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Correlation between Circadian Gene Variants and Serum Levels of Sex Steroids and Insulin-like Growth Factor-I

¹ Division of Cancer Epidemiology and Genetics and ² Cancer Prevention Fellowship Program, Office of Preventive Oncology, National Cancer Institute, NIH, Bethesda, Maryland; ³ Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut; ⁴ Division of Epidemiology, School of Public Health, University of California at Berkeley, Berkeley, California; ⁵ Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California; and ⁶ Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China

Requests for reprints: Lisa W. Chu, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, MSC 7234, Bethesda, MD 20892. Phone: 510-333-9400; Fax: 301-402-0916. E-mail: chulisa{at}mail.nih.gov

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 (P_trend = 0.03), decreasing 5-androstane-3, 17β-diol glucuronide levels (P_trend = 0.02), and decreasing IGFBP3 levels (P_trend = 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. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3268–73)