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Nuclear Receptor Coactivator-3 Alleles Are Associated with Serum Bioavailable Testosterone, Insulin-Like Growth Factor-1, and Vertebral Bone Mass in Men

Departments of Epidemiology (Y.-T.S., J.M.Z., J.A.C., S.P.M.) and Human Genetics (C.I., R.E.F.), Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and Maine Center for Osteoporosis Research and Education (C.J.R.), St. Joseph Hospital, Bangor, Maine 04401

Address all correspondence and requests for reprints to: Joseph M. Zmuda, Ph.D., Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, Pennsylvania 15261. E-mail: zmudaj{at}edc.pitt.edu.

Context: Nuclear receptor coactivator-3 (NCOA3) is a member of the steroid receptor coactivator family that interacts with nuclear hormone receptors to enhance their transcriptional activation function and may play a role in somatic growth.

Objective: The aim of this study was to examine the relationships between the CAG/CAA (glutamine) length variation at the NCOA3 locus, sex steroid hormone, and IGF-I levels and bone mineral density (BMD) in a cohort of older Caucasian men.

Design and Methods: We analyzed the association between potentially functional alleles at this locus, serum sex steroid hormone, and IGF-I levels and lumbar spine and proximal femur BMD (Hologic QDR) in 263 community-dwelling Caucasian men (age 66 ± 7 yr, mean ± SD; range 51–84 yr). Men were genotyped for a CAG/CAA repeat polymorphism in NCOA3, which encodes a polyglutamine tract of variable length in the C-terminal transcriptional activation domain of the protein.

Results: We found a significant monotonic decrease in lumbar spine, but not hip, BMD with increasing copies of the most common allele (29 repeats, 53%). For example, men with the 29/29 genotype had 6% or nearly 0.5 SD lower spine BMD than men without this genotype, and NCOA3 genotype explained 3.2% of the phenotypic variation in this trait. Serum levels of bioavailable testosterone and IGF-I paralleled genotype-related differences in lumbar spine BMD.

Conclusion: Allelic variation at the NCOA3 locus may contribute to the genetic control of androgenic hormone and IGF levels and vertebral bone mass among older men.