title: 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.
abstract: BACKGROUND
  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.
  
  
  METHODS
  This was a population-based, prospective, and cross-sectional study, the Swedish MrOS Study, and the Malmö OPRA Study, respectively.
  
  
  METHODS
  The study was conducted at three academic medical centers: Sahlgrenska Academy in Gothenburg, Malmö University Hospital, and Uppsala University Hospital.
  
  
  METHODS
  In total, 4058 men and women, aged 69-81 yr, were randomly selected from population registries.
  
  
  METHODS
  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.
authors.affiliation: Department of Medical Sciences, Uppsala University Hospital, Ing 70, 3 tr, Uppsala, Sweden. elin.grundberg@medsci.uu.se
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.forename: Kristina
authors.initials: K
authors.lastname: Akesson
authors.forename: Andreas
authors.initials: A
authors.lastname: Kindmark
authors.forename: Paul
authors.initials: P
authors.lastname: Gerdhem
authors.forename: Anna
authors.initials: A
authors.lastname: Holmberg
authors.forename: Dan
authors.initials: D
authors.lastname: Mellström
authors.forename: Osten
authors.initials: O
authors.lastname: Ljunggren
authors.forename: Eric
authors.initials: E
authors.lastname: Orwoll
authors.forename: Hans
authors.initials: H
authors.lastname: Mallmin
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.forename: Helena
authors.initials: H
authors.lastname: Brändström
mesh_terms: D015502:Absorptiometry, Photon; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density / Q000235:genetics*; D001851:Bone Diseases, Metabolic / Q000453:epidemiology / Q000235:genetics*; D003430:Cross-Sectional Studies; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004958:Estradiol / Q000097:blood*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005272:Femur Neck / Q000000981:diagnostic imaging / Q000473:pathology; D017353:Gene Deletion; D005838:Genotype; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000473:pathology; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012042:Registries / Q000706:statistics & numerical data; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D004958:Estradiol; D011495:Histone-Lysine N-Methyltransferase; C093563:PRDM2 protein, human