Genetic Polymorphism CYP17 rs2486758 and Metabolic Risk Factors Predict Daily Salivary 17β-Estradiol Concentration in Healthy Premenopausal Norwegian Women. The EBBA-I Study

Context: The relationship between low-penetrance genes, metabolic risk factors, and levels of endogenous 17β-estradiol and progesterone, which play a role in breast cancer risk, remains unclear. Objective: The aim of this study was to determine whether common polymorphisms in CYP17, in combination with metabolic risk factors (individually or clustered), alter salivary concentrations of free biologically active 17β-estradiol and progesterone among healthy premenopausal Norwegian women. Design: Eight single nucleotide polymorphisms in CYP17 were genotyped in 203 healthy premenopausal women aged 25–35 yr in the Norwegian EBBA-I Study, conducted in 2000–2002. Daily salivary concentrations of 17β-estradiol and progesterone were measured throughout one menstrual cycle. A clustered metabolic score was calculated, including waist circumference, mean arterial pressure, insulin resistance, fasting triglycerides, and total cholesterol/high-density lipoprotein cholesterol ratio. The study hypothesis was tested in multivariable linear regression and generalized estimating equation models. Results: Women in the upper tertile of clustered metabolic score with the CYP17 rs2486758 minor allele had daily salivary 17β-estradiol concentrations that were 53% higher than other study women throughout the menstrual cycle (P < 0.001). Similarly, women in the upper tertile of total cholesterol/high-density lipoprotein cholesterol ratio, fasting triglycerides, and insulin resistance had 44, 32, and 24% higher daily salivary 17β-estradiol concentrations, respectively (all P < 0.05). Conclusion: The CYP17 rs2486758 minor allele may predispose to higher 17β-estradiol levels, particularly in premenopausal women with a high clustered metabolic score. Thus, modification of metabolic risk factors may have significant implications for the prevention of breast cancer in women with the minor allele of CYP17 rs2486758.