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Table of Contents
Vol. 65, No. 4, 2008
Issue release date: January 2008
Section title: Original Paper
Hum Hered 2008;65:232–239
(DOI:10.1159/000112370)

Association of Low-Density Lipoprotein Receptor-Related Protein 5 (LRP5) Promoter SNP with Peak Bone Mineral Density in Chinese Women

Cheung C.-L. · Huang Q.-Y. · Chan V. · Kung A.W.C.
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
email Corresponding Author

Abstract

Objective: Low-density lipoprotein receptor-related protein 5 (LRP5) is important for osteoblast differentiation and mutations of the gene are associated with both low and high bone mass syndromes. Our study aimed to evaluate the importance of LRP5 in the determination of peak bone mass acquisition in Chinese females in the general population. Methods: A total of 286 young southern Chinese females (aged 22–44 years) with low bone mineral density (BMD) (defined by a BMD Z score ≤–1.28 at either the hip or spine) or high BMD (Z score ≧+1) were studied. The LRP5 gene was sequenced for single nucleotide polymorphisms (SNPs) and 4 SNPs were tagged from 8 genotyped SNPs for this study. Results: Single locus allele association tests revealed significant associations of rs682429 and rs686921 with BMD variation (p < 0.05). Omnibus test (likelihood ratio test) revealed overall significant association between LRP5 gene locus and total hip BMD, with rs682429 being most predictive. rs682429 is located in 5′UTR, 2 bases adjacent to a consensus recognition site for the Elk-1 binding element. Conclusion: Common variations of the LRP5 promoter are associated with BMD in young women. These significant associations appear to be driven by rs682429. Functional studies are necessary to elucidate the role of this SNP on the effect of Elk-1 binding element transcriptional activity of LRP5 gene.

© 2007 S. Karger AG, Basel


  

Key Words

  • BMD
  • SNP
  • Association study
  • LRP5
  • Osteoporosis
  • Genetic association
  • Chinese

