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Hum Mol Genet. 2017 Jan 1;26(1):233-242. doi: 10.1093/hmg/ddw380.

Identification of novel loci affecting circulating chromogranins and related peptides.

Author information

1
Institute for Molecular Bioscience, University of Queensland, Australia.
2
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
3
Department of Psychiatry.
4
Cognitive Science.
5
Medicine.
6
Bioengineering.
7
University of California at San Diego, La Jolla, CA.
8
Department of Medical Sciences, Uppsala University, Sweden and.
9
J Craig Venter Institute, La Jolla, CA, USA.

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.

PMID:
28011710
PMCID:
PMC6075630
DOI:
10.1093/hmg/ddw380
[Indexed for MEDLINE]
Free PMC Article

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