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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.

Journal article
Authors Elin Grundberg
Kristina Akesson
Andreas Kindmark
Paul Gerdhem
Anna Holmberg
Dan Mellström
Osten Ljunggren
Eric Orwoll
Hans Mallmin
Claes Ohlsson
Helena Brändström
Published in The Journal of clinical endocrinology and metabolism
Volume 92
Issue 6
Pages 2300-6
ISSN 0021-972X
Publication year 2007
Published at Institute of Medicine, School of Public Health and Community Medicine
Institute of Medicine, Department of Internal Medicine
Pages 2300-6
Language en
Keywords Absorptiometry, Photon, Aged, Aged, 80 and over, Bone Density, genetics, Bone Diseases, Metabolic, epidemiology, genetics, Cross-Sectional Studies, DNA-Binding Proteins, genetics, metabolism, Estradiol, blood, Estrogen Receptor alpha, metabolism, Female, Femur Neck, pathology, radiography, Gene Deletion, Genotype, Humans, Lumbar Vertebrae, pathology, radiography, Male, Nuclear Proteins, genetics, metabolism, Polymorphism, Genetic, Predictive Value of Tests, Prospective Studies, Registries, statistics & numerical data, Transcription Factors, genetics, metabolism
Subject categories Medical and Health Sciences


CONTEXT: Estrogens regulate bone mass by binding to the estrogen receptor (ER)-alpha as well as ER-beta. The specific ERalpha cofactor retinoblastoma-interacting zinc finger protein (RIZ)-1 enhances ERalpha function in the presence of estrogen. OBJECTIVE: The objective of the study was to determine whether a RIZ P704 insertion (+)/deletion (-) (indel) polymorphism modulates the impact of estradiol on bone mineral density (BMD) and study the association between the polymorphism and BMD in elderly subjects. DESIGN: This was a population-based, prospective, and cross-sectional study, the Swedish MrOS Study, and the Malmö OPRA Study, respectively. SETTING: The study was conducted at three academic medical centers: Sahlgrenska Academy in Gothenburg, Malmö University Hospital, and Uppsala University Hospital. PARTICIPANTS: In total, 4058 men and women, aged 69-81 yr, were randomly selected from population registries. MAIN OUTCOME MEASURES: BMD (grams per square centimeter) was measured at femoral neck, trochanter, lumbar spine, and total body. RESULTS: The RIZ P704(+/+) genotype was associated with low BMD in both women (femoral neck, P < 0.001; trochanter, P < 0.01; lumbar spine, P < 0.05; total body, P < 0.01) and men (lumbar spine, P < 0.05). However, the association between the polymorphism and BMD was dependent on estradiol status. The positive correlation between serum estradiol and BMD was significantly modulated by the genotype with a stronger correlation in the P704(+/+) group than the P704(-/-) group (r = 0.19 vs. r = 0.08, P < 0.05). CONCLUSIONS: These large-scale studies of elderly men and women indicate that the ERalpha cofactor RIZ gene has a prominent effect on BMD, and the P704 genotype modulates the impact of estradiol on BMD. Further studies are required to determine whether this polymorphism modulates the estrogenic response to estradiol treatment.

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