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- Title
A common hypofunctional genetic variant of GPER is associated with increased blood pressure in women.
- Authors
Feldman, Ross D.; Gros, Robert; Ding, Qingming; Hussain, Yasin; Ban, Matthew R.; McIntyre, Adam D.; Hegele, Robert A.
- Abstract
Aims Activation of vascular GPER has been linked to vasodepressor effects in animals. However, the significance of GPER regulation on chronic blood pressure control in humans is unknown. Methods To examine this question we determined the functional significance of expression of a common missense single nucleotide variant of GPER, P16 L in vascular smooth muscle cells, and its association with blood pressure in humans. Further, to validate the importance of carrying GPER P16 L in the development of hypertension we assessed allele frequency in a cohort of hard-to-treat hypertensive patients referred to a tertiary care clinic. Results Expression of the GPER P16 L variant ( V) vs. wild type ( WT) in rat aortic vascular smooth muscle cells, was associated with a significant decrease in G1 (1 μ m, a GPER agonist)-mediated ERK phosphorylation (slope of the function of G1-stimulated ERK phosphorylation: GPER content WT: 16.2, 95% CI 9.9, 22.6; V: 5.0, 95% CI 1.0, 9.0; P < 0.005) and apoptosis (slope of the function of G1-stimulated apoptosis: GPER content: WT: 4.4, 95% CI: 3.4, 5.4; V: 2.5, 95% CI 1.6, 2.3 P < 0.005). Normotensive female subjects, but not male subjects, carrying this hypofunctional variant (allele frequency 22%) have increased blood pressure [mean arterial pressure: P16/ P16: 80 ± 1 mmHg ( n = 204) vs. P16 L carriers: 82 ± 1 mmHg ( n = 127), 95% CI for difference: 0.6, 4.0 mmHg, P < 0.05], [systolic blood pressure: P16/P16: 105 ± 1 mmHg vs. P16 L carriers: 108 ± 1 mmHg, 95% CI for difference:1.0, 5.1 mmHg, P < 0.05], [diastolic blood pressure: P16/ P16: 66 ± 0.5 mmHg vs. P16 L carriers 68 ± 0.7, 95% CI for difference: 0.2, 3.6 mmHg, P < 0.05]. Further, the P16 L allele frequency was almost two-fold higher in female vs. male hypertensive patients (31% vs. 16%, allele ratio 0.5, 95% CI 0.32, 0.76, P < 0.05). Conclusions The common genetic variant, GPER P16 L, is hypofunctional and female carriers of this allele have increased blood pressure. There was an increased prevalence in a population of hard-to-treat hypertensive female patients. Cumulatively, these data suggest that in females, impaired GPER function might be associated with increased blood pressure and risk of hypertension.
- Subjects
BLOOD pressure; PHOSPHORYLATION; CARDIOVASCULAR system; ALLELES; HYPERTENSION
- Publication
British Journal of Clinical Pharmacology, 2014, Vol 78, Issue 6, p1441
- ISSN
0306-5251
- Publication type
Article
- DOI
10.1111/bcp.12471