Functional characterization of genetic variation in the Frizzled 1 (FZD1) promoter and association with bone phenotypes: more to the LRP5 story?
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 >or=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.
Yerges
Laura M
LM
Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Zhang
Yingze
Y
Cauley
Jane A
JA
Kammerer
Candace M
CM
Nestlerode
Cara S
CS
Wheeler
Victor W
VW
Patrick
Alan L
AL
Bunker
Clareann H
CH
Moffett
Susan P
SP
Ferrell
Robert E
RE
Zmuda
Joseph M
JM
D000328:Adult; D000483:Alleles; D001665:Binding Sites; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism*; D051157:Frizzled Receptors / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014300:Trinidad and Tobago
C489740:FZD1 protein, human; D051157:Frizzled Receptors; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5