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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
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Chen, Yuqing (author)
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Rao, Fangwen (author)
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Rodriguez-Flores, Juan L (author)
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Mahata, Manjula (author)
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Fung, Maple M. (author)
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- Stridsberg, Mats (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper,Clinical Chemstry
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Vaingankar, Sucheta M (author)
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Wen, Gen (author)
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Salem, Rany M. (author)
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Das, Madhusudan (author)
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Cockburn, Myles G. (author)
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Schork, Nicholas J. (author)
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Ziegler, Michael G. (author)
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Hamilton, Bruce A. (author)
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Mahata, Sushil K. (author)
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Taupenot, Laurent (author)
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O'Connor, Daniel T. (author)
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(creator_code:org_t)
- Elsevier BV, 2008
- 2008
- English.
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 52:18, s. 1468-81
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
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- 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.
Keyword
- MEDICINE
- MEDICIN
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Chen, Yuqing
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Rao, Fangwen
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Rodriguez-Flores ...
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Mahata, Manjula
-
Fung, Maple M.
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Stridsberg, Mats
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show more...
-
Vaingankar, Such ...
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Wen, Gen
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Salem, Rany M.
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Das, Madhusudan
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Cockburn, Myles ...
-
Schork, Nicholas ...
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Ziegler, Michael ...
-
Hamilton, Bruce ...
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Mahata, Sushil K ...
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Taupenot, Lauren ...
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O'Connor, Daniel ...
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show less...
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Journal of the A ...
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Uppsala University