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

Objectives 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 similar to 12/similar to 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 similar to 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 12 mm Hg, and the response was smaller in women (by similar to 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 similar to 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. (J Am Coll Cardiol 2008; 52: 1468-81) (C) 2008 by the American College of Cardiology Foundation