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J Am Soc Nephrol. 2008 Mar;19(3):600-14. doi: 10.1681/ASN.2007070754. Epub 2008 Jan 30.

Chromogranin A polymorphisms are associated with hypertensive renal disease.

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  • 1Department of Medicine and Center for Molecular Genetics, University of California at San Diego and Veterans Administration San Diego Healthcare System (0838), 9500 Gilman Drive, La Jolla, CA 92093-0838, USA.

Abstract

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.

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PMID:
18235090
PMCID:
PMC2391050
DOI:
10.1681/ASN.2007070754
[PubMed - indexed for MEDLINE]
Free PMC Article
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