Open AccessChromogranin A Polymorphisms Are Associated With Hypertensive Renal Disease
Author(s) -
Rany M. Salem,
Peter E. Cadman,
Yuqing Chen,
Fangwen Rao,
Gen Wen,
Bruce A. Hamilton,
Brinda K. Rana,
Douglas W. Smith,
Mats Stridsberg,
Harry J. Ward,
Manjula Mahata,
Sushil K. Mahata,
Donald W. Bowden,
Pamela J. Hicks,
Barry I. Freedman,
Nicholas J. Schork,
Daniel T. O’Connor
Publication year - 2008
Publication title -
journal of the american society of nephrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.451
H-Index - 279
eISSN - 1533-3450
pISSN - 1046-6673
DOI - 10.1681/asn.2007070754
Subject(s) - chromogranin a , haplotype , medicine , endocrinology , end stage renal disease , pathogenesis , odds ratio , disease , biology , allele , gene , genetics , immunohistochemistry
Chromogranin A is released together with epinephrine and norepinephrine from catecholaminergic cells. Specific endopeptidases cleave chromogranin A into biologically active peptide fragments, including catestatin, which inhibits catecholamine release. Previous studies have suggested that a deficit in this sympathetic "braking" system might be an early event in the pathogenesis of human hypertension. Whether chromogranin A (CHGA) polymorphisms predict end-organ complications of hypertension, such as end-stage renal disease, is unknown. Among blacks, we studied common genetic variants spanning the CHGA locus in 2 independent case-control studies of hypertensive ESRD. Two haplotypes were significantly more frequent among subjects with hypertensive ESRD: 1) in the promoter (5') region, G-462A-->T-415C-->C-89A, haplotype ATC (adjusted odds ratio = 2.65; P = 0.037), and 2) at the 3'-end, C11825T (3'-UTR, C+87T)-->G12602C, haplotype TC (adjusted odds ratio = 2.73, P = 0.0196). Circulating levels of catestatin were lower among those with hypertensive ESRD than controls, an unexpected finding given that peptide levels are usually elevated in ESRD because of reduced renal elimination. We found that the 3'-UTR + 87T variant decreased reporter gene expression, providing a possible mechanistic explanation for diminished catestatin. In summary, common variants in chromogranin A associate with the risk of hypertensive ESRD in blacks.