Chromogranin A polymorphisms are associated with hypertensive renal disease.
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.
Salem
Rany M
RM
Department 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.
Cadman
Peter E
PE
Chen
Yuqing
Y
Rao
Fangwen
F
Wen
Gen
G
Hamilton
Bruce A
BA
Rana
Brinda K
BK
Smith
Douglas W
DW
Stridsberg
Mats
M
Ward
Harry J
HJ
Mahata
Manjula
M
Mahata
Sushi K
SK
Bowden
Donald W
DW
Hicks
Pamela J
PJ
Freedman
Barry I
BI
Schork
Nicholas J
NJ
O'Connor
Daniel T
DT
D020413:3' Untranslated Regions; D001741:Black or African American / Q000235:genetics*; D053379:Chromogranin A / Q000097:blood / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006977:Hypertension, Renal / Q000208:ethnology / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000208:ethnology / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010446:Peptide Fragments / Q000097:blood; D020641:Polymorphism, Single Nucleotide
D020413:3' Untranslated Regions; D053379:Chromogranin A; D010446:Peptide Fragments; C109084:chromogranin A (344-364)