影响循环嗜铬粒蛋白及相关肽的新基因座的鉴定。
Identification of novel loci affecting circulating chromogranins and related peptides.
作者信息
Benyamin Beben, Maihofer Adam X, Schork Andrew J, Hamilton Bruce A, Rao Fangwen, Schmid-Schönbein Geert W, Zhang Kuixing, Mahata Manjula, Stridsberg Mats, Schork Nicholas J, Biswas Nilima, Hook Vivian Y, Wei Zhiyun, Montgomery Grant W, Martin Nicholas G, Nievergelt Caroline M, Whitfield John B, O'Connor Daniel T
机构信息
Institute for Molecular Bioscience, University of Queensland, Australia.
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
出版信息
Hum Mol Genet. 2017 Jan 1;26(1):233-242. doi: 10.1093/hmg/ddw380.
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.
嗜铬粒蛋白是从神经内分泌细胞释放的前体激素分泌蛋白，对血压控制有影响。我们对545名美国人和1252名澳大利亚人进行了一项全基因组关联研究，研究对象为血浆抑胃肽（一种源自嗜铬粒蛋白A（CHGA）的儿茶酚胺释放抑制肽）以及其他与CHGA或嗜铬粒蛋白B（CHGB）相关的肽。研究确定了4号染色体长臂3区5带和5号染色体长臂3区4带影响抑胃肽浓度的基因座（rs4253311的P值为3.40×10⁻³⁰，rs2731672的P值为1.85×10⁻¹⁹）。这些区域的基因包括蛋白水解酶激肽释放酶（KLKB1）和凝血因子XII（F12）。在嗜铬细胞中，CHGA和KLKB1蛋白共定位于儿茶酚胺储存颗粒中。在体外，激肽释放酶将重组人CHGA切割为抑胃肽，经质谱验证。从该消化过程中鉴定出的肽（CHGA360 - 373）选择性抑制烟碱胆碱能刺激嗜铬细胞释放儿茶酚胺。一种涉及激肽释放酶和凝血因子XII的蛋白水解级联反应在体内和体外均可将嗜铬粒蛋白切割为活性化合物。
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