Naturally occurring genetic variants in human chromogranin A (CHGA) associated with hypertension as well as hypertensive renal disease.
Chromogranin A (CHGA) plays a fundamental role in the biogenesis of catecholamine secretory granules. Changes in storage and release of CHGA in clinical and experimental hypertension prompted us to study whether genetic variation at the CHGA locus might contribute to alterations in autonomic function, and hence hypertension and its target organ consequences such as hypertensive renal disease (nephrosclerosis). Systematic polymorphism discovery across the human CHGA locus revealed both common and unusual variants in both the open reading frame and such regulatory regions as the proximal promoter and 30-UTR. In chromaffin cell-transfected CHGA 30-UTR and promoter/luciferase reporter plasmids, the functional consequences of the regulatory/non-coding allelic variants were documented. Variants in both the proximal promoter and the 30-UTR displayed statistical associations with hypertension. Genetic variation in the proximal CHGA promoter predicted glomerular filtration rate in healthy twins. However, for hypertensive renal damage, both end-stage renal disease and rate of progression of earlier disease were best predicted by variants in the 30-UTR. Finally, mechanistic studies were undertaken initiated by the clue that CHGA promoter variation predicted circulating endothelin-1. In cultured endothelial cells, CHGA triggered co-release of not only the vasoconstrictor and pro-fibrotic endothelin-1, but also the pro-coagulant von Willebrand Factor and the pro-angiogenic angiopoietin-2. These findings, coupled with stimulation of endothelin-1 release from glomerular capillary endothelial cells by CHGA, suggest a plausible mechanism whereby genetic variation at the CHGA locus eventuates in alterations in human renal function. These results document the consequences of genetic variation at the CHGA locus for cardiorenal disease and suggest mechanisms whereby such variation achieves functional effects.
Renal Division, Peking University First Hospital, Beijing 100034, China.
Yuqing
Y
Chen
Fangwen
F
Rao
Gen
G
Wen
Jiaur R
JR
Gayen
Kuixing
K
Zhang
Sucheta M
SM
Vaingankar
Nilima
N
Biswas
Manjula
M
Mahata
Ryan S
RS
Friese
Maple M
MM
Fung
Rany M
RM
Salem
Caroline
C
Nievergelt
Vibha
V
Bhatnagar
Vivian Y
VY
Hook
Michael G
MG
Ziegler
Sushil K
SK
Mahata
Bruce A
BA
Hamilton
Daniel T
DT
O'Connor
D053379:Chromogranin A / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D006977:Hypertension, Renal / Q000235:genetics* / Q000503:physiopathology; D007668:Kidney / Q000503:physiopathology; D007677:Kidney Function Tests; D009400:Nephrosclerosis / Q000235:genetics / Q000503:physiopathology; D010641:Phenotype; D012727:Sex Characteristics
C506150:CHGA protein, human; D053379:Chromogranin A