{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T16:24:42Z","timestamp":1759940682792},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2007,3,1]],"date-time":"2007-03-01T00:00:00Z","timestamp":1172707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2007,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>In this study, the associations of novel LRP5 variants with BMD variation were detected and some replicated in the two ethnic groups of Chinese and white origins, respectively. These data support the concept that LRP5 variation can contribute to minor and major variation in bone structure.<\/jats:p>\n               <jats:p>Introduction: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene have been shown to cause both high and low bone mass. However, it is still controversial whether LRP5 is associated with normal BMD variation. This study explored the association of LRP5 with BMD phenotypes at three clinically important skeletal sites\u2014the spine, hip, and ultradistal radius (UD)\u2014in two independent populations of Chinese and white ethnicities, respectively.<\/jats:p>\n               <jats:p>Materials and Methods: The Chinese sample consisted of 733 unrelated subjects. The white sample was made up of 1873 subjects from 405 nuclear families. High-density single nucleotide polymorphisms (SNPs) across the whole LRP5 gene were genotyped and analyzed in both samples.<\/jats:p>\n               <jats:p>Results: Linkage disequilibrium (LD) analyses showed that the haplotype structures of LRP5 between Chinese and whites were in good agreement. Association tests showed that polymorphisms in block 5 spanning intron 7 to intron 19 of LRP5 significantly associated with spine BMD variation in both samples. Particularly, the significant association of SNP rs491347 in intron 7 with spine BMD in the Chinese sample (p = 0.002) was replicated in whites, even after adjusting for multiple testing (p = 0.005). Its strongly associated SNP rs1784235 could cause the loss of an estrogen receptor \u03b1 (ER\u03b1) binding site in LRP5, which could partially explain the above replicated association. However, we did not observe any significant replication with BMD variation at the hip and UD. After accounting for multiple testing, associations with BMD variation at these two sites were mainly found in Chinese. Sex-stratified analyses further revealed that the LRP5 associations with BMD in Chinese and whites were driven by male and female subjects, respectively.<\/jats:p>\n               <jats:p>Conclusions: Our work supported LRP5 genetic variants as possible susceptibility factors for osteoporosis and fractures in humans. Especially, the SNP rs491347 and its strongly associated SNPs (e.g., rs1784235) could be important to human osteoporosis phenotypes.<\/jats:p>","DOI":"10.1359\/jbmr.061116","type":"journal-article","created":{"date-parts":[[2006,12,5]],"date-time":"2006-12-05T13:24:13Z","timestamp":1165325053000},"page":"385-393","source":"Crossref","is-referenced-by-count":31,"title":["Low-Density <i>Lipoprotein Receptor\u2013Related Protein 5<\/i> (<i>LRP5<\/i>) Gene Polymorphisms Are Associated With Bone Mass in Both Chinese and Whites"],"prefix":"10.1093","volume":"22","author":[{"given":"Dong-Hai","family":"Xiong","sequence":"first","affiliation":[{"name":"Osteoporosis Research Center and Department of Biomedical Sciences, Creighton University, Omaha, Nebraska, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu-Feng","family":"Lei","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Yang","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Wang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Mei","family":"Peng","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert R","family":"Recker","sequence":"additional","affiliation":[{"name":"Osteoporosis Research Center and Department of Biomedical Sciences, Creighton University, Omaha, Nebraska, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong-Wen","family":"Deng","sequence":"additional","affiliation":[{"name":"Departments of Orthopedic Surgery and Basic Medical Sciences, University of Missouri\u2013Kansas City, Kansas City, Missouri, USA"},{"name":"The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China"},{"name":"Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China"},{"name":"Osteoporosis Research Center and Department of Biomedical Sciences, Creighton University, Omaha, Nebraska, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,12,4]]},"reference":[{"key":"2024020319324541300_bib1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.gene.2005.07.016","article-title":"The insulin-like growth factor-I gene and osteoporosis: A critical appraisal","volume":"361","author":"Niu","year":"2005","journal-title":"Gene"},{"key":"2024020319324541300_bib2","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1002\/gepi.1040","article-title":"Relevance of the genes for bone mass variation to susceptibility to osteoporotic fractures and its implications to gene search for complex human diseases","volume":"22","author":"Deng","year":"2002","journal-title":"Genet