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4.2 Functional Genetic Polymorphisms in the Catestatin (CST)
Domain
4.2.1 Discovery of CST SNPs
Resequencing of all eight exons and adjacent intronic regions from 180 ethnically
diverse human subjects (2n = 360 chromosomes) at UCSD as described above
revealed two non-synonymous SNPs in the CST region: Gly364Ser variation
(rs9658667; occurred in 11 of 180 subjects; minor allele frequency, 3.1%) and
Pro370Leu (rs9658668; occurred in 2 of 180 subjects; minor allele frequency, 0.6%)
(Wen et al. 2004 ). Although the Gly364Ser variant was distributed across other
ethnic groups (5 Asian American, 5 European American, and 1 Hispanic American),
it was absent in African American sample. In contrast, Pro370Leu variant occurred
only in African American samples. Resequencing CST region of CHGA in an Indian
population (n = 1010 subjects) at IITM detected 2 SNPs: Gly364Ser (minor allele
frequency, 7.92%, ~2.6-fold higher than UCSD population) (Fig. 4b, c), and a new
SNP Gly367Val (rs200576557) (minor allele frequency, 0.099%), which was not
detected in UCSD population (Sahu et al. 2012 ). Resequencing of 343 Japanese
subjects also detected Gly364Ser with a minor allele frequency of 6.1%, which is
comparable to the Indian population (Choi et al. 2015 ). Thus, Gly364Ser variant is
much more preponderant in Asian populations.
4.2.2 Functional Consequences of CST SNPs
Effects of CST Variants on Catecholamine Secretion
UCSD studies in PC12 cells revealed that the Gly364Ser variant of CST was ~4.7-
fold less potent than WT-CST and Pro370Leu variant was ~2.3-fold more potent
than WT-CST in terms of the inhibition of nicotine-evoked catecholamine secretion
(Mahata et al. 2004 ; Wen et al. 2004 ) (Fig. 5b). IITM study in PC12 cells also found
comparable loss of potency for Gly364Ser variant in inhibition of nicotine-evoked
catecholamine secretion (Sahu et al. 2012 ). In addition, UCSD studies revealed less
renal catecholamine secretion in Gly364Ser heterozygotes (n = 13) compared to
Gly364/Gly364 homozygotes (n = 236) (Rao et al. 2007 ) (Fig. 5c). Furthermore,
IITM study found marked decrease in plasma catecholamines in both the Gly364Ser
heterozygotes and Ser364Ser homozygotes (Sahu et al. 2012 ).
Effects of CST Variants on Cardiovascular Function
The initial UCSD study consisted of 166 hypertensive (DBP > 95 mm Hg) indi-
viduals (146 men, 20 women) and 353 unmedicated normotensive controls
(DBP < 85 mm Hg; 186 men, 167 women) from European descent. The replication
study (Kaiser Permanente) included 1361 white (European ancestry; 643 male,
N.R. Mahapatra et al.