Abstract 488: Investigation of the Impact of Germ Line Variation in the K Channel Kcnj5 on the Renin-angiotensin Axis and Aldosterone Release in Human Subjects (linked)

Abstract

Introduction: Somatic mutations in the KCNJ5 potassium channel are found in significant number of patients with primary aldosteronism (PA). In a previous study, a rare non-synonymous E>Q (E282Q) single nucleotide polymorphism (SNP) rs7102584 in the KCNJ5 channel was identified and an in vitro study confirmed its functionality. This study tested the hypothesis that this germline SNP would affect release of aldosterone and raise blood pressure (BP) under salt-loaded conditions. Methods: Healthy volunteers (30 Group A = SNP heterozygous carriers and 30 Group B = homozygous wild type, mean age: 59±11) were recruited through the UK BioResource, with equal gender distribution in the two groups (40% males, 60% females). Investigators were blinded to the genotype of each recruit. Volunteers were on a low salt diet (≤6 g/d) for a week, and then exposed to high oral salt intake (>9 g/d) for a week. Clinic BP, 24hour ambulatory blood pressure measurements (ABPM), 24hour urine electrolytes, renal biochemistry, renin, aldosterone and renin aldosterone ratio (ARR), were measured before and after high salt exposure. Data were analysed using repeated measures ANOVA and adjusted for age. Results: Following salt loading, the mean day average systolic blood pressure (SBP) and diastolic blood pressure (DBP) rise on ABPM was 2.5 ± 1 mm Hg and 0.7± 0.7 mm Hg. Similarly, night-time average SBP and DBP rise was 2.2 ±1.2 mm Hg and 1.6 ± 0.9 mm Hg respectively. The ARR fell by a mean of 5.0 ±1.7 pmol/mU. There were no significant differences between carriers of the E/Q KCNJ5 variant and wild-type subjects in BP values and biochemical parameters at baseline or under salt-loading. Conclusions: This is the first study we are aware of, that has attempted in vivo translation of this KCNJ5 germline variant. The germline variation does not seem to drive hyperaldosteronism in vivo, although we cannot exclude this in the rare subjects who are homozygous for the variation (mean allele frequency approximately <1 in 1000).