Epidemiol"},{"key":"2024020319324541300_bib3","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/35035117","article-title":"LDL-receptor-related proteins in Wnt signal transduction","volume":"407","author":"Tamai","year":"2000","journal-title":"Nature"},{"key":"2024020319324541300_bib4","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1056\/NEJMoa013444","article-title":"High bone density due to a mutation in LDL-receptor-related protein 5","volume":"346","author":"Boyden","year":"2002","journal-title":"N Engl J Med"},{"key":"2024020319324541300_bib5","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/S0092-8674(01)00571-2","article-title":"LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development","volume":"107","author":"Gong","year":"2001","journal-title":"Cell"},{"key":"2024020319324541300_bib6","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1086\/338450","article-title":"A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait","volume":"70","author":"Little","year":"2002","journal-title":"Am J Hum Genet"},{"key":"2024020319324541300_bib7","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1086\/420771","article-title":"Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whites","volume":"74","author":"Ferrari","year":"2004","journal-title":"Am J Hum Genet"},{"key":"2024020319324541300_bib8","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1359\/JBMR.040704","article-title":"Influence of LRP5 polymorphisms on normal variation in BMD","volume":"19","author":"Koay","year":"2004","journal-title":"J Bone Miner Res"},{"key":"2024020319324541300_bib9","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1359\/JBMR.041019","article-title":"Contribution of the LRP5 gene to normal variation in peak BMD in women","volume":"20","author":"Koller","year":"2005","journal-title":"J Bone Miner Res"},{"key":"2024020319324541300_bib10","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1007\/s10038-003-0111-6","article-title":"LRP5, low-density-lipoprotein-receptor-related protein 5, is a determinant for bone mineral density","volume":"49","author":"Mizuguchi","year":"2004","journal-title":"J Hum Genet"},{"key":"2024020319324541300_bib11","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00774-003-0492-9","article-title":"Association of a single-nucleotide polymorphism in low-density lipoprotein receptor-related protein 5 gene with bone mineral density","volume":"22","author":"Urano","year":"2004","journal-title":"J Bone Miner Metab"},{"key":"2024020319324541300_bib12","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1359\/JBMR.050904","article-title":"Common genetic variation of the low-density lipoprotein receptor-related protein 5 and 6 genes determines fracture risk in elderly white men","volume":"21","author":"van Meurs","year":"2006","journal-title":"J Bone Miner Res"},{"key":"2024020319324541300_bib13","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3346\/jkms.2004.19.3.407","article-title":"Association between bone mineral density and LDL receptor-related protein 5 gene polymorphisms in young Korean men","volume":"19","author":"Koh","year":"2004","journal-title":"J Korean Med Sci"},{"key":"2024020319324541300_bib14","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1007\/s00198-005-2011-4","article-title":"Association analysis of estrogen receptor alpha gene polymorphisms with cross-sectional geometry of the femoral neck in Caucasian nuclear families","volume":"16","author":"Xiong","year":"2005","journal-title":"Osteoporos Int"},{"key":"2024020319324541300_bib15","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1086\/301904","article-title":"PedCheck: A program for identification of genotype incompatibilities in linkage analysis","volume":"63","author":"O'Connell","year":"1998","journal-title":"Am J Hum Genet"},{"key":"2024020319324541300_bib16","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/ng786","article-title":"Merlin\u2013rapid analysis of dense genetic maps using sparse gene flow trees","volume":"30","author":"Abecasis","year":"2002","journal-title":"Nat Genet"},{"key":"2024020319324541300_bib17","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1093\/bioinformatics\/bti282","article-title":"PowerMarker: An integrated analysis environment for genetic marker analysis","volume":"21","author":"Liu","year":"2005","journal-title":"Bioinformatics"},{"key":"2024020319324541300_bib18","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1093\/bioinformatics\/bth457","article-title":"Haploview: Analysis and visualization of LD and haplotype maps","volume":"21","author":"Barrett","year":"2005","journal-title":"Bioinformatics"},{"key":"2024020319324541300_bib19","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1126\/science.1069424","article-title":"The structure of haplotype blocks in the human genome","volume":"296","author":"Gabriel","year":"2002","journal-title":"Science"},{"key":"2024020319324541300_bib20","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1086\/302959","article-title":"Association mapping in