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Functional Characterization of Genetic Variation in the Frizzled 1 (FZD1) Promoter and Association With Bone Phenotypes: More to the LRP5 Story?
Author(s) -
Yerges Laura M,
Zhang Yingze,
Cauley Jane A,
Kammerer Candace M,
Nestlerode Cara S,
Wheeler Victor W,
Patrick Alan L,
Bunker Clareann H,
Moffett Susan P,
Ferrell Robert E,
Zmuda Joseph M
Publication year - 2009
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.080816
Subject(s) - single nucleotide polymorphism , genetics , biology , frizzled , wnt signaling pathway , minor allele frequency , lrp5 , allele , genotype , gene
WNT signaling is an important determinant of bone formation. The WNT co‐receptor, Frizzled homolog 1 (FZD1), initiates WNT signal transduction. To study the influence of FZD1 genetic variation on measures of bone health, we first sequenced a 6.8‐kb region surrounding FZD1 in 48 samples of African ancestry. We genotyped all common polymorphisms and performed association analysis with bone phenotypes in a larger sample. Only 3 of 35 SNPs identified were present in ≥5% of the sample and assayed further in 1084 men of African ancestry. Two of these SNPs were in the FZD1 promoter (rs2232157, rs2232158) and were associated with femoral neck areal BMD ( p = 0.041 and 0.009, respectively). The minor alleles of these two SNPs were also associated with larger bone size at the radius ( p < 0.05 for both), and rs2232158 was associated with greater strength‐strain index, an indicator of bone's ability to withstand torsion. Functional experiments were completed to assess the influence of the rs2232158 promoter polymorphism on transcriptional regulation of FZD1. The minor C allele in rs2232158 creates a binding site for the transcription factor Egr1, has higher Egr1 binding affinity, and has greater FZD1 promoter activity in MG63 and SaOS‐2 cells, providing a plausible molecular mechanism for the population associations. This study indicates that a cis ‐regulatory polymorphism in the FZD1 promoter region may have a functional role in determining bone structural geometry.