title: A haplotype-based analysis of the LRP5 gene in relation to osteoporosis phenotypes in Spanish postmenopausal women.
abstract: LRP5 encodes the low-density lipoprotein receptor-related protein 5, a transmembrane protein involved in Wnt signaling. LRP5 is an important regulator of osteoblast growth and differentiation, affecting bone mass in vertebrates. Whether common variations in LRP5 are associated with normal BMD variation or osteoporotic phenotypes is of great relevance. We used a haplotype-based approach to search for common disease-associated variants in LRP5 in a cohort of 964 Spanish postmenopausal women. Twenty-four SNPs were selected, covering the LRP5 region, including the missense changes p.V667M and p.A1330V. The SNPs were genotyped and evaluated for association with BMD at the lumbar spine (LS) or femoral neck (FN) and with osteoporotic fracture, at single SNP and haplotype levels, by regression methods. Association with LS BMD was found for SNP 1, rs312009, located in the 5'-flanking region (p = 0.011, recessive model). SNP 6, rs2508836, in intron 1, was also associated with BMD, both at LS (p = 0.025, additive model) and FN (p = 0.031, recessive model). Two polymorphisms were associated with fracture: SNP 11, rs729635, in intron 1, and SNP 15, rs643892, in intron 5 (p = 0.007 additive model and p = 0.019 recessive model, respectively). Haplotype analyses did not provide additional information, except for haplotype "GC" of the block located at the 3'end of the gene. This haplotype spans intron 22 and the 3' untranslated region and was associated with FN BMD (p = 0.029, one copy of the haplotype versus none). In silico analyses showed that SNP 1 (rs312009) lies in a putative RUNX2 binding site. Electro-mobility shift assays confirmed RUNX2 binding to this site.
authors.affiliation: Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Lídia
authors.initials: L
authors.lastname: Agueda
authors.forename: Mariona
authors.initials: M
authors.lastname: Bustamante
authors.forename: Susana
authors.initials: S
authors.lastname: Jurado
authors.forename: Natalia
authors.initials: N
authors.lastname: Garcia-Giralt
authors.forename: Manel
authors.initials: M
authors.lastname: Ciria
authors.forename: Guillem
authors.initials: G
authors.lastname: Saló
authors.forename: Ramon
authors.initials: R
authors.lastname: Carreras
authors.forename: Xavier
authors.initials: X
authors.lastname: Nogués
authors.forename: Leonardo
authors.initials: L
authors.lastname: Mellibovsky
authors.forename: Adolfo
authors.initials: A
authors.lastname: Díez-Pérez
authors.forename: Daniel
authors.initials: D
authors.lastname: Grinberg
authors.forename: Susana
authors.initials: S
authors.lastname: Balcells
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D001665:Binding Sites; D015519:Bone Density; D015331:Cohort Studies; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008875:Middle Aged; D010024:Osteoporosis / Q000208:ethnology* / Q000235:genetics*; D010641:Phenotype; D017698:Postmenopause; D013030:Spain
chemical_list: D020413:3' Untranslated Regions; D050659:Core Binding Factor Alpha 1 Subunit; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C493709:RUNX2 protein, human