Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density
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 to...
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| Veröffentlicht in: | Human molecular genetics 2012-04, Vol.21 (7), p.1648-1657 |
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| creator | Xiao, Su-Mei Kung, Annie Wai Chee Gao, Yi Lau, Kam-Shing Ma, Alvin Zhang, Zhen-Lin Liu, Jian-Min Xia, Wiebo He, Jin-Wei Zhao, Lin Nie, Min Fu, Wei-Zhen Zhang, Min-Jia Sun, Jing Kwan, Johnny S.H. Tso, Gloria Hoi Wan Dai, Zhi-Jie Cheung, Ching-Lung Bow, Cora H. Leung, Anskar Yu Hung Tan, Kathryn Choon Beng Sham, Pak Chung |
| description | 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 (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. |
| doi_str_mv | 10.1093/hmg/ddr586 |
| format | Article |
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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.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddr586</identifier><identifier>PMID: 22171069</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Alleles ; Animals ; Binding Sites ; Biological and medical sciences ; Bone Density - genetics ; Bone mass ; Bone mineral density ; Cell Line ; Danio rerio ; Data processing ; Electrophoretic mobility ; Female ; Fundamental and applied biological sciences. Psychology ; GATA2 Transcription Factor - metabolism ; Gene expression ; Genetics of eukaryotes. Biological and molecular evolution ; Genome, Human ; Genome-Wide Association Study ; Genotype ; HapMap Project ; Hip ; Humans ; Male ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; Molecular and cellular biology ; Osteoblasts ; Osteoblasts - metabolism ; Osteogenesis ; Peripheral blood mononuclear cells ; Plasma membranes ; Polymorphism, Single Nucleotide ; Reviews ; RNA, Messenger - metabolism ; Single-nucleotide polymorphism ; Spine ; Vertebrae ; Zebrafish - genetics ; Zebrafish Proteins - genetics</subject><ispartof>Human molecular genetics, 2012-04, Vol.21 (7), p.1648-1657</ispartof><rights>The Author 2011. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2011</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-7f07196d32f04e5eb3d2e4940c4f7a4444c3ec90d1fb3f2d2361daca8c4d19b43</citedby><cites>FETCH-LOGICAL-c415t-7f07196d32f04e5eb3d2e4940c4f7a4444c3ec90d1fb3f2d2361daca8c4d19b43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1584,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25609396$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22171069$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xiao, Su-Mei</creatorcontrib><creatorcontrib>Kung, Annie Wai Chee</creatorcontrib><creatorcontrib>Gao, Yi</creatorcontrib><creatorcontrib>Lau, Kam-Shing</creatorcontrib><creatorcontrib>Ma, Alvin</creatorcontrib><creatorcontrib>Zhang, Zhen-Lin</creatorcontrib><creatorcontrib>Liu, Jian-Min</creatorcontrib><creatorcontrib>Xia, Wiebo</creatorcontrib><creatorcontrib>He, Jin-Wei</creatorcontrib><creatorcontrib>Zhao, Lin</creatorcontrib><creatorcontrib>Nie, Min</creatorcontrib><creatorcontrib>Fu, Wei-Zhen</creatorcontrib><creatorcontrib>Zhang, Min-Jia</creatorcontrib><creatorcontrib>Sun, Jing</creatorcontrib><creatorcontrib>Kwan, Johnny S.H.</creatorcontrib><creatorcontrib>Tso, Gloria Hoi Wan</creatorcontrib><creatorcontrib>Dai, Zhi-Jie</creatorcontrib><creatorcontrib>Cheung, Ching-Lung</creatorcontrib><creatorcontrib>Bow, Cora H.</creatorcontrib><creatorcontrib>Leung, Anskar Yu Hung</creatorcontrib><creatorcontrib>Tan, Kathryn Choon Beng</creatorcontrib><creatorcontrib>Sham, Pak Chung</creatorcontrib><title>Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>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 (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.