202
BP response showed molecular heterosis with the greatest change in blood pressure
in heterozygotes (haplotype A/haplotype B) (Chen et al. 2008a). Besides playing a
prominent role in CHGA expression, a G-462A variant that altered a COUP-TF
transcriptional control motif was found to predict resting BP. Molecular heterosis
was also evident in this variant because of the presence of high BP in heterozygotes
(Chen et al. 2008a).
3.3 Regulation of Autonomic Activity and Blood Pressure
by CHGA 3′-UTR SNPs
The association of CHGA 3 ′-UTR with autonomic activity and BP was estab-
lished at UCSD from genotype (resequencing) and phenotype (plasma CgA, BP,
catecholamines) data in four different cohorts. The 1st cohort consisted of initial
resequencing of CHGA locus (8 exons, intron/exon borders, UTRs, and proximal
promoters) in 180 subjects as described above. The 2nd cohort comprised of twin
pairs from Southern California were 69% monozygotic (MZ) and 31% dizygotic
(DZ): n = 103 monozygotic (MZ) pairs (M/M 21, F/F 82), and n = 45 dizygotic
(DZ) pairs (8 M/M, 30 F/F, and 7 M/F). Amongst these twin pairs, 9.9% were
hypertensive (8.8% treated with antihypertensive medications). Changes in BP in
response to environmental (cold) stress were conducted in 149 twin pairs. The
third cohort was from a population cohort with extreme BPs consisted of 470
male and 558 female European American, which were selected based on DBP in
the upper or lower most extreme (fifth) percentiles of DBP distribution in 25,599
men and 27,479 women is a primary care practice at Kaiser-Permanente of
Southern California medical group. The DBP status was as follows: 189 men with
DBP ≥96 mm Hg and 281 men with DBP ≤61 mm Hg; 175 women with DBP
≥92 mm Hg and 383 women with DBP ≤59 mm Hg. The 4th cohort (purely phe-
notypic) consisted of 724 individuals with normal renal function (serum creati-
nine ≤1.5 mg/dl), stratified by BP status: normal BP (SBP < 135 and DBP < 85 mm
Hg, on no medications), versus a diagnosis of essential hypertension (DBP ≥ 90 mm
Hg, 75% were on antihypertensive medications). Consistent with previous stud-
ies, hypertensive subjects showed increased plasma CgA. A common (~27% fre-
quency) genetic variant in the CHGA 3 ′-UTR (C+87T) was found to be strongly
associated with human essential hypertension (Chen et al. 2008b). C+87T caused
significant effects on both SBP and DBP as well as with genotype-by-sex interac-
tions. Substantial BP differences between homozygote (C/C, T/T) classes were
evidenced in men: ~12 mm Hg for SBP and ~9 mm Hg for DBP. While C+87T
accounted for ~1.9% of the population variance in SBP (or ~13.7 mm Hg), and
~1.2% of the variance for DBP (or ~5.8 mm Hg) in men, C+87T did not affect
either SBP or DBP in women. Increased numbers of the minor T allele was found
to be associated with diminished plasma CgA (by ~10%) (Chen et al. 2008b).
Likewise, increased numbers of the minor T allele blunted cold-stress-induced
N.R. Mahapatra et al.