Pleiotropic effects of novel trans-acting loci influencing human sympathochromaffin secretion.
Family studies have suggested a genetic contribution to variation in blood pressure, but the genes responsible have thus far eluded identification. The use of intermediate phenotypes associated with hypertension, such as chromogranin plasma concentrations, may assist the discovery of hypertension-predisposing loci. We measured the concentrations of four chromogranin A (CHGA) and B (CHGB) peptides in 742 individuals from 235 nuclear families. The CHGA- and CHGB-derived peptides displayed significant heritability and revealed significant genetic correlations, most strikingly observed between CHGA(361-372) (catestatin) and CHGB(439-451). A 5-cM microsatellite genome scan revealed significant and suggestive evidence for linkage on several chromosomes for three of the peptides. Subsequent bivariate linkage analysis for peptides CHGA(361-372) and CHGB(439-451), which showed evidence for convergent linkage peaks on chromosomes 2, 7, and 13, resulted in increased evidence for linkage to these regions, suggesting pleiotropic effects of these three loci on multiple chromogranin traits. Because CHGA itself is on chromosome 14q32, and CHGB itself is on chromosome 20pter-p12, the pleiotropic regions on chromosomes 2, 7, and 13 must represent trans-acting quantitative trait loci coordinately affecting CHGA/CHGB biosynthesis and/or exocytotic secretion, likely by regulating efferent sympathetic outflow, a conclusion consistent with the in vitro studies presented here of the dual control of both exocytosis and transcription of these peptides by secretory stimuli in chromaffin cells. The results suggest a new approach to heritable autonomic control of circulation and the genetic basis of cardiovascular diseases such as systemic hypertension.
Department of Medicine, University of California-San Diego, La Jolla, USA.
Tiffany A
TA
Greenwood
Fangwen
F
Rao
Mats
M
Stridsberg
Nitish R
NR
Mahapatra
Manjula
M
Mahata
Elizabeth O
EO
Lillie
Sushil K
SK
Mahata
Laurent
L
Taupenot
Nicholas J
NJ
Schork
Daniel T
DT
O'Connor
D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D002395:Catecholamines / Q000378:metabolism; D019439:Chromaffin Cells / Q000187:drug effects / Q000378:metabolism*; D053379:Chromogranin A / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D053378:Chromogranin B / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D017930:Genes, Reporter; D008040:Genetic Linkage; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000235:genetics / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000097:blood; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D051381:Rats; D014162:Transfection
D002395:Catecholamines; D053379:Chromogranin A; D053378:Chromogranin B; D018722:Nicotinic Agonists; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D009538:Nicotine