Diversity of Human Clock Genotypes and Consequences - Progress in Molecular Biology and Translational Science - page 57

suggesting a role for CLOCK in metabolic pathways. Clock mutant mice
nicely recapitulate many of the metabolic phenotypes associated with human
CLOCK gene polymorphisms. These animals are hyperphagic and obese
and develop hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglyce-
mia, and hypoinsulinemia. 57 This supports the idea that the polymorphisms
in the human CLOCK gene are causatively linked to metabolic alterations
observed in human subjects.
Lastly, CLOCK variants correlate with the risk and survival rate of can-
cer. Several SNPs located in intronic regions and 3 0 -UTR of CLOCK ,
including rs1801260, are significantly associated with susceptibility to pros-
tate cancer or breast cancer. 23,58,59 Both rs1801260 and rs3749474, which
have been implicated in various metabolic traits as described earlier, exhibit
significant association with survival of colorectal cancer. 60
4. NPAS2
As a paralogue of CLOCK, NPAS2 has also been implicated in circa-
dian timing and sleep. A SNP in intron 3 of the NPAS2 gene is associated
with timing of sleep in nurses on shift-work schedule, while another SNP in
intron 3 correlates with sleepiness during shift work and self-reported adap-
tation levels to shift-work schedule. 61 Notably, this latter SNP is also signif-
icantly linked to alcohol consumption. 61 Consistently, Npas2 -deficient mice
show reduction in sleep during the active phase and enhanced adaptability to
phase advance of light-dark schedule. 62
Like the other two circadian activators, BMAL1 and CLOCK, NPAS2
may be involved in mood regulation as well. In patients with SAD, the fre-
quency of NPAS2 471 Leu/Leu genotype is significantly higher than in con-
trols, suggesting that NPAS2 471 Leu/Leu contributes to disease
susceptibility. 24,63 Furthermore, NPAS2 394 Thr correlates with lack of
experiencing seasonal variation, assayed by Global Seasonal Scores which
measures six items, including seasonal variation of sleep length, social activ-
ity, mood, weight, appetite, and energy level, whereas an intronic variant of
NPAS2 is associated with seasonal variation of weight. 25 Another intronic
SNP is related to the number of miscarriages, implying that NPAS2 influ-
ences fertility. 25 Intronic polymorphisms in NPAS2 have also been linked to
unipolar major mood depression, autistic disorder, and chronic fatigue syn-
drome. 44,64,65 Notably, NPAS2 expression is increased in patients with
chronic fatigue syndrome. 65