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Genetic Variations in Sex Steroid-Related Genes as Predictors of Serum Estrogen Levels in Men

Center for Bone Research at the Sahlgrenska Academy (A.L.E., M.L., L.V., D.M., C.O.), Departments of Internal Medicine and Geriatrics, Gothenburg University, SE-413 45 Gothenburg, Sweden; Laboratory of Molecular Endocrinology and Oncology (F.L.), Laval University Hospital Research Center and Laval University, Québec City, Quebec G1V 4G2, Canada; Department of Medical Sciences (M.L., A.-C.S., O.L.), Uppsala University, SE-751 05 Uppsala, Sweden; Bone and Mineral Unit (E.S.O.), Department of Medicine, Oregon Health and Science University, Portland, Oregon 97239; San Francisco Coordinating Center (S.R.C.), Research Institute, California Pacific Medical Center, San Francisco, California 94107-1762; Department of Epidemiology (J.M.Z.), Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and Clinical and Molecular Osteoporosis Research Unit (M.K.K.), Department of Clinical Sciences, Lund University, and Department of Orthopaedics, Malmö University Hospital, SE-205 02 Malmö, Sweden

Address all correspondence and requests for reprints to: Claes Ohlsson, M.D., Ph.D., Professor, Division of Endocrinology, Department of Internal Medicine, Sahlgrenska University Hospital, SE-41345 Göteborg, Sweden. E-mail: Claes.Ohlsson{at}medic.gu.se.

Context: The risk of many conditions, including prostate cancer, breast cancer, and osteoporosis, is associated with serum levels of sex steroids.

Objective: The aim of the study was to identify genetic variations in sex steroid-related genes that are associated with serum levels of estradiol (E2) and/or testosterone in men.

Design: Genotyping of 604 single nucleotide polymorphisms in 50 sex steroid-related candidate genes was performed in the Gothenburg Osteoporosis and Obesity Determinants (GOOD) study (n = 1041 men; age, 18.9 ± 0.6 yr). Replications of significant associations were performed in the Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2568 men; age, 75.5 ± 3.2 yr) and in the MrOS US study (n = 1922 men; age, 73.5 ± 5.8 yr). Serum E2, testosterone, and estrone (E1) levels were analyzed using gas chromatography/mass spectrometry.

Results: The screening in the GOOD cohort identified the single nucleotide polymorphism rs2470152 in intron 1 of the CYP19 gene, which codes for aromatase, responsible for the final step of the biosynthesis of E2 and E1, to be most significantly associated with serum E2 levels (P = 2 x 10^–6). This association was confirmed both in the MrOS Sweden study (P = 9 x 10^–7) and in the MrOS US study (P = 1 x 10^–4). When analyzed in all subjects (n = 5531), rs2470152 was clearly associated with both E2 (P = 2 x 10^–14) and E1 (P = 8 x 10^–19) levels. In addition, this polymorphism was modestly associated with lumbar spine BMD (P < 0.01) and prevalent self-reported fractures (P < 0.05).

Conclusions: rs2470152 of the CYP19 gene is clearly associated with serum E2 and E1 levels in men.

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