References

  1. Wang MC, Aguirre M, Bhudhikanok GS, Kendall CG, Kirsch S, Marcus R, Bachrach LK: Bone mass and hip axis length in healthy asian, black, hispanic, and white american youths. J Bone Miner Res 1997;12:1922–1935.
  2. Eisman JA: Genetics of osteoporosis. Endocr Rev 1999;20:788–804.
  3. Flicker L, Hopper JL, Rodgers L, Kaymakci B, Green RM, Wark JD: Bone density determinants in elderly women: A twin study. J Bone Miner Res 1995;10:1607–1613.
  4. Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S: Genetic determinants of bone mass in adults. A twin study. J Clin Invest 1987;80:706–710.
  5. Smith DM, Nance WE, Kang KW, Christian JC, Johnston CC Jr: Genetic factors in determining bone mass. J Clin Invest 1973;52:2800–2808.
  6. Hey PJ, Twells RC, Phillips MS, Yusuke N, Brown SD, Kawaguchi Y, Cox R, Guochun X, Dugan V, Hammond H, Metzker ML, Todd JA, Hess JF: Cloning of a novel member of the low-density lipoprotein receptor family. Gene 1998;216:103–111.
  7. Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC: An ldl-receptor-related protein mediates wnt signalling in mice. Nature 2000;407:535–538.
  8. Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X: Ldl-receptor-related proteins in wnt signal transduction. Nature 2000;407:530–535.
  9. Wehrli M, Dougan ST, Caldwell K, O’Keefe L, Schwartz S, Vaizel-Ohayon D, Schejter E, Tomlinson A, DiNardo S: Arrow encodes an ldl-receptor-related protein essential for wingless signalling. Nature 2000;407:527–530.
  10. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Juppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML: Ldl receptor-related protein 5 (lrp5) affects bone accrual and eye development. Cell 2001;107:513–523.
  11. Cheung WM, Jin LY, Smith DK, Cheung PT, Kwan E, Low L, Kung AWC: A family with osteoporosis pseudoglioma syndrome due to compound heterozygosity of two novel mutations in the lrp5 gene. Bone 2006;39:470–476.
  12. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP: High bone density due to a mutation in ldl-receptor-related protein 5. N Engl J Med 2002;346:1513–1521.
  13. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, Manning SP, Swain PM, Zhao SC, Eustace B, Lappe MM, Spitzer L, Zweier S, Braunschweiger K, Benchekroun Y, Hu X, Adair R, Chee L, FitzGerald MG, Tulig C, Caruso A, Tzellas N, Bawa A, Franklin B, McGuire S, Nogues X, Gong G, Allen KM, Anisowicz A, Morales AJ, Lomedico PT, Recker SM, Van Eerdewegh P, Recker RR, Johnson ML: A mutation in the ldl receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 2002;70:11–19.
  14. Rickels MR, Zhang X, Mumm S, Whyte MP: Oropharyngeal skeletal disease accompanying high bone mass and novel lrp5 mutation. J Bone Miner Res 2005;20:878–885.
  15. Van Wesenbeeck L, Cleiren E, Gram J, Beals RK, Benichou O, Scopelliti D, Key L, Renton T, Bartels C, Gong Y, Warman ML, De Vernejoul MC, Bollerslev J, Van Hul W: Six novel missense mutations in the ldl receptor-related protein 5 (lrp5) gene in different conditions with an increased bone density. Am J Hum Genet 2003;72:763–771.
  16. Ferrari SL, Deutsch S, Choudhury U, Chevalley T, Bonjour JP, Dermitzakis ET, Rizzoli R, Antonarakis SE: 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. Am J Hum Genet 2004;74:866–875.
  17. Koay MA, Woon PY, Zhang Y, Miles LJ, Duncan EL, Ralston SH, Compston JE, Cooper C, Keen R, Langdahl BL, MacLelland A, O’Riordan J, Pols HA, Reid DM, Uitterlinden AG, Wass JA, Brown MA: Influence of lrp5 polymorphisms on normal variation in bmd. J Bone Miner Res 2004;19:1619–1627.
  18. Lau HH, Ng MY, Ho AY, Luk KD, Kung AW: Genetic and environmental determinants of bone mineral density in chinese women. Bone 2005;36:700–709.
  19. van Meurs JB, Rivadeneira F, Jhamai M, Hugens W, Hofman A, van Leeuwen JP, Pols HA, Uitterlinden AG: Common genetic variation of the low-density lipoprotein receptor-related protein 5 and 6 genes determines fracture risk in elderly white men. J Bone Miner Res 2006;21:141–150.
  20. Ezura Y, Nakajima T, Urano T, Sudo Y, Kajita M, Yoshida H, Suzuki T, Hosoi T, Inoue S, Shiraki M, Emi M: Association of a single-nucleotide variation (a1330v) in the low-density lipoprotein receptor-related protein 5 gene (lrp5) with bone mineral density in adult japanese women. Bone 2007;40:997–1005.
