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, JM1 5
Xia, W4
He, JW3
Zhao, L1 5
Nie, M4
Fu, WZ3
Zhang, MJ1 5
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 (P meta = 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
2011 Impact Factor: 7.636
2011 SCImago Journal Rankings: 1.308
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 Field
Value
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 (P meta = 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.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
2011 Impact Factor: 7.636
2011 SCImago Journal Rankings: 1.308
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
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