A common variant in fibroblast growth factor binding protein 1 (FGFBP1) is associated with bone mineral density and influences gene expression in vitro

Nicole Hoppman, John C. McLenithan, Daniel J. McBride, Haiqing Shen, Jan M Bruder, Richard L Bauer, John R. Shaffer, Jie Liu, Elizabeth A. Streeten, Alan R. Shuldiner, Candace M. Kammerer, Braxton D. Mitchell

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)272-280
Number of pages9
JournalBone
Volume47
Issue number2
DOIs
StatePublished - Aug 2010

Fingerprint

Fibroblast Growth Factors
Bone Density
Carrier Proteins
Gene Expression
Luciferases
Single Nucleotide Polymorphism
Population
Genes
Linkage Disequilibrium
Reporter Genes
Forearm
Haplotypes
Osteoporosis
Testosterone
Homeostasis
Cohort Studies
Up-Regulation
Chromosomes
In Vitro Techniques
Bone and Bones

Keywords

  • Bone mineral density
  • FGFBP1
  • Osteoporosis
  • Polymorphisms
  • Testosterone

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology
  • Medicine(all)

Cite this

A common variant in fibroblast growth factor binding protein 1 (FGFBP1) is associated with bone mineral density and influences gene expression in vitro. / Hoppman, Nicole; McLenithan, John C.; McBride, Daniel J.; Shen, Haiqing; Bruder, Jan M; Bauer, Richard L; Shaffer, John R.; Liu, Jie; Streeten, Elizabeth A.; Shuldiner, Alan R.; Kammerer, Candace M.; Mitchell, Braxton D.

In: Bone, Vol. 47, No. 2, 08.2010, p. 272-280.

Research output: Contribution to journalArticle

Hoppman, N, McLenithan, JC, McBride, DJ, Shen, H, Bruder, JM, Bauer, RL, Shaffer, JR, Liu, J, Streeten, EA, Shuldiner, AR, Kammerer, CM & Mitchell, BD 2010, 'A common variant in fibroblast growth factor binding protein 1 (FGFBP1) is associated with bone mineral density and influences gene expression in vitro', Bone, vol. 47, no. 2, pp. 272-280. https://doi.org/10.1016/j.bone.2010.04.607
Hoppman, Nicole ; McLenithan, John C. ; McBride, Daniel J. ; Shen, Haiqing ; Bruder, Jan M ; Bauer, Richard L ; Shaffer, John R. ; Liu, Jie ; Streeten, Elizabeth A. ; Shuldiner, Alan R. ; Kammerer, Candace M. ; Mitchell, Braxton D. / A common variant in fibroblast growth factor binding protein 1 (FGFBP1) is associated with bone mineral density and influences gene expression in vitro. In: Bone. 2010 ; Vol. 47, No. 2. pp. 272-280.
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