A common variant in fibroblast growth factor binding protein 1 (FGFBP1) is associated with bone mineral density and influences gene expression in vitro.
We previously detected strong evidence for linkage of forearm bone mineral density (BMD) to chromosome 4p (lod=4.3) in a set of 29 large Mexican American families. Fibroblast growth factor binding protein 1 (FGFBP1) is a strong candidate gene for bone homeostasis in this region. We sequenced the coding region of FGFBP1 in a subset of our Mexican American study population and performed association studies with BMD on SNPs genotyped in the entire cohort. We then attempted to replicate these findings in an independent study cohort and performed in vitro functional studies on replicated, potentially functional polymorphisms using a luciferase reporter construct to evaluate influence on gene expression. Several SNPs spanning the gene, all in one large block of linkage disequilibrium, were significantly associated with BMD at various skeletal sites (n=872, p=0.001-0.04). The associations were then replicated in an independent population of European ancestry (n=972; p=0.02-0.04). Sex-stratified association analyses in both study populations suggest this association is much stronger in men. Subsequent luciferase reporter gene assays revealed marked differences in FGFBP1 expression among the three common haplotypes. Further experiments revealed that a promoter polymorphism, rs12503796, results in decreased expression of FGFBP1 and inhibits upregulation of the gene by testosterone in vitro. Collectively, these findings suggest that sequence variation in FGFBP1 may contribute to variation in BMD, possibly influencing osteoporosis risk.
Hoppman
Nicole
N
Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA. hoppmanchaney.nicole@mayo.edu
McLenithan
John C
JC
McBride
Daniel J
DJ
Shen
Haiqing
H
Bruder
Jan
J
Bauer
Richard L
RL
Shaffer
John R
JR
Liu
Jie
J
Streeten
Elizabeth A
EA
Shuldiner
Alan R
AR
Kammerer
Candace M
CM
Mitchell
Braxton D
BD
D000328:Adult; D001665:Binding Sites; D015519:Bone Density / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D017058:Mexican Americans / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000378:metabolism; D044465:White People / Q000235:genetics
D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D014157:Transcription Factors; C070699:FGFBP1 protein, human
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