at SMARCA4/LDLR (p=5.85E-8), previously related to lipid metabolism. We also report a novel suggestive association between angiotensin I and rs2274978 in the Xaa-Pro aminopeptidase I (XPNPEP1; p=9.49E-6). Conclusions: While some results await replication in an independent cohort, findings are consistent with known physiology, and shed light on genetic background of BP regulation.