Received July 11, 2007
Accepted on September 18, 2007

CLINICAL RESEARCH

Chromogranin A Polymorphisms Are Associated With Hypertensive Renal Disease

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 ^*, Sushi K. Mahata ^*, Donald W. Bowden , Pamela J. Hicks , Barry I. Freedman ¹, Nicholas J. Schork ¹, and Daniel T. O’Connor ^*||1

Departments of *Medicine, Psychiatry, and ||||Pharmacology, ||Division of Biology, Polymorphism Research Laboratory, and Center for Human Genetics and Genomics, University of California at San Diego, La Jolla, California; Veterans Administration San Diego Healthcare System, San Diego, California; ¶Department of Medical Sciences, Clinical Chemistry, University Hospital, Uppsala, Sweden; Scripps Genomic Medicine, Scripps Research Institute, La Jolla, California; **Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California; and Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina

¹ To whom correspondence should be addressed. E-mail: bfreedma{at}wfubmc.edu.

	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-462AT-415CC-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.