title: Correlation between circadian gene variants and serum levels of sex steroids and insulin-like growth factor-I.
abstract: A variety of biological processes, including steroid hormone secretion, have circadian rhythms, which are influenced by nine known circadian genes. Previously, we reported that certain variants in circadian genes were associated with risk for prostate cancer. To provide some biological insight into these findings, we examined the relationship of five variants of circadian genes, including NPAS2 (rs2305160:G > A), PER1 (rs2585405:G > C), CSNK1E (rs1005473:A > C), PER3 (54-bp repeat length variant), and CRY2 (rs1401417:G > C), with serum levels of sex steroids and insulin-like growth factor (IGF)-I and IGF-binding protein 3 (IGFBP3) in 241 healthy elderly Chinese men (mean age of 71.5). Age-adjusted and waist-to-hip ratio-adjusted ANOVA followed by likelihood ratio tests (LRT) showed that the NPAS2 variant A allele was associated with lower free and bioavailable testosterone (P(LRT) = 0.02 and 0.01, respectively) compared with the GG genotype. In addition, the PER1 variant was associated with higher serum levels of sex hormone-binding globulin levels (Ptrend = 0.03), decreasing 5alpha-androstane-3alpha, 17beta-diol glucuronide levels (Ptrend = 0.02), and decreasing IGFBP3 levels (Ptrend = 0.05). Furthermore, the CSNK1E variant C allele was associated with higher testosterone to dihydrotestosterone ratios (P(LRT) = 0.01) compared with the AA genotype, whereas the longer PER3 repeat was associated with higher serum levels of IGF-I (P(LRT) = 0.03) and IGF-I to IGFBP3 ratios (P(LRT) = 0.04). The CRY2 polymorphism was not associated with any biomarkers analyzed. Our findings, although in need of confirmation, suggest that variations in circadian genes are associated with serum hormone levels, providing biological support for the role of circadian genes in hormone-related cancers.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 6120 Executive Boulevard, MSC 7234, Bethesda, MD 20892, USA. chulisa@mail.nih.gov
authors.forename: Lisa W
authors.initials: LW
authors.lastname: Chu
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.forename: Tongzhang
authors.initials: T
authors.lastname: Zheng
authors.forename: Anand P
authors.initials: AP
authors.lastname: Chokkalingam
authors.forename: Frank Z
authors.initials: FZ
authors.lastname: Stanczyk
authors.forename: Yu-Tang
authors.initials: YT
authors.lastname: Gao
authors.forename: Ann W
authors.initials: AW
authors.lastname: Hsing
mesh_terms: D000368:Aged; D000483:Alleles; D000704:Analysis of Variance; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D016022:Case-Control Studies; D048149:Casein Kinase 1 epsilon / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D002681:China / Q000453:epidemiology; D002940:Circadian Rhythm; D056931:Cryptochromes; D005420:Flavoproteins / Q000235:genetics; D005819:Genetic Markers; D014644:Genetic Variation; D005838:Genotype; D012739:Gonadal Steroid Hormones / Q000097:blood*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D056950:Period Circadian Proteins; D011471:Prostatic Neoplasms / Q000453:epidemiology / Q000235:genetics; D011795:Surveys and Questionnaires; D014157:Transcription Factors / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D048149:Casein Kinase 1 epsilon; D018797:Cell Cycle Proteins; D056931:Cryptochromes; D005420:Flavoproteins; D005819:Genetic Markers; D012739:Gonadal Steroid Hormones; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D014157:Transcription Factors; C538966:CRY2 protein, human; C104264:NPAS2 protein, human; C539022:PER1 protein, human; C512644:PER3 protein, human