title: A common variant in fibroblast growth factor binding protein 1 (FGFBP1) is associated with bone mineral density and influences gene expression in vitro.
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.
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA. hoppmanchaney.nicole@mayo.edu
authors.forename: Nicole
authors.initials: N
authors.lastname: Hoppman
authors.forename: John C
authors.initials: JC
authors.lastname: McLenithan
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: McBride
authors.forename: Haiqing
authors.initials: H
authors.lastname: Shen
authors.forename: Jan
authors.initials: J
authors.lastname: Bruder
authors.forename: Richard L
authors.initials: RL
authors.lastname: Bauer
authors.forename: John R
authors.initials: JR
authors.lastname: Shaffer
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Streeten
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Candace M
authors.initials: CM
authors.lastname: Kammerer
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
mesh_terms: 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
chemical_list: D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D014157:Transcription Factors; C070699:FGFBP1 protein, human
references.citation: Mutat Res. 2005 Jun 3;573(1-2):111-35
references.pmid: 15829242
references.citation: J Cell Biol. 2000 Jun 12;149(6):1297-308
references.pmid: 10851026
references.citation: Genet Epidemiol. 2004 Sep;27(2):153-61
references.pmid: 15305331
references.citation: Oncogene. 2005 Aug 11;24(34):5269-77
references.pmid: 15806171
references.citation: J Bone Miner Res. 2003 Dec;18(12):2245-52
references.pmid: 14672361
references.citation: Biochem Biophys Res Commun. 2004 May 21;318(1):162-7
references.pmid: 15110768
references.citation: Mol Endocrinol. 1997 Jul;11(8):1129-44
references.pmid: 9212060
references.citation: Nat Genet. 2009 May;41(5):527-34
references.pmid: 19396169
references.citation: Histol Histopathol. 2002;17(3):877-85
references.pmid: 12168799
references.citation: J Bone Miner Res. 2004 Feb;19(2):308-13
references.pmid: 14969401
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: J Clin Invest. 1987 Sep;80(3):706-10
references.pmid: 3624485
references.citation: J Cell Biochem. 2001;81(1):68-81
references.pmid: 11180398
references.citation: Bone. 1987;8(4):207-9
references.pmid: 3446256
references.citation: BMC Med Genet. 2007 Sep 19;8 Suppl 1:S14
references.pmid: 17903296
references.citation: J Bone Miner Res. 2000 Mar;15(3):466-73
references.pmid: 10750561
references.citation: J Biol Chem. 2001 Oct 26;276(43):40247-53
references.pmid: 11509569
references.citation: Nat Genet. 2009 Jan;41(1):15-7
references.pmid: 19079262
references.citation: J Bone Miner Res. 2006 Sep;21(9):1433-42
references.pmid: 16939402
references.citation: J Biol Chem. 2000 Oct 6;275(40):31444-50
references.pmid: 10896947
references.citation: Arthritis Rheum. 2004 Aug;50(8):2450-8
references.pmid: 15334457
references.citation: Curr Opin Rheumatol. 2005 Jul;17(4):475-9
references.pmid: 15956846
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3651-3
references.pmid: 12824386
references.citation: Bioinformatics. 2002 Feb;18(2):333-4
references.pmid: 11847087
references.citation: Int J Cancer. 2001 May 15;92(4):510-7
references.pmid: 11304685
references.citation: J Bone Miner Res. 1997 Dec;12(12):2076-81
references.pmid: 9421240
references.citation: Osteoporos Int. 2005 Dec;16(12):1849-56
references.pmid: 15997421
references.citation: Am J Hum Genet. 1998 Jul;63(1):259-66
references.pmid: 9634505
references.citation: Lancet. 2008 May 3;371(9623):1505-12
references.pmid: 18455228
references.citation: J Clin Invest. 1973 Nov;52(11):2800-8
references.pmid: 4795916
references.citation: J Bone Miner Res. 2006 Oct;21(10):1511-35
references.pmid: 16995806
references.citation: Cell Biol Int. 2001;25(6):567-70
references.pmid: 11407864
references.citation: Am J Hum Genet. 2009 Mar;84(3):388-98
references.pmid: 19249006
references.citation: Nucleic Acids Res. 1998 Jan 1;26(1):362-7
references.pmid: 9399875
references.citation: Bone. 2003 Nov;33(5):839-46
references.pmid: 14623060
references.citation: N Engl J Med. 2008 May 29;358(22):2355-65
references.pmid: 18445777
references.citation: J Biol Chem. 1991 Sep 5;266(25):16778-85
references.pmid: 1885605
references.citation: J Biol Chem. 2002 Mar 1;277(9):7493-500
references.pmid: 11741978