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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

TitlePost-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density
Authors
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/
Citation
Human Molecular Genetics, 2012, v. 21 n. 7, p. 1648-1657 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/152725
ISSN
2014 Impact Factor: 6.393
ISI Accession Number ID
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.

References

 

DC FieldValueLanguage
dc.contributor.authorXiao, SMen_HK
dc.contributor.authorKung, AWCen_HK
dc.contributor.authorGao, Yen_HK
dc.contributor.authorLau, KSen_HK
dc.contributor.authorMa, Aen_HK
dc.contributor.authorZhang, ZLen_HK
dc.contributor.authorLiu, JMen_HK
dc.contributor.authorXia, Wen_HK
dc.contributor.authorHe, JWen_HK
dc.contributor.authorZhao, Len_HK
dc.contributor.authorNie, Men_HK
dc.contributor.authorFu, WZen_HK
dc.contributor.authorZhang, MJen_HK
dc.contributor.authorSun, Jen_HK
dc.contributor.authorKwan, JSHen_HK
dc.contributor.authorTso, GHWen_HK
dc.contributor.authorDai, ZJen_HK
dc.contributor.authorCheung, CLen_HK
dc.contributor.authorBow, CHen_HK
dc.contributor.authorLeung, AYHen_HK
dc.contributor.authorTan, KCBen_HK
dc.contributor.authorSham, PCen_HK
dc.date.accessioned2012-07-16T09:47:20Z-
dc.date.available2012-07-16T09:47:20Z-
dc.date.issued2012en_HK
dc.identifier.citationHuman Molecular Genetics, 2012, v. 21 n. 7, p. 1648-1657en_HK
dc.identifier.issn0964-6906en_HK
dc.identifier.urihttp://hdl.handle.net/10722/152725-
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.en_HK
dc.languageengen_US
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/en_HK
dc.relation.ispartofHuman Molecular Geneticsen_HK
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 densityen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0964-6906&volume=&spage=&epage=&date=2011&atitle=Post-genome+wide+association+studies+and+functional+analyses+identify+association+of+MPP7+gene+variants+with+site-specific+bone+mineral+densityen_US
dc.identifier.emailKung, AWC: awckung@hku.hken_HK
dc.identifier.emailCheung, CL: lung1212@hku.hken_HK
dc.identifier.emailLeung, AYH: ayhleung@hku.hken_HK
dc.identifier.emailTan, KCB: kcbtan@hku.hken_HK
dc.identifier.emailSham, PC: kcbtan@hku.hken_HK
dc.identifier.authorityKung, AWC=rp00368en_HK
dc.identifier.authorityCheung, CL=rp01749en_HK
dc.identifier.authorityLeung, AYH=rp00265en_HK
dc.identifier.authorityTan, KCB=rp00402en_HK
dc.identifier.authoritySham, PC=rp00402en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1093/hmg/ddr586en_HK
dc.identifier.pmid22171069en_HK
dc.identifier.scopuseid_2-s2.0-84863247591en_HK
dc.identifier.hkuros200615en_US
dc.identifier.hkuros200614-
dc.identifier.hkuros234453-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84863247591&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume21en_HK
dc.identifier.issue7en_HK
dc.identifier.spage1648en_HK
dc.identifier.epage1657en_HK
dc.identifier.isiWOS:000301299700018-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridXiao, SM=7402022586en_HK
dc.identifier.scopusauthoridKung, AWC=7102322339en_HK
dc.identifier.scopusauthoridGao, Y=34876578200en_HK
dc.identifier.scopusauthoridLau, KS=35205833900en_HK
dc.identifier.scopusauthoridMa, A=52664122100en_HK
dc.identifier.scopusauthoridZhang, ZL=34878137400en_HK
dc.identifier.scopusauthoridLiu, JM=36076735400en_HK
dc.identifier.scopusauthoridXia, W=55276464900en_HK
dc.identifier.scopusauthoridHe, JW=35215101000en_HK
dc.identifier.scopusauthoridZhao, L=55493562900en_HK
dc.identifier.scopusauthoridNie, M=55277737200en_HK
dc.identifier.scopusauthoridFu, WZ=55278193000en_HK
dc.identifier.scopusauthoridZhang, MJ=7601553697en_HK
dc.identifier.scopusauthoridSun, J=55085519800en_HK
dc.identifier.scopusauthoridKwan, JSH=37063349600en_HK
dc.identifier.scopusauthoridTso, GHW=8617703000en_HK
dc.identifier.scopusauthoridDai, ZJ=39560959900en_HK
dc.identifier.scopusauthoridCheung, CL=14520953400en_HK
dc.identifier.scopusauthoridBow, CH=36055977600en_HK
dc.identifier.scopusauthoridLeung, AYH=7403012668en_HK
dc.identifier.scopusauthoridTan, KCB=8082703100en_HK
dc.identifier.scopusauthoridSham, PC=8082703100en_HK

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