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
Cites Hypertension. 1999 Nov;34(5):1152-62 10567198
Cites Am J Hum Genet. 2000 Jan;66(1):279-92 10631157
Cites Curr Hypertens Rep. 2000 Feb;2(1):16-22 10982526
Cites Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9971-6 11481435
Cites Bioinformatics. 2001 Aug;17(8):742-3 11524377
Cites Nat Genet. 2002 Jan;30(1):97-101 11731797
Cites J Neurosci. 2002 Jan 15;22(2):377-88 11784782
Cites J Hypertens. 2002 Jul;20(7):1335-45 12131530
Cites Nat Rev Genet. 2002 Nov;3(11):872-82 12415317
Cites Nat Rev Mol Cell Biol. 2002 Dec;3(12):919-31 12461558
Cites Biochem Biophys Res Commun. 2002 Dec 20;299(5):770-9 12470645
Cites Twin Res. 2002 Oct;5(5):460-7 12537877
Cites Hypertension. 2003 Jun;41(6):1196-201 12719445
Cites Biochemistry. 2003 Jun 17;42(23):6938-46 12795588
Cites Biol Cell. 2003 Oct;95(7):453-7 14597263
Cites Twin Res. 2003 Oct;6(5):432-41 14624727
Cites Regul Pept. 2004 Mar 15;117(3):219-27 14749043
Cites Behav Genet. 2004 Mar;34(2):153-9 14755180
Cites Am J Hum Genet. 2004 Mar;74(3):403-17 14750073
Cites Biochim Biophys Acta. 2004 Jul 23;1658(1-2):106-14 15282181
Cites Mol Pharmacol. 2004 Nov;66(5):1180-91 15326220
Cites Circulation. 1990 Jan;81(1):185-95 2404624
Cites Hypertension. 1993 Nov;22(5):789-95 8225539
Cites Science. 1994 Sep 30;265(5181):2037-48 8091226
Cites Hypertension. 1996 Oct;28(4):599-603 8843884
Cites J Clin Invest. 1997 Sep 15;100(6):1623-33 9294131
Cites J Clin Invest. 1998 Feb 15;101(4):863-76 9466982
Cites Clin Chem. 1998 Dec;44(12):2480-9 9836715
Cites Circulation. 1999 Jul 27;100(4):354-60 10421594
Cites Clin Sci. 1963 Feb;24:91-108 13952342
Cites Physiol Genomics. 2004 Nov 17;19(3):277-91 15367723
Cites Hypertension. 2005 Jan;45(1):80-5 15557390
Cites J Biol Chem. 2005 Feb 4;280(5):3885-97 15542860
Cites J Clin Invest. 2005 Jul;115(7):1942-52 16007257
Cites Clin Chim Acta. 2006 Jan;363(1-2):83-94 16165119
Cites Twin Res Hum Genet. 2005 Dec;8(6):616-32 16363087
Cites J Exp Biol. 2006 Feb;209(Pt 4):577-89 16449553
Cites Hypertension. 2006 Mar;47(3):331-3 16446388
Cites J Hypertens. 2006 May;24(5):895-904 16612252
Cites Hypertension. 2006 May;47(5):937-47 16585408
Cites Hypertension. 2007 Jan;49(1):96-106 17159089
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
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