Chromogranin A Polymorphisms Are Associated With Hypertensive Renal Disease

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 (5Ј) region, G-462A3T-415C3C-89A, haplotype ATC (adjusted odds ratio ϭ 2.65; P ϭ 0.037), and 2) at the 3Ј-end, C11825T (3Ј-UTR, Cϩ87T)3G12602C, haplotype TC (adjusted odds ratio ϭ 2.73, P ϭ 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 3Ј-UTR ϩ 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.

Naturally Too Sympathetic to a Bad Diet?

“…This report 4 is rigorous in validating initial haplotype findings in a second population, although the studies presented nonetheless have weaknesses (e.g., sympathetic tone changes with age and control subjects are an average 10 yr younger). It seems that further study is warranted for both this interesting EDITORIALS www.jasn.org candidate gene and the theory that sympathetic overactivity is an underestimated contributor to ESRD.…”

“…3 Increasingly in this postgenomic, post-HapMap era, the rigor of candidate gene reports warrants serious consideration. In this issue of JASN, Salem et al 4 report that variations in chromogranin A (CHGA) genotype are associated with ESRD in hypertensive black individuals versus control subjects with normal renal function and hypertension or normotension. Multiple single-nucleotide polymorphisms (SNP) analyzed in a Californian cohort across the CHGA locus identify significant associations with a three-SNP proximal promoter haplotype and a 3Јend/3Јuntranslated region two-SNP haplotype.…”

“…In both haplotype regions variation has potential to alter CHGA expression 4,5 with the 3Јhaplotype 87T SNP allele reducing expression in vitro by Ͼ40%. 4 Consistent with such haplotype effects to lower gene transcription, circulating levels of catestatin (a chromogranin A cleavage product) were significantly reduced in patients with ESRD versus control subjects despite the tendency for accumulation in ESRD.…”

“…In both haplotype regions variation has potential to alter CHGA expression 4,5 with the 3Јhaplotype 87T SNP allele reducing expression in vitro by Ͼ40%. 4 Consistent with such haplotype effects to lower gene transcription, circulating levels of catestatin (a chromogranin A cleavage product) were significantly reduced in patients with ESRD versus control subjects despite the tendency for accumulation in ESRD. Because catestatin is active in limiting catecholamine release, these findings suggest the ESRD-associated haplotypes would leave the sympathetic nervous system (SNS) less restrained, implying that relative SNS overactivity is pathophysiologically involved in the susceptibility to renal decline.…”

Complex Renal Traits

“…The contribution of polymorphisms at specific loci are now documented for hypertensive ESRD, including the nonmuscle myosin variant, MYH9, 4 and the catecholamine storage vesicle protein chromogranin A, CHGA. 5 Systematic family studies have not been conducted in acute kidney injury (AKI), perhaps because of the transient nature of the illness coupled with unavailability of appropriate first-degree relatives for study during hospitalization.…”