203increments in SBP (decreased in men by ~12 mm Hg and in women by ~6 mm
Hg) (Chen et al. 2008b). Sex-dependent responses to acute adrenergic stimuli, and
the sex-dependent long- term consequences of repeated stressors on resting BP or
the late appearance of hypertension may account for the above different conse-
quences in men and women for CHGA C+87T 3′-UTR variant.
3.4 Association of CHGA Promoter and 3′-UTR
Polymorphisms with Hypertensive Nephrosclerosis
UCSD study revealed that plasma CgA was inversely proportional to renal function
as plasma CgA rose systematically (from 3.9 ± 1 nM to >10 nM) with the decline in
renal function, from healthy individuals (GFR 101 ± 1 ml/min), to subjects with
chronic kidney diseases (CKD, GFR 28 ± 3 ml/min), to subjects with end-stage
renal disease (ESRD: GFR <10 ml/min). Like ESRD, plasma CgA level was also
high in hypertensive subjects (Salem et al. 2008 ). In contrast, plasma CST was posi-
tively correlated with decreased renal function. In black ESRD subjects, plasma
CST decreased by ~34% (from 1.2 ± 0.11 nM in black controls to 0.79 ± 0.03 nM
in black ESRD) (Salem et al. 2008 ). Like ESRD, patients with essential hyperten-
sion also showed decreased (by ~14%) plasma CST (from 1.47 ± 0.06 in normoten-
sive to 1.26 ± 0.08 in hypertensive subjects). The demographic description of the
ESRD and control population included the following: age, gender, diabetes, hyper-
tension, the family history of hypertension or ESRD, body mass index, and serum
creatinine. Because of the important role of CgA in storage and release of catechol-
amines and its association with hypertension, the role of CHGA variants has been
explored for their effects on hypertensive nephrosclerosis in three cohorts. The
UCSD cohort consisted of 58 African American patients with hypertensive ESRD
and 150 control subjects (74 normotensive and 76 hypertensive). The ESRD cases
had a glomerular filtration rate (GFR) of essentially zero (all were sustained by
chronic hemodialysis) as compared to the control group, which had a mean GFR of
~111 ml/min. The hypertensive control (with or without antihypertensive medica-
tion) subjects had a SBP >140 mm Hg or DBP >90 mm Hg. Replication study in
North Carolina cohort included 301 hypertension-associated ESRD and 305 con-
trols (normotensive as well as hypertensive). The National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK) African American Study of Kidney
Disease and Hypertension (AASK) trial cohort comprised of 830 subjects with pro-
gressive renal disease. CHGA promoter and 3′-UTR polymorphisms showed sig-
nificant association with hypertensive (HT)-ESRD. CHGA promoter haplotype
ATC (G-462A, T-415C, and C-89A) were more common in ESRD cases than con-
trols. While the ATC haplotype was found in only ~14% individuals without renal
failure, it was found in ~34% subjects with HT-ESRD. This indicates that ATC
haplotype constitute a risk factor for developing ESRD. Likewise, CHGA 3 ′-UTR
minor allele haplotype TC (C+87T and G+864C) were more common in ~40% of
Chromogranin A SNPs and Disease Association