Diversity of Human Clock Genotypes and Consequences - Progress in Molecular Biology and Translational Science - page 64

allele correlates with higher levels of serum insulin-like growth factor-I
(IGF) and the ratio of IGF-I to IGF-binding protein 3, which may contrib-
ute to hormone-related cancer. 69 Furthermore, inflammation is an
established cancer risk factor and carriers of the 5-repeat allele show elevated
levels of the cytokine interleukin-6. 103
Lastly, the 4-repeat allele of PER3 is significantly linked to heroin depen-
dence and postpartum onset of BP. 104,105
8. CRY1
Two SNPs located in the promoter region of CRY1 are associated
with susceptibility to and mortality from prostate cancer, respectively. 23,106
On the other hand, a SNP within 3 0 -UTR of CRY1 correlates with risk of
breast cancer. 59 In addition, a SNP located 3 0 downstream of CRY1 is sig-
nificantly associated with MDD.
9. CRY2
CRY2 has been suggested by various studies to act as a modulator of
cancer development. Two intronic SNPs in CRY2 are significantly associ-
ated with susceptibility to prostate cancer. 23,67 For one of these SNPs located
in intron 2, rs1401417 G/C, carriers of the C allele exhibit 1.7-fold
increased risk of prostate cancer. 67 This risk is increased to 4.1-fold in the
C allele carriers with higher insulin resistance. This allele is also linked to
breast cancer risk, along with two additional SNPs, and all three of these
SNPs are significantly associated with the risk of non-Hodgkin's lym-
phoma. 59,107,108 Breast cancer patients have significantly higher levels of
CRY2 promoter methylation relative to controls, consistent with lower
levels of CRY2 in tumor tissues compared to adjacent normal tissues. 108 Fur-
thermore, in vitro analysis identifies alterations in the expression of breast
cancer-relevant genes, immune response genes, and hematologic system
development genes in response to CRY2 knockdown. 107,108 Some of these
genes are predicted to have significant effects on several disease processes,
including cancer. 107 Taken together, these findings suggest that CRY2
may exert significant effects on cancer susceptibility.
Genome-wide association study identified an intronic SNP in CRY2 to
be significantly associated with fasting glucose levels in nondiabetic adults. 109
Subsequent studies reported this locus to be correlated with T2D, as well as
fasting glucose in healthy children and adolescents. 110,111