  21. Giroux S, Elfassihi L, Cardinal G, Laflamme N, Rousseau F: Lrp5 coding polymorphisms influence the variation of peak bone mass in a normal population of French-Canadian women. Bone 2007;40:1299–1307.
  22. Koay MA, Tobias JH, Leary SD, Steer CD, Vilarino-Guell C, Brown MA: The effect of lrp5 polymorphisms on bone mineral density is apparent in childhood. Calcif Tissue Int 2007;81:1–9.
  23. Koller DL, Ichikawa S, Johnson ML, Lai D, Xuei X, Edenberg HJ, Conneally PM, Hui SL, Johnston CC, Peacock M, Foroud T, Econs MJ: Contribution of the lrp5 gene to normal variation in peak bmd in women. J Bone Miner Res 2005;20:75–80.
  24. Zhang ZL, Qin YJ, He JW, Huang QR, Li M, Hu YQ, Liu YJ: Association of polymorphisms in low-density lipoprotein receptor-related protein 5 gene with bone mineral density in postmenopausal chinese women. Acta Pharmacol Sin 2005;26:1111–1116.
  25. Lau HH, Ng MY, Cheung WM, Paterson AD, Sham PC, Luk KD, Chan V, Kung AW: Assessment of linkage and association of 13 genetic loci with bone mineral density. J Bone Miner Metab 2006;24:226–234.
  26. Saarinen A, Valimaki VV, Valimaki MJ, Loyttyniemi E, Auro K, Uusen P, Kuris M, Lehesjoki AE, Makitie O: The a1330v polymorphism of the low-density lipoprotein receptor-related protein 5 gene (lrp5) associates with low peak bone mass in young healthy men. Bone 2007;40:1006–1012.
  27. Bollerslev J, Wilson SG, Dick IM, Islam FM, Ueland T, Palmer L, Devine A, Prince RL: Lrp5 gene polymorphisms predict bone mass and incident fractures in elderly australian women. Bone 2005;36:599–606.
  28. Xiong DH, Shen H, Zhao LJ, Xiao P, Yang TL, Guo Y, Wang W, Guo YF, Liu YJ, Recker RR, Deng HW: Robust and comprehensive analysis of 20 osteoporosis candidate genes by very high-density single-nucleotide polymorphism screen among 405 white nuclear families identified significant association and gene-gene interaction. J Bone Miner Res 2006;21:1678–1695.
  29. Mizuguchi T, Furuta I, Watanabe Y, Tsukamoto K, Tomita H, Tsujihata M, Ohta T, Kishino T, Matsumoto N, Minakami H, Niikawa N, Yoshiura K: Lrp5, low-density-lipoprotein-receptor-related protein 5, is a determinant for bone mineral density. J Hum Genet 2004;49:80–86.
  30. Mei J, Yeung SS, Kung AW: High dietary phytoestrogen intake is associated with higher bone mineral density in postmenopausal but not premenopausal women. J Clin Endocrinol Metab 2001;86:5217–5221.
  31. Cheung CL, Chan V, Kung AW: A differential association of alox15 polymorphisms with bone mineral density in pre- and post-menopausal women. Hum Hered 2008;65:1–8.
  32. Barrett JC, Fry B, Maller J, Daly MJ: Haploview: Analysis and visualization of ld and haplotype maps. Bioinformatics 2005;21:263–265.
  33. Abecasis GR, Cookson WO: Gold – graphical overview of linkage disequilibrium. Bioinformatics 2000;16:182–183.
  34. Purcell S, Cherny SS, Sham PC: Genetic power calculator: Design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003;19:149–150.
  35. Cartharius K, Frech K, Grote K, Klocke B, Haltmeier M, Klingenhoff A, Frisch M, Bayerlein M, Werner T: Matinspector and beyond: Promoter analysis based on transcription factor binding sites. Bioinformatics 2005;21:2933–2942.
  36. Twells RC, Mein CA, Phillips MS, Hess JF, Veijola R, Gilbey M, Bright M, Metzker M, Lie BA, Kingsnorth A, Gregory E, Nakagawa Y, Snook H, Wang WY, Masters J, Johnson G, Eaves I, Howson JM, Clayton D, Cordell HJ, Nutland S, Rance H, Carr P, Todd JA: Haplotype structure, ld blocks, and uneven recombination within the lrp5 gene. Genome Res 2003;13:845–855.
  37. Koh JM, Jung MH, Hong JS, Park HJ, Chang JS, Shin HD, Kim SY, Kim GS: Association between bone mineral density and ldl receptor-related protein 5 gene polymorphisms in young korean men. J Korean Med Sci 2004;19:407–412.
  38. Figueroa DJ, Hess JF, Ky B, Brown SD, Sandig V, Hermanowski-Vosatka A, Twells RCJ, Todd JA, Austin CP: Expression of the type i diabetes-associated gene lrp5 in macrophages, vitamin a system cells, and the islets of Langerhans suggests multiple potential roles in diabetes. J Histochem Cytochem 2000;48:1357–1368.
  39. Wiren KM, Toombs AR, Zhang XW: Androgen inhibition of map kinase pathway and elk-1 activation in proliferating osteoblasts. J Mol Endocrinol 2004;32:209–226.
  40. Zagar Y, Chaumaz G, Lieberherr M: Signaling cross-talk from gbeta4 subunit to elk-1 in the rapid action of androgens. J Biol Chem 2004;279:2403–2413.

