Naturally Occurring Human Genetic Variation in the 3′-Untranslated Region of the Secretory Protein Chromogranin A Is Associated With Autonomic Blood Pressure Regulation and Hypertension in a Sex-Dependent Fashion

Abstract

Objective Determination whether common variation at the CHGA locus increases susceptibility to hypertension. Background Chromogranin A (CHGA) regulates catecholamine storage and release. Previously we systematically identified genetic variants across CHGA. Methods Dense genotyping across the CHGA locus in >1000 individuals with the most extreme BPs in the population, as well twin pairs with autonomic phenotypes. Characterizing function of a trait-associated 3'-UTR variant with transfected CHGA 3'-UTR/luciferase reporter plasmids. Results CHGA was overexpressed in patients with hypertension, especially hypertensive men, and CHGA predicted catecholamines. In individuals with extreme BPs, CHGA genetic variants predicted BP, especially in men, with a peak association occurred in the 3'-UTR at C+87T, accounting for up to ~12/~9 mmHg. The C+87T genotype predicted CHGA secretion in vivo, with the +87T allele (associated with lower BP) also diminishing plasma CHGA by ~10%. The C+87T 3'-UTR variant also predicted the BP response to environmental (cold) stress; the same allele (+87T) that diminished basal BP in the population also decreased the SBP response to stress by ~12 mmHg, and the response was smaller in women (by ~6 mmHg). In a chromaffin cell-transfected CHGA 3'-UTR/luciferase reporter plasmid, the +87T allele associated with lower BP also decreased reporter expression by ~30%. In cultured chromaffin cells, reducing endogenous Chga expression by si-RNA caused ~2/3 depletion of catecholamine storage vesicles. Conclusions Common variant C+87T in the CHGA 3'-UTR is a functional polymorphism causally associated with hypertension especially in men of the population, and propose steps ("intermediate phenotypes") whereby in sex-dependent fashion this genetic variant influences the ultimate disease trait. These observations suggest new molecular strategies to probe the pathophysiology, risk, and rational treatment of hypertension.

Molecular Mechanism for Hypertensive Renal Disease

“…5 CHGA is also a prohormone that gives rise to biologically active peptides, such as the catecholamine release inhibitor catestatin, 6 the dysglycemic peptide pancreastatin, 7,8 and the vasodilator vasostatin. 9 Previously, we found that naturally occurring human genetic variation in the 39-region of the CHGA gene was associated with autonomic BP regulation and hypertension in several human populations 10 as well as hypertensive renal disease in African Americans, 11 and it predicts the rate of chronic GFR decline in such patients. 12 In a case/control study of hypertensive ESRD, 11 the 39-region of CHGA was associated with ESRD, and the effect was replicated in an independent case/control sample.…”

“…To explore whether the C+87T variant 10 might be functional, we searched for motifs potentially disrupted by the singlenucleotide polymorphism. A partial match for micro-RNA (miR) hsa-miR-107 was identified that displayed differential binding ability between the C+87 and +87T alleles, with a superior match for the Tallele, which was evidenced by a lower minimum free energy and higher alignment score.…”

“…The human CHGA 39-UTR C+87T (rs7610) common (approximately 10% allele frequency) polymorphism is associated with autonomic BP regulation and hypertension in several human populations 10 as well as hypertensive renal disease in African Americans. 11 Is there a role for CHGA in control of hypertension and renal function across different human biogeographic ancestries?…”

“…Previously, we determined that human CHGA 39-UTR rs7610 +87T allele conferred elevated risk for developing hypertension 10 and hypertensive renal disease. 11 Now, we find that, both computationally and experimentally, the +87Tallele seems to exhibit enhanced inhibition by the miR hsa-miR-107, decreasing CHGA as well as catestatin expression and perhaps leading to higher BP and ultimately, ESRD.…”

Investigation of polymorphisms of CHGA gene's promoter region in patients with essential hypertension

“…Bu çalışma CHGA geninin kan basıncı regülasyonunda önemli fonksiyonları olduğunu düşündürmüştür [11]. CHGA geninin promotor, 5'UTR, 3'UTR, ekzon ve intronik bölgelerinde çeşitli varyasyonlar (değişiklikler) tespit edilmiş olup özellikle promotor bölge, catestatin peptit bölgesi ve 3'UTR'deki DNA varyasyonlarının kan basıncı ve otonomik aktivitesinde değişikliklere neden olduğunun gösterilmesi ile de CHGA geni esansiyel hipertansiyonda yeni bir aday gen olarak gösterilmiştir [12][13][14].…”