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.
OBJECTIVE
We aimed to determine whether the common variation at the chromogranin A (CHGA) locus increases susceptibility to hypertension.


BACKGROUND
CHGA regulates catecholamine storage and release. Previously we systematically identified genetic variants across CHGA.


METHODS
We carried out dense genotyping across the CHGA locus in >1,000 individuals with the most extreme blood pressures (BPs) in the population, as well as twin pairs with autonomic phenotypes. We also characterized the function of a trait-associated 3'-untranslated region (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 occurring in the 3'-UTR at C+87T, accounting for up to approximately 12/ approximately 9 mm Hg. The C+87T genotype predicted CHGA secretion in vivo, with the +87T allele (associated with lower BP) also diminishing plasma CHGA by approximately 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 systolic BP response to stress by approximately 12 mm Hg, and the response was smaller in women (by approximately 6 mm Hg). In a chromaffin cell-transfected CHGA 3'-UTR/luciferase reporter plasmid, the +87T allele associated with lower BP also decreased reporter expression by approximately 30%. In cultured chromaffin cells, reducing endogenous CHGA expression by small interfering ribonucleic acid caused approximately two-thirds 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 we propose steps ("intermediate phenotypes") whereby in a 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.
Chen
Yuqing
Y
Department of Medicine, Center for Human Genetics and Genomics, University of California at San Diego, San Diego, California 92093, USA.
Rao
Fangwen
F
Rodriguez-Flores
Juan L
JL
Mahata
Manjula
M
Fung
Maple M
MM
Stridsberg
Mats
M
Vaingankar
Sucheta M
SM
Wen
Gen
G
Salem
Rany M
RM
Das
Madhusudan
M
Cockburn
Myles G
MG
Schork
Nicholas J
NJ
Ziegler
Michael G
MG
Hamilton
Bruce A
BA
Mahata
Sushil K
SK
Taupenot
Laurent
L
O'Connor
Daniel T
DT
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001341:Autonomic Nervous System / Q000503:physiopathology*; D001794:Blood Pressure; D002395:Catecholamines / Q000235:genetics; D053379:Chromogranin A / Q000235:genetics* / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012737:Sex Factors; D014427:Twins; D055815:Young Adult
C506150:CHGA protein, human; D002395:Catecholamines; D053379:Chromogranin A