  

Author Contacts

Annie W.C. Kung
Department of Medicine, The University of Hong Kong
Queen Mary Hospital
Hong Kong (China)
Tel. +852 2855 4769, Fax +852 2816 2187, E-Mail awckung@hkucc.hku.hk

  

Article Information

Received: April 10, 2007
Accepted after revision: August 14, 2007
Published online: December 11, 2007
Number of Print Pages : 8
Number of Figures : 1, Number of Tables : 3, Number of References : 40

  

Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 65, No. 4, Year 2008 (Cover Date: January 2008)

Journal Editor: Devoto, M. (Philadelphia, Pa.)
ISSN: 0001–5652 (Print), eISSN: 1423–0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Objective: Low-density lipoprotein receptor-related protein 5 (LRP5) is important for osteoblast differentiation and mutations of the gene are associated with both low and high bone mass syndromes. Our study aimed to evaluate the importance of LRP5 in the determination of peak bone mass acquisition in Chinese females in the general population. Methods: A total of 286 young southern Chinese females (aged 22–44 years) with low bone mineral density (BMD) (defined by a BMD Z score ≤–1.28 at either the hip or spine) or high BMD (Z score ≧+1) were studied. The LRP5 gene was sequenced for single nucleotide polymorphisms (SNPs) and 4 SNPs were tagged from 8 genotyped SNPs for this study. Results: Single locus allele association tests revealed significant associations of rs682429 and rs686921 with BMD variation (p < 0.05). Omnibus test (likelihood ratio test) revealed overall significant association between LRP5 gene locus and total hip BMD, with rs682429 being most predictive. rs682429 is located in 5′UTR, 2 bases adjacent to a consensus recognition site for the Elk-1 binding element. Conclusion: Common variations of the LRP5 promoter are associated with BMD in young women. These significant associations appear to be driven by rs682429. Functional studies are necessary to elucidate the role of this SNP on the effect of Elk-1 binding element transcriptional activity of LRP5 gene.

© 2007 S. Karger AG, Basel


  

Author Contacts

Annie W.C. Kung
Department of Medicine, The University of Hong Kong
Queen Mary Hospital
Hong Kong (China)
Tel. +852 2855 4769, Fax +852 2816 2187, E-Mail awckung@hkucc.hku.hk

  

Article Information

Received: April 10, 2007
Accepted after revision: August 14, 2007
Published online: December 11, 2007
Number of Print Pages : 8
Number of Figures : 1, Number of Tables : 3, Number of References : 40

  

Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 65, No. 4, Year 2008 (Cover Date: January 2008)

Journal Editor: Devoto, M. (Philadelphia, Pa.)
ISSN: 0001–5652 (Print), eISSN: 1423–0062 (Online)

For additional information: http://www.karger.com/HHE


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 4/10/2007
Accepted: 8/14/2007
Published online: 12/11/2007
Issue release date: January 2008

Number of Print Pages: 8
Number of Figures: 1
Number of Tables: 3

ISSN: 0001-5652 (Print)
eISSN: 1423-0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Wang MC, Aguirre M, Bhudhikanok GS, Kendall CG, Kirsch S, Marcus R, Bachrach LK: Bone mass and hip axis length in healthy asian, black, hispanic, and white american youths. J Bone Miner Res 1997;12:1922–1935.
  2. Eisman JA: Genetics of osteoporosis. Endocr Rev 1999;20:788–804.
  3. Flicker L, Hopper JL, Rodgers L, Kaymakci B, Green RM, Wark JD: Bone density determinants in elderly women: A twin study. J Bone Miner Res 1995;10:1607–1613.
  4. Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S: Genetic determinants of bone mass in adults. A twin study. J Clin Invest 1987;80:706–710.
  5. Smith DM, Nance WE, Kang KW, Christian JC, Johnston CC Jr: Genetic factors in determining bone mass. J Clin Invest 1973;52:2800–2808.
  6. Hey PJ, Twells RC, Phillips MS, Yusuke N, Brown SD, Kawaguchi Y, Cox R, Guochun X, Dugan V, Hammond H, Metzker ML, Todd JA, Hess JF: Cloning of a novel member of the low-density lipoprotein receptor family. Gene 1998;216:103–111.
  7. Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC: An ldl-receptor-related protein mediates wnt signalling in mice. Nature 2000;407:535–538.
  8. Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X: Ldl-receptor-related proteins in wnt signal transduction. Nature 2000;407:530–535.
  9. Wehrli M, Dougan ST, Caldwell K, O’Keefe L, Schwartz S, Vaizel-Ohayon D, Schejter E, Tomlinson A, DiNardo S: Arrow encodes an ldl-receptor-related protein essential for wingless signalling. Nature 2000;407:527–530.
  10. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Juppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML: Ldl receptor-related protein 5 (lrp5) affects bone accrual and eye development. Cell 2001;107:513–523.
  11. Cheung WM, Jin LY, Smith DK, Cheung PT, Kwan E, Low L, Kung AWC: A family with osteoporosis pseudoglioma syndrome due to compound heterozygosity of two novel mutations in the lrp5 gene. Bone 2006;39:470–476.
  12. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP: High bone density due to a mutation in ldl-receptor-related protein 5. N Engl J Med 2002;346:1513–1521.
  13. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, Manning SP, Swain PM, Zhao SC, Eustace B, Lappe MM, Spitzer L, Zweier S, Braunschweiger K, Benchekroun Y, Hu X, Adair R, Chee L, FitzGerald MG, Tulig C, Caruso A, Tzellas N, Bawa A, Franklin B, McGuire S, Nogues X, Gong G, Allen KM, Anisowicz A, Morales AJ, Lomedico PT, Recker SM, Van Eerdewegh P, Recker RR, Johnson ML: A mutation in the ldl receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 2002;70:11–19.
  14. Rickels MR, Zhang X, Mumm S, Whyte MP: Oropharyngeal skeletal disease accompanying high bone mass and novel lrp5 mutation. J Bone Miner Res 2005;20:878–885.
  15. Van Wesenbeeck L, Cleiren E, Gram J, Beals RK, Benichou O, Scopelliti D, Key L, Renton T, Bartels C, Gong Y, Warman ML, De Vernejoul MC, Bollerslev J, Van Hul W: Six novel missense mutations in the ldl receptor-related protein 5 (lrp5) gene in different conditions with an increased bone density. Am J Hum Genet 2003;72:763–771.
  16. Ferrari SL, Deutsch S, Choudhury U, Chevalley T, Bonjour JP, Dermitzakis ET, Rizzoli R, Antonarakis SE: 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. Am J Hum Genet 2004;74:866–875.
  17. Koay MA, Woon PY, Zhang Y, Miles LJ, Duncan EL, Ralston SH, Compston JE, Cooper C, Keen R, Langdahl BL, MacLelland A, O’Riordan J, Pols HA, Reid DM, Uitterlinden AG, Wass JA, Brown MA: Influence of lrp5 polymorphisms on normal variation in bmd. J Bone Miner Res 2004;19:1619–1627.
  18. Lau HH, Ng MY, Ho AY, Luk KD, Kung AW: Genetic and environmental determinants of bone mineral density in chinese women. Bone 2005;36:700–709.
  19. van Meurs JB, Rivadeneira F, Jhamai M, Hugens W, Hofman A, van Leeuwen JP, Pols HA, Uitterlinden AG: Common genetic variation of the low-density lipoprotein receptor-related protein 5 and 6 genes determines fracture risk in elderly white men. J Bone Miner Res 2006;21:141–150.
  20. Ezura Y, Nakajima T, Urano T, Sudo Y, Kajita M, Yoshida H, Suzuki T, Hosoi T, Inoue S, Shiraki M, Emi M: Association of a single-nucleotide variation (a1330v) in the low-density lipoprotein receptor-related protein 5 gene (lrp5) with bone mineral density in adult japanese women. Bone 2007;40:997–1005.
  21. Giroux S, Elfassihi L, Cardinal G, Laflamme N, Rousseau F: Lrp5 coding polymorphisms influence the variation of peak bone mass in a normal population of French-Canadian women. Bone 2007;40:1299–1307.
  22. Koay MA, Tobias JH, Leary SD, Steer CD, Vilarino-Guell C, Brown MA: The effect of lrp5 polymorphisms on bone mineral density is apparent in childhood. Calcif Tissue Int 2007;81:1–9.
  23. Koller DL, Ichikawa S, Johnson ML, Lai D, Xuei X, Edenberg HJ, Conneally PM, Hui SL, Johnston CC, Peacock M, Foroud T, Econs MJ: Contribution of the lrp5 gene to normal variation in peak bmd in women. J Bone Miner Res 2005;20:75–80.
  24. Zhang ZL, Qin YJ, He JW, Huang QR, Li M, Hu YQ, Liu YJ: Association of polymorphisms in low-density lipoprotein receptor-related protein 5 gene with bone mineral density in postmenopausal chinese women. Acta Pharmacol Sin 2005;26:1111–1116.
  25. Lau HH, Ng MY, Cheung WM, Paterson AD, Sham PC, Luk KD, Chan V, Kung AW: Assessment of linkage and association of 13 genetic loci with bone mineral density. J Bone Miner Metab 2006;24:226–234.
  26. Saarinen A, Valimaki VV, Valimaki MJ, Loyttyniemi E, Auro K, Uusