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Article: Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density
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TitlePost-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density
 
AuthorsXiao, SM2
Kung, AWC2
Gao, Y2
Lau, KS2
Ma, A2
Zhang, ZL3
Liu, JM5 1
Xia, W4
He, JW3
Zhao, L5 1
Nie, M4
Fu, WZ3
Zhang, MJ5 1
Sun, J4
Kwan, JSH2
Tso, GHW2
Dai, ZJ2
Cheung, CL2
Bow, CH2
Leung, AYH2
Tan, KCB2
Sham, PC2
 
KeywordsMessenger RNA
Transcription factor GATA 2
Allele
Animal cell
Bone density
 
Issue Date2012
 
PublisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
 
CitationHuman Molecular Genetics, 2012, v. 21 n. 7, p. 1648-1657 [How to Cite?]
DOI: http://dx.doi.org/10.1093/hmg/ddr586
 
AbstractOur previous genome-wide association study (GWAS) in a Hong Kong Southern Chinese population with extreme bone mineral density (BMD) scores revealed suggestive association with MPP7, which ranked second after JAG1 as a candidate gene for BMD. To follow-up this suggestive signal, we replicated the top single-nucleotide polymorphism rs4317882 of MPP7 in three additional independent Asian-descent samples (n = 2684). The association of rs4317882 reached the genome-wide significance in the meta-analysis of all available subjects (Pmeta = 4.58 × 10-8, n = 4204). Site heterogeneity was observed, with a larger effect on spine than hip BMD. Further functional studies in a zebrafish model revealed that vertebral bone mass was lower in an mpp7 knock-down model compared with the wide-type (P = 9.64 × 10-4, n = 21). In addition, MPP7 was found to have constitutive expression in human bone-derived cells during osteogenesis. Immunostaining of murine MC3T3-E1 cells revealed that the Mpp7 protein is localized in the plasma membrane and intracytoplasmic compartment of osteoblasts. In an assessment of the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of transcriptional factor GATA2 to the risk allele 'A' but not the 'G' allele of rs4317882. An mRNA expression study in human peripheral blood mononuclear cells confirmed that the low BMD-related allele 'A' of rs4317882 was associated with lower MPP7 expression (P = 9.07 × 10-3, n = 135). Our data suggest a genetic and functional association of MPP7 with BMD variation. © The Author 2011. Published by Oxford University Press. All rights reserved.
 
ISSN0964-6906
2012 Impact Factor: 7.692
2012 SCImago Journal Rankings: 4.103
 
DOIhttp://dx.doi.org/10.1093/hmg/ddr586
 
ISI Accession Number IDWOS:000301299700018
Funding AgencyGrant Number
Research Grant Council of the Hong Kong GovernmentHKU768610M
Osteoporosis and Endocrine Research Fund
KC Wong Education Foundation
University of Hong Kong
Funding Information:

This work was supported by the Research Grant Council of the Hong Kong Government (HKU768610M), the Osteoporosis and Endocrine Research Fund, the KC Wong Education Foundation and the Genomics Strategic Research Theme of the University of Hong Kong.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorXiao, SM
 
