Abstract 352: A Common Hypofunctional Genetic Variant of GPER: Increased Blood Pressure in Female Carriers and Increased Expression in Female Hypertensive Patients

Abstract

Activation of the aldosterone/estrogen GPCR, GPER, has been linked to vasodepressor effects. Further, genetic deletion of GPER in one mouse model has been linked to increased blood pressure in female but not male mice. However, the significance of GPER regulation for chronic blood pressure control in humans is unknown. To examine this question we determined the functional significance of expression of a common missense single nucleotide variant of GPER, P16L, and the impact of its expression on blood pressure and in the development of hypertension. Expression of the GPER P16L variant in rat aortic vascular smooth muscle cells vs. expression of wild type (WT) GPER, was associated with a significant decrease in G1 (1μM, a GPER agonist)-mediated ERK activation and G1-mediated inhibition of apoptosis. In normotensive subjects, expression of this hypofunctional GPER variant (allele frequency=22%) paralleled an increase in mean arterial blood pressure in females [P16/P16: 80±1 mmHg (n=236) vs P16L carriers: 82±1 mmHg (n=156), p<0.05] but not in males. To validate the importance of expression of the GPER P16L variant on the development of hypertension, we compared the allele frequency in normotensive vs. hypertensive subjects, the latter recruited from patients referred to a tertiary care level hypertension clinic (n=151). In this hypertensive patient population, the P16L allele frequency was increased in female patients with hypertension (1.4 fold, p<0.05 vs. allele frequency in normotensives) but was not increased in hypertensive males. In summary, we have determined that the common genetic variant, P16L GPER, is hypofunctional and that expression of this missense single nucleotide polymorphism is associated with increased blood pressure in normotensive subjects and with an increased frequency in hypertensive female but not male patients. Cumulatively, these data suggest that in females, impaired GPER function is associated with increased blood pressure and risk of hypertension.