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This version published online on August 22, 2006
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-0679
A more recent version of this article appeared on December 1, 2006
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Submitted on March 29, 2006
Accepted on August 14, 2006

SHBG gene promoter polymorphisms in men are associated with serum SHBG, androgen and androgen metabolite levels and hip BMD

A L Eriksson, M Lorentzon, D Mellström, L Vandenput, C Swanson, N Andersson, G L Hammond, J Jakobsson, A Rane, E S Orwoll, Ö Ljunggren, O Johnell, F Labrie, S H Windahl, and C Ohlsson*

Center for Bone Research at the Sahlgrenska Academy, Departments of Internal Medicine and Geriatrics, Göteborg University, Göteborg, Sweden; Department of Obstetrics and Gynaecology, University of British Columbia, and Child and Family Research Institute, Vancouver, Canada; Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Bone and Mineral Research Unit, Oregon Health & Sciences University and Portland Veterans Affairs Medical Center, Portland, Oregon, United States; Department of Medical Sciences, University of Uppsala, Uppsala, Sweden; Department of Orthopaedics, Malmö General Hospital, Malmö, Sweden; Laboratory of Molecular Endocrinology and Oncology, Laval University Hospital Research Center (CRCHUL) and Laval University, Quebec, Canada

* To whom correspondence should be addressed. E-mail: claes.ohlsson{at}medic.gu.se.

Context: Sex Hormone Binding Globulin (SHBG) regulates free sex steroid levels, which in turn regulate skeletal homeostasis. Twin studies have demonstrated that genetic factors largely account for inter-individual variation in SHBG levels. Glucuronidated androgen metabolites have been proposed as markers of androgenic activity.

Objective: To investigate if polymorphisms in the SHBG gene promoter ((TAAAA)n microsatellite and rs 1799941 SNP) are associated with serum levels of SHBG, sex steroids or BMD in men.

Design and study subjects: Population based study of two cohorts of Swedish men; elderly men (Mr Os Sweden; n {cong} 3000, average age 75.4) and young adult men (GOOD study; n = 1068, average age 18.9).

Main outcome measures: Serum levels of SHBG, testosterone, estradiol, dihydrotestosterone (DHT), 5{alpha}-androstane-3{alpha},17{beta}-diol glucuronides (3{alpha}-DIOL-Gs), androsterone glucuronide (ADTG), and bone mineral density (BMD) determined by DXA.

Results: In both cohorts, (TAAAA)n and rs 1799941 genotypes were associated with serum levels of SHBG (P < 0.001), DHT (P < 0.05) and 3{alpha}-DIOL-Gs (P < 0.05). In the elderly men they were also associated with testosterone and BMD at all hip bone sites. The genotype associated with high levels of SHBG was also associated with high BMD. Interestingly, male mice over-expressing human SHBG had increased cortical bone mineral content in the femur, suggesting that elevated SHBG levels may cause increased bone mass.

Conclusions: Our findings demonstrate that polymorphisms in the SHBG promoter predict serum levels of SHBG, androgens and glucuronidated androgen metabolites, and hip BMD in men.
Key words: SHBG polymorphisms • SHBG levels • glucuronidated androgen metabolites • BMD • men




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