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E. Grundberg, T. Carling, H. Brändström, S. Huang, E. L. Ribom, Ö. Ljunggren, H. Mallmin, A. Kindmark, 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, The Journal of Clinical Endocrinology & Metabolism, Volume 89, Issue 12, 1 December 2004, Pages 6173–6178, https://doi.org/10.1210/jc.2004-0403
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Abstract
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 α (ERα). RIZ1 has previously been shown to be a specific ERα 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 ERα 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 ERα 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.
