Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
18591442
TITLE
Heritability and genome-wide linkage in US and australian twins identify novel genomic regions controlling chromogranin a: implications for secretion and blood pressure.
ABSTRACT
BACKGROUND NlmCategory: 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 NlmCategory: 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 NlmCategory: 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.
DATE PUBLISHED
2008 Jul 15
HISTORY
PUBSTATUS PUBSTATUSDATE
aheadofprint 2008/06/30
pubmed 2008/07/02 09:00
medline 2008/08/14 09:00
entrez 2008/07/02 09:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
O'Connor DT O'Connor Daniel T DT Departments of Medicine and Pharmacology and Center for Human Genetics and Genomics, University of California at San Diego School of Medicine, Veterans Affairs San Diego Healthcare System, La Jolla, CA 92093-0838, USA. doconnor@ucsd.edu
Zhu G Zhu Gu G
Rao F Rao Fangwen F
Taupenot L Taupenot Laurent L
Fung MM Fung Maple M MM
Das M Das Madhusudan M
Mahata SK Mahata Sushil K SK
Mahata M Mahata Manjula M
Wang L Wang Lei L
Zhang K Zhang Kuixing K
Greenwood TA Greenwood Tiffany A TA
Shih PA Shih Pei-an Betty PA
Cockburn MG Cockburn Myles G MG
Ziegler MG Ziegler Michael G MG
Stridsberg M Stridsberg Mats M
Martin NG Martin Nicholas G NG
Whitfield JB Whitfield John B JB
INVESTIGATORS
JOURNAL
VOLUME: 118
ISSUE: 3
TITLE: Circulation
ISOABBREVIATION: Circulation
YEAR: 2008
MONTH: Jul
DAY: 15
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1524-4539
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Circulation
COUNTRY: United States
ISSNLINKING: 0009-7322
NLMUNIQUEID: 0147763
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
MD000220 NIMHD NIH HHS United States
P01 HL058120 NHLBI NIH HHS United States
P01 HL058120-09 NHLBI NIH HHS United States
P01 HL058120-090004 NHLBI NIH HHS United States
P01 HL058120-099006 NHLBI NIH HHS United States
R01 DK060702 NIDDK NIH HHS United States
R01 DK060702-05 NIDDK NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Alleles
Australia
Blood Pressure genetics
Chromaffin Cells secretion
Chromogranin A secretion
Chromosome Mapping secretion
Chromosomes, Human, Pair 17 secretion
Environment secretion
Exocytosis secretion
Female secretion
Genetic Linkage secretion
Genetic Variation secretion
Genome, Human secretion
Humans secretion
Hypertension genetics
Male genetics
Middle Aged genetics
Peptide Fragments genetics
Proton-Translocating ATPases metabolism
Quantitative Trait, Heritable metabolism
Siblings metabolism
Twins genetics
United States genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Chromogranin A
0 Peptide Fragments
0 chromogranin A (344-364)
EC 3.6.3.14 Proton-Translocating ATPases
OTHER ID's
OTHERID SOURCE
NIHMS57916 NLM
PMC2654229 NLM