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CLINICAL RESEARCH: HYPERTENSION

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

Yuqing Chen, MD, PhD^_*,#, Fangwen Rao, MM^_*, Juan L. Rodriguez-Flores, MS^_*, Manjula Mahata, PhD^_*, Maple M. Fung, MD^_*, Mats Stridsberg, PhD^¶, Sucheta M. Vaingankar, PhD^_*, Gen Wen, MD^_*, Rany M. Salem, MPH^_*, Madhusudan Das, PhD^_*, Myles G. Cockburn, PhD^||, Nicholas J. Schork, PhD, Michael G. Ziegler, MD^_*, Bruce A. Hamilton, PhD^_*, Sushil K. Mahata, PhD^_*,, Laurent Taupenot, PhD^_* and Daniel T. O'Connor, MD^_*,,,_*

^_* Department of Medicine, Center for Human Genetics and Genomics, University of California at San Diego, San Diego, California
Department of Psychiatry, Center for Human Genetics and Genomics, University of California at San Diego, San Diego, California
Department of Pharmacology, Center for Human Genetics and Genomics, University of California at San Diego, San Diego, California
VA San Diego Healthcare System, La Jolla, California
^|| Department of Preventive Medicine, USC School of Medicine, Los Angeles, California
^¶ Department of Medical Sciences, Uppsala University, Uppsala, Sweden
^# Renal Division, Peking University First Hospital, Beijing, China

Manuscript received April 16, 2008; revised manuscript received July 14, 2008, accepted July 17, 2008.

^_* Reprint requests and correspondence: Dr. Daniel T. O'Connor, Department of Medicine (0838), UCSD School of Medicine and VASDHS, 9500 Gilman Drive, La Jolla, California 92093 (Email: doconnor{at}ucsd.edu).

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 12/9 mm Hg. The C+87T genotype predicted CHGA secretion in vivo, with the +87T allele (associated with lower BP) also diminishing plasma CHGA by 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 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 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.

Key Words: hypertension • chromaffin • catecholamine • adrenal • sympathetic

Abbreviations and Acronyms   BP = blood pressure   CHGA = chromogranin A   DBP = diastolic blood pressure   LD = linkage disequilibrium   PCR = polymerase chain reaction   SBP = systolic blood pressure   siRNA = small interfering ribonucleic acid   SNP = single nucleotide polymorphism   SNPEM = single nucleotide polymorphism expectation maximation   3'-UTR = 3'-untranslated region

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