dc.contributor.authorKung, AWC
 
dc.contributor.authorGao, Y
 
dc.contributor.authorLau, KS
 
dc.contributor.authorMa, A
 
dc.contributor.authorZhang, ZL
 
dc.contributor.authorLiu, JM
 
dc.contributor.authorXia, W
 
dc.contributor.authorHe, JW
 
dc.contributor.authorZhao, L
 
dc.contributor.authorNie, M
 
dc.contributor.authorFu, WZ
 
dc.contributor.authorZhang, MJ
 
dc.contributor.authorSun, J
 
dc.contributor.authorKwan, JSH
 
dc.contributor.authorTso, GHW
 
dc.contributor.authorDai, ZJ
 
dc.contributor.authorCheung, CL
 
dc.contributor.authorBow, CH
 
dc.contributor.authorLeung, AYH
 
dc.contributor.authorTan, KCB
 
dc.contributor.authorSham, PC
 
dc.date.accessioned2012-07-16T09:47:20Z
 
dc.date.available2012-07-16T09:47:20Z
 
dc.date.issued2012
 
dc.description.abstractOur previous genome-wide association study (GWAS) in a Hong Kong Southern Chinese population with extreme bone mineral density (BMD) scores revealed suggestive association with MPP7, which ranked second after JAG1 as a candidate gene for BMD. To follow-up this suggestive signal, we replicated the top single-nucleotide polymorphism rs4317882 of MPP7 in three additional independent Asian-descent samples (n = 2684). The association of rs4317882 reached the genome-wide significance in the meta-analysis of all available subjects (Pmeta = 4.58 × 10-8, n = 4204). Site heterogeneity was observed, with a larger effect on spine than hip BMD. Further functional studies in a zebrafish model revealed that vertebral bone mass was lower in an mpp7 knock-down model compared with the wide-type (P = 9.64 × 10-4, n = 21). In addition, MPP7 was found to have constitutive expression in human bone-derived cells during osteogenesis. Immunostaining of murine MC3T3-E1 cells revealed that the Mpp7 protein is localized in the plasma membrane and intracytoplasmic compartment of osteoblasts. In an assessment of the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of transcriptional factor GATA2 to the risk allele 'A' but not the 'G' allele of rs4317882. An mRNA expression study in human peripheral blood mononuclear cells confirmed that the low BMD-related allele 'A' of rs4317882 was associated with lower MPP7 expression (P = 9.07 × 10-3, n = 135). Our data suggest a genetic and functional association of MPP7 with BMD variation. © The Author 2011. Published by Oxford University Press. All rights reserved.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationHuman Molecular Genetics, 2012, v. 21 n. 7, p. 1648-1657 [How to Cite?]
DOI: http://dx.doi.org/10.1093/hmg/ddr586
 
dc.identifier.doihttp://dx.doi.org/10.1093/hmg/ddr586
 
dc.identifier.epage1657
 
dc.identifier.hkuros200615
 
dc.identifier.hkuros200614
 
dc.identifier.isiWOS:000301299700018
Funding AgencyGrant Number
Research Grant Council of the Hong Kong GovernmentHKU768610M
Osteoporosis and Endocrine Research Fund
KC Wong Education Foundation
University of Hong Kong
Funding Information:

This work was supported by the Research Grant Council of the Hong Kong Government (HKU768610M), the Osteoporosis and Endocrine Research Fund, the KC Wong Education Foundation and the Genomics Strategic Research Theme of the University of Hong Kong.

 
dc.identifier.issn0964-6906
2012 Impact Factor: 7.692
2012 SCImago Journal Rankings: 4.103
 
dc.identifier.issue7
 
dc.identifier.openurl
 
dc.identifier.pmid22171069
 
dc.identifier.scopuseid_2-s2.0-84863247591
 
dc.identifier.spage1648
 
dc.identifier.urihttp://hdl.handle.net/10722/152725
 
dc.identifier.volume21
 
dc.languageeng
 
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofHuman Molecular Genetics
 
dc.relation.referencesReferences in Scopus
 
dc.subjectMessenger RNA
 
dc.subjectTranscription factor GATA 2
 
dc.subjectAllele
 
dc.subjectAnimal cell
 
dc.subjectBone density
 
dc.titlePost-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density
 
dc.typeArticle
 
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<description.abstract>Our previous genome-wide association study (GWAS) in a Hong Kong Southern Chinese population with extreme bone mineral density (BMD) scores revealed suggestive association with MPP7, which ranked second after JAG1 as a candidate gene for BMD. To follow-up this suggestive signal, we replicated the top single-nucleotide polymorphism rs4317882 of MPP7 in three additional independent Asian-descent samples (n = 2684). The association of rs4317882 reached the genome-wide significance in the meta-analysis of all available subjects (Pmeta = 4.58 &#215; 10-8, n = 4204). Site heterogeneity was observed, with a larger effect on spine than hip BMD. Further functional studies in a zebrafish model revealed that vertebral bone mass was lower in an mpp7 knock-down model compared with the wide-type (P = 9.64 &#215; 10-4, n = 21). In addition, MPP7 was found to have constitutive expression in human bone-derived cells during osteogenesis. Immunostaining of murine MC3T3-E1 cells revealed that the Mpp7 protein is localized in the plasma membrane and intracytoplasmic compartment of osteoblasts. In an assessment of the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of transcriptional factor GATA2 to the risk allele &apos;A&apos; but not the &apos;G&apos; allele of rs4317882. An mRNA expression study in human peripheral blood mononuclear cells confirmed that the low BMD-related allele &apos;A&apos; of rs4317882 was associated with lower MPP7 expression (P = 9.07 &#215; 10-3, n = 135). Our data suggest a genetic and functional association of MPP7 with BMD variation. &#169; The Author 2011. Published by Oxford University Press. All rights reserved.</description.abstract>
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Author Affiliations
  1. Shanghai Clinical Center for Endocrine and Metabolic Diseases
  2. The University of Hong Kong
  3. Shanghai Jiaotong University
  4. Peking Union Medical College
  5. Shanghai Jiao Tong University School of Medicine