| 1. |
- Chen, Yuqing, et al.
(författare)
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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
- 2008
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 52:18, s. 1468-81
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- O'Connor, Daniel T., et al.
(författare)
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Heritability and genome-wide linkage in US and australian twins identify novel genomic regions controlling chromogranin a : implications for secretion and blood pressure
- 2008
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 118:3, s. 247-57
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Chromogranin A (CHGA) triggers catecholamine secretory granule biogenesis, and its catestatin fragment inhibits catecholamine release. We approached catestatin heritability using twin pairs, coupled with genome-wide linkage, in a series of twin and sibling pairs from 2 continents. METHODS AND RESULTS: Hypertensive patients had elevated CHGA coupled with reduction in catestatin, suggesting diminished conversion of precursor to catestatin. Heritability for catestatin in twins was 44% to 60%. Six hundred fifteen nuclear families yielded 870 sib pairs for linkage, with significant logarithm of odds peaks on chromosomes 4p, 4q, and 17q. Because acidification of catecholamine secretory vesicles determines CHGA trafficking and processing to catestatin, we genotyped at positional candidate ATP6N1, bracketed by peak linkage markers on chromosome 17q, encoding a subunit of vesicular H(+)-translocating ATPase. The minor allele diminished CHGA secretion and processing to catestatin. The ATP6N1 variant also influenced blood pressure in 1178 individuals with the most extreme blood pressure values in the population. In chromaffin cells, inhibition of H(+)-ATPase diverted CHGA from regulated to constitutive secretory pathways. CONCLUSIONS: We established heritability of catestatin in twins from 2 continents. Linkage identified 3 regions contributing to catestatin, likely novel determinants of sympathochromaffin exocytosis. At 1 such positional candidate (ATP6N1), variation influenced CHGA secretion and processing to catestatin, confirming the mechanism of a novel trans-QTL for sympathochromaffin activity and blood pressure.
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