Identification of novel loci affecting circulating chromogranins and related peptides.

Human molecular genetics 2017 Jan 01

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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. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Citation

Beben Benyamin, Adam X Maihofer, Andrew J Schork, Bruce A Hamilton, Fangwen Rao, Geert W Schmid-Schönbein, Kuixing Zhang, Manjula Mahata, Mats Stridsberg, Nicholas J Schork, Nilima Biswas, Vivian Y Hook, Zhiyun Wei, Grant W Montgomery, Nicholas G Martin, Caroline M Nievergelt, John B Whitfield, Daniel T O'Connor. Identification of novel loci affecting circulating chromogranins and related peptides. Human molecular genetics. 2017 Jan 01;26(1):233-242