title: Replication of associations between LRP5 and ESRRA variants and bone density in premenopausal women.
abstract: Replication is a critical step to validate positive genetic associations. In this study, we tested two previously reported positive associations. The low density lipoprotein receptor-related protein 5 (LRP5) Val667Met and lumbar spine bone density are replicated. This result is in line with results from large consortiums such as Genomos. However, the estrogen-related receptor alpha (ESRRA) repeat in the promoter is not replicated although the polymorphism studied was functional and could have been a causative variant.
  
  
  BACKGROUND
  We sought to validate associations previously reported between LRP5 V667M polymorphism and lumbar spine (LS, p = 0.013) and femoral neck (FN, p = 0.0002) bone mineral density (BMD), and between ESRRA 23 base pair repeat polymorphism and LS BMD (p = 0.0036) in a sample of premenopausal Caucasian women using an independent sample.
  
  
  METHODS
  For the replication sample, we recruited 673 premenopausal women from the Toronto metropolitan area. All women were Caucasian and had BMD measured. LRP5 V667M was genotyped by allele-specific PCR and ESRRA repeats by sizing of PCR products on agarose gels.
  
  
  RESULTS
  We reproduced the same association as we reported previously between LRP5 V667M and LS BMD (p = 0.015) but not with FN BMD (p = 0.254). The combined data from the two populations indicate an effect size of 0.28SD for LS BMD (p = 0.00048) and an effect size of 0.26 SD for FN BMD (p = 0.00037). In contrast, the association we reported earlier between ESRRA repeats and LS BMD was not replicated in the sample from Toronto (p = 0.645).
  
  
  CONCLUSIONS
  The association between LRP5 V667M and LS BMD is confirmed but not that between ESRRA repeats and LS BMD. This result indicates that it is imperative to validate any positive association in an independent sample.
authors.affiliation: Centre de Recherche de l'Hôpital, St-François d'Assise, Centre Hospitalier Universitaire de Québec, Quebec, Canada. Sylvie.giroux@crsfa.ulaval.ca
authors.forename: S
authors.initials: S
authors.lastname: Giroux
authors.forename: L
authors.initials: L
authors.lastname: Elfassihi
authors.forename: D E C
authors.initials: DE
authors.lastname: Cole
authors.forename: F
authors.initials: F
authors.lastname: Rousseau
mesh_terms: D000293:Adolescent; D000328:Adult; D015519:Bone Density / Q000235:genetics* / Q000502:physiology; D004261:DNA Replication / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008159:Lumbar Vertebrae / Q000503:physiopathology; D009864:Ontario; D010024:Osteoporosis / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control; D011110:Polymorphism, Genetic; D017697:Premenopause / Q000235:genetics*; D011960:Receptors, Estrogen; D055815:Young Adult; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C555482:LRP5 protein, human