Sökning: onr:"swepub:oai:DiVA.org:uu-103851" >
Naturally occurring...
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
-
Chen, Yuqing (författare)
-
Rao, Fangwen (författare)
-
Rodriguez-Flores, Juan L (författare)
-
visa fler...
-
Mahata, Manjula (författare)
-
Fung, Maple M. (författare)
-
- Stridsberg, Mats (författare)
- Uppsala universitet,Institutionen för medicinska vetenskaper,Clinical Chemstry
-
Vaingankar, Sucheta M (författare)
-
Wen, Gen (författare)
-
Salem, Rany M. (författare)
-
Das, Madhusudan (författare)
-
Cockburn, Myles G. (författare)
-
Schork, Nicholas J. (författare)
-
Ziegler, Michael G. (författare)
-
Hamilton, Bruce A. (författare)
-
Mahata, Sushil K. (författare)
-
Taupenot, Laurent (författare)
-
O'Connor, Daniel T. (författare)
-
visa färre...
-
(creator_code:org_t)
- Elsevier BV, 2008
- 2008
- Engelska.
-
Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 52:18, s. 1468-81
- Relaterad länk:
-
https://doi.org/10.1...
-
visa fler...
-
https://urn.kb.se/re...
-
https://doi.org/10.1...
-
visa färre...
Abstract
Ämnesord
Stäng
- 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 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.
Nyckelord
- MEDICINE
- MEDICIN
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas
- Av författaren/redakt...
-
Chen, Yuqing
-
Rao, Fangwen
-
Rodriguez-Flores ...
-
Mahata, Manjula
-
Fung, Maple M.
-
Stridsberg, Mats
-
visa fler...
-
Vaingankar, Such ...
-
Wen, Gen
-
Salem, Rany M.
-
Das, Madhusudan
-
Cockburn, Myles ...
-
Schork, Nicholas ...
-
Ziegler, Michael ...
-
Hamilton, Bruce ...
-
Mahata, Sushil K ...
-
Taupenot, Lauren ...
-
O'Connor, Daniel ...
-
visa färre...
- Artiklar i publikationen
-
Journal of the A ...
- Av lärosätet
-
Uppsala universitet