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A Deletion Polymorphism in the RIZ Gene, a Female Sex Steroid Hormone Receptor Coactivator, Exhibits Decreased Response to Estrogen in Vitro and Associates with Low Bone Mineral Density in Young Swedish Women

Department of Medical Sciences (E.G., H.B., Ö.L., A.K.) and Department of Surgical Sciences, Section of Orthopedics (E.L.R., H.M.), Uppsala University, SE-751 85 Uppsala, Sweden; Department of Surgery, Yale University School of Medicine (T.C.), New Haven, Connecticut 06510; and Program in Oncogenes and Tumor Suppressor Genes, The Burnham Institute (S.H.), La Jolla, California 92037

Address all correspondence and requests for reprints to: Dr. Elin Grundberg, Department of Medical Sciences, Uppsala University Hospital, Entrance 70, Third Floor, Clinical Research Department 2/3, SE-751 85 Uppsala, Sweden. E-mail: elin.grundberg{at}medsci.uu.se.

Low bone mineral density (BMD) is a major risk factor for osteoporotic fracture, and the trait is under genetic control by a large number of genes. It is recognized that estrogen plays an important role in the maintenance of bone mass by binding to estrogen receptor (ER). RIZ1 has previously been shown to be a specific ER coactivator and strongly enhances its function both in vivo and in vitro. We performed in vitro studies comparing the abilities of RIZ1 P704 polymorphic variants (homozygous presence, P704⁺; absence, P704^–; heterozygosity P704^+/– of a proline at position 704) to coactivate the ER and also examined the polymorphism associated to BMD of 343 Swedish women, aged 20–39 yr. The expression vector containing P704^– RIZ1 showed an impaired response in coactivating ER in a ligand- and dose-dependent manner compared with P704⁺ RIZ (P < 0.0001). The genotype frequencies were 19% (P704⁺), 32% (P704^–), and 49% (P704^+/–) and were in Hardy-Weinberg equilibrium. BMD at the heel was higher in the P704⁺ genotype group than in the P704^+/– group (P = 0.02), which was evident also after corrections for fat and lean mass (P = 0.03). We conclude that RIZ1 may be a new candidate gene for involvement in the variation seen in BMD.

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				E. Grundberg, K. Akesson, A. Kindmark, P. Gerdhem, A. Holmberg, D. Mellstrom, O. Ljunggren, E. Orwoll, H. Mallmin, C. Ohlsson, et al. The Impact of Estradiol on Bone Mineral Density Is Modulated by the Specific Estrogen Receptor-{alpha} Cofactor Retinoblastoma-Interacting Zinc Finger Protein-1 Insertion/Deletion Polymorphism J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2300 - 2306. [Abstract] [Full Text] [PDF]