</description><subject>Alleles</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Bone Density - genetics</subject><subject>Bone mass</subject><subject>Bone mineral density</subject><subject>Cell Line</subject><subject>Danio rerio</subject><subject>Data processing</subject><subject>Electrophoretic mobility</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>GATA2 Transcription Factor - metabolism</subject><subject>Gene expression</subject><subject>Genetics of eukaryotes. Biological and molecular evolution</subject><subject>Genome, Human</subject><subject>Genome-Wide Association Study</subject><subject>Genotype</subject><subject>HapMap Project</subject><subject>Hip</subject><subject>Humans</subject><subject>Male</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Molecular and cellular biology</subject><subject>Osteoblasts</subject><subject>Osteoblasts - metabolism</subject><subject>Osteogenesis</subject><subject>Peripheral blood mononuclear cells</subject><subject>Plasma membranes</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Reviews</subject><subject>RNA, Messenger - metabolism</subject><subject>Single-nucleotide polymorphism</subject><subject>Spine</subject><subject>Vertebrae</subject><subject>Zebrafish - genetics</subject><subject>Zebrafish Proteins - genetics</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90c1u1DAUBWALgehQ2PAAyBtEhRTqvzjxsqooIBUxC1hHjn3dGiX2kOuA5il4ZVzNQMWm3li-_ny8OIS85OwdZ0ae3843594vba8fkQ1XmjWC9fIx2TCjVaMN0yfkGeJ3xrhWsntKToTgHWfabMjvbcbS3EDKM9Bf0QO1iNlFW2JOFMvqIyC1ydOwJnc3tFM92mmPdV59KjHs_3uUA_283Xa0hgL9aZdoU8GaXW4pxgIN7sDFEB0dcwVzTLDUzJpUb_fPyZNgJ4QXx_2UfLt6__XyY3P95cOny4vrxinelqYLrONGeykCU9DCKL0AZRRzKnRW1eUkOMM8D6MMwgupubfO9k55bkYlT8mbQ-5uyT9WwDLMER1Mk02QVxyM6HrJRMerPHtQcsb6Xra8Z5W-PVC3ZMQFwrBb4myXfUXDXVVDrWo4VFXxq2PuOs7g_9G_3VTw-ggsOjuFxSYX8d61uiYafe_yunvowz9GoqxO</recordid><startdate>20120401</startdate><enddate>20120401</enddate><creator>Xiao, Su-Mei</creator><creator>Kung, Annie Wai Chee</creator><creator>Gao, Yi</creator><creator>Lau, Kam-Shing</creator><creator>Ma, Alvin</creator><creator>Zhang, Zhen-Lin</creator><creator>Liu, Jian-Min</creator><creator>Xia, Wiebo</creator><creator>He, Jin-Wei</creator><creator>Zhao, Lin</creator><creator>Nie, Min</creator><creator>Fu, Wei-Zhen</creator><creator>Zhang, Min-Jia</creator><creator>Sun, Jing</creator><creator>Kwan, Johnny S.H.</creator><creator>Tso, Gloria Hoi Wan</creator><creator>Dai, Zhi-Jie</creator><creator>Cheung, Ching-Lung</creator><creator>Bow, Cora H.</creator><creator>Leung, Anskar Yu Hung</creator><creator>Tan, Kathryn Choon Beng</creator><creator>Sham, Pak Chung</creator><general>Oxford University Press</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20120401</creationdate><title>Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density</title><author>Xiao, Su-Mei ; Kung, Annie Wai Chee ; Gao, Yi ; Lau, Kam-Shing ; Ma, Alvin ; Zhang, Zhen-Lin ; Liu, Jian-Min ; Xia, Wiebo ; He, Jin-Wei ; Zhao, Lin ; Nie, Min ; Fu, Wei-Zhen ; Zhang, Min-Jia ; Sun, Jing ; Kwan, Johnny S.H. ; Tso, Gloria Hoi Wan ; Dai, Zhi-Jie ; Cheung, Ching-Lung ; Bow, Cora H. ; Leung, Anskar Yu Hung ; Tan, Kathryn Choon Beng ; Sham, Pak Chung</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-7f07196d32f04e5eb3d2e4940c4f7a4444c3ec90d1fb3f2d2361daca8c4d19b43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Alleles</topic><topic>Animals</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Bone Density - genetics</topic><topic>Bone mass</topic><topic>Bone mineral density</topic><topic>Cell Line</topic><topic>Danio rerio</topic><topic>Data processing</topic><topic>Electrophoretic mobility</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. 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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.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>22171069</pmid><doi>10.1093/hmg/ddr586</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Alleles Animals Binding Sites Biological and medical sciences Bone Density - genetics Bone mass Bone mineral density Cell Line Danio rerio Data processing Electrophoretic mobility Female Fundamental and applied biological sciences. Psychology GATA2 Transcription Factor - metabolism Gene expression Genetics of eukaryotes. Biological and molecular evolution Genome, Human Genome-Wide Association Study Genotype HapMap Project Hip Humans Male Membrane Proteins - genetics Membrane Proteins - metabolism Mice Molecular and cellular biology Osteoblasts Osteoblasts - metabolism Osteogenesis Peripheral blood mononuclear cells Plasma membranes Polymorphism, Single Nucleotide Reviews RNA, Messenger - metabolism Single-nucleotide polymorphism Spine Vertebrae Zebrafish - genetics Zebrafish Proteins - genetics |
| title | Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density |
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