title: 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
  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.
authors.affiliation: Department of Medicine, Center for Human Genetics and Genomics, University of California at San Diego, San Diego, California 92093, USA.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.forename: Fangwen
authors.initials: F
authors.lastname: Rao
authors.forename: Juan L
authors.initials: JL
authors.lastname: Rodriguez-Flores
authors.forename: Manjula
authors.initials: M
authors.lastname: Mahata
authors.forename: Maple M
authors.initials: MM
authors.lastname: Fung
authors.forename: Mats
authors.initials: M
authors.lastname: Stridsberg
authors.forename: Sucheta M
authors.initials: SM
authors.lastname: Vaingankar
authors.forename: Gen
authors.initials: G
authors.lastname: Wen
authors.forename: Rany M
authors.initials: RM
authors.lastname: Salem
authors.forename: Madhusudan
authors.initials: M
authors.lastname: Das
authors.forename: Myles G
authors.initials: MG
authors.lastname: Cockburn
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ziegler
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Hamilton
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.forename: Laurent
authors.initials: L
authors.lastname: Taupenot
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: 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
chemical_list: C506150:CHGA protein, human; D002395:Catecholamines; D053379:Chromogranin A