structured populations","volume":"67","author":"Pritchard","year":"2000","journal-title":"Am J Hum Genet"},{"key":"2024020319324541300_bib21","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/gepi.10252","article-title":"Pedigree disequilibrium tests for multilocus haplotypes","volume":"25","author":"Dudbridge","year":"2003","journal-title":"Genet Epidemiol"},{"key":"2024020319324541300_bib22","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1086\/383251","article-title":"A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other","volume":"74","author":"Nyholt","year":"2004","journal-title":"Am J Hum Genet"},{"key":"2024020319324541300_bib23","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1086\/301844","article-title":"Multipoint quantitative-trait linkage analysis in general pedigrees","volume":"62","author":"Almasy","year":"1998","journal-title":"Am J Hum Genet"},{"key":"2024020319324541300_bib24","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/sj.ejhg.5200625","article-title":"The family based association test method: Strategies for studying general genotype\u2013phenotype associations","volume":"9","author":"Horvath","year":"2001","journal-title":"Eur J Hum Genet"},{"issue":"Suppl 1","key":"2024020319324541300_bib25","doi-asserted-by":"crossref","first-page":"S36","DOI":"10.1002\/1098-2272(2000)19:1+<::AID-GEPI6>3.0.CO;2-M","article-title":"Implementing a unified approach to family-based tests of association","volume":"19","author":"Laird","year":"2000","journal-title":"Genet Epidemiol"},{"key":"2024020319324541300_bib26","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/gepi.10295","article-title":"Family-based tests for associating haplotypes with general phenotype data: Application to asthma genetics","volume":"26","author":"Horvath","year":"2004","journal-title":"Genet Epidemiol"},{"key":"2024020319324541300_bib27","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1101\/gr.563703","article-title":"Haplotype structure, LD blocks, and uneven recombination within the LRP5 gene","volume":"13","author":"Twells","year":"2003","journal-title":"Genome Res"},{"key":"2024020319324541300_bib28","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.bone.2005.01.006","article-title":"LRP5 gene polymorphisms predict bone mass and incident fractures in elderly Australian women","volume":"36","author":"Bollerslev","year":"2005","journal-title":"Bone"},{"key":"2024020319324541300_bib29","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.bone.2005.06.017","article-title":"LRP5 gene polymorphisms and idiopathic osteoporosis in men","volume":"37","author":"Ferrari","year":"2005","journal-title":"Bone"},{"key":"2024020319324541300_bib30","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1111\/j.1745-7254.2005.00173.x","article-title":"Association of polymorphisms in low-density lipoprotein receptor-related protein 5 gene with bone mineral density in postmenopausal Chinese women","volume":"26","author":"Zhang","year":"2005","journal-title":"Acta Pharmacol Sin"},{"key":"2024020319324541300_bib31","first-page":"S387","article-title":"LRP5 Amino Acid Substitutions: Differences in allele frequencies and association with Bone Density and Structure in Afro-Caribbean Men","volume":"19","author":"Oakley","year":"2004","journal-title":"J Bone Miner Res"},{"key":"2024020319324541300_bib32","doi-asserted-by":"crossref","first-page":"W273","DOI":"10.1093\/nar\/gkh458","article-title":"VISTA: Computational tools for comparative genomics","volume":"32","author":"Frazer","year":"2004","journal-title":"Nucleic Acids Res"},{"key":"2024020319324541300_bib33","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1136\/jmg.2006.041715","article-title":"Polymorphisms of the Low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family-based association study","volume":"43","author":"Guo","year":"2006","journal-title":"J Med Genet"},{"key":"2024020319324541300_bib34","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1359\/jbmr.060808","article-title":"A Robust and Comprehensive Analysis of 20 Osteoporosis Candidate Genes by Very High-Density Single-Nucleotide Polymorphism Screen among 405 Caucasian Nuclear Families Identified Significant Association and Gene-Gene Interaction","volume":"21","author":"Xiong","year":"2006","journal-title":"J Bone Miner Res"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1359%2Fjbmr.061116","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/22\/3\/385\/56552691\/5650220306.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/22\/3\/385\/56552691\/5650220306.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:48:03Z","timestamp":1710341283000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/22\/3\/385-393\/7597367"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,3,1]]},"references-count":34,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2009,12,4]]},"published-print":{"date-parts":[[2007,3,1]]}},"URL":"https:\/\/doi.org\/10.1359\/jbmr.061116","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2007,3,1]]},"published":{"date-parts":[[2007,3,1]]}}}