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.