title: Identification of novel loci affecting circulating chromogranins and related peptides.
abstract: Chromogranins are pro-hormone secretory proteins released from neuroendocrine cells, with effects on control of blood pressure. We conducted a genome-wide association study for plasma catestatin, the catecholamine release inhibitory peptide derived from chromogranin A (CHGA), and other CHGA- or chromogranin B (CHGB)-related peptides, in 545 US and 1252 Australian subjects. This identified loci on chromosomes 4q35 and 5q34 affecting catestatin concentration (P = 3.40 × 10-30 for rs4253311 and 1.85 × 10-19 for rs2731672, respectively). Genes in these regions include the proteolytic enzymes kallikrein (KLKB1) and Factor XII (F12). In chromaffin cells, CHGA and KLKB1 proteins co-localized in catecholamine storage granules. In vitro, kallikrein cleaved recombinant human CHGA to catestatin, verified by mass spectrometry. The peptide identified from this digestion (CHGA360-373) selectively inhibited nicotinic cholinergic stimulated catecholamine release from chromaffin cells. A proteolytic cascade involving kallikrein and Factor XII cleaves chromogranins to active compounds both in vivo and in vitro.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Australia.|QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Beben
authors.initials: B
authors.lastname: Benyamin
authors.affiliation: Department of Psychiatry.
authors.forename: Adam X
authors.initials: AX
authors.lastname: Maihofer
authors.affiliation: Cognitive Science.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schork
authors.affiliation: Medicine.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Hamilton
authors.affiliation: Medicine.
authors.forename: Fangwen
authors.initials: F
authors.lastname: Rao
authors.affiliation: Bioengineering.
authors.forename: Geert W
authors.initials: GW
authors.lastname: Schmid-Schönbein
authors.affiliation: Medicine.
authors.forename: Kuixing
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Medicine.
authors.forename: Manjula
authors.initials: M
authors.lastname: Mahata
authors.affiliation: University of California at San Diego, La Jolla, CA.|Department of Medical Sciences, Uppsala University, Sweden and.
authors.forename: Mats
authors.initials: M
authors.lastname: Stridsberg
authors.affiliation: J Craig Venter Institute, La Jolla, CA, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.affiliation: Medicine.
authors.forename: Nilima
authors.initials: N
authors.lastname: Biswas
authors.affiliation: Medicine.
authors.forename: Vivian Y
authors.initials: VY
authors.lastname: Hook
authors.affiliation: Medicine.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Wei
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Department of Psychiatry.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Nievergelt
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: John B
authors.initials: JB
authors.lastname: Whitfield
authors.affiliation: Medicine.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: D000293:Adolescent; D000311:Adrenal Glands / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D001315:Australia; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism*; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000378:metabolism*; D053379:Chromogranin A / Q000097:blood*; D005174:Factor XII / Q000235:genetics / Q000378:metabolism; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000235:genetics*; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood*; D051381:Rats; D014481:United States; D055815:Young Adult
chemical_list: D015415:Biomarkers; C506150:CHGA protein, human; D002395:Catecholamines; D053379:Chromogranin A; D010446:Peptide Fragments; D005174:Factor XII; D007610:Kallikreins