We aimed to determine whether the common variation at the chromogranin A (CHGA) locus
increases susceptibility to hypertension.
CHGA regulates catecholamine storage and release. Previously we systematically identified
genetic variants across CHGA.
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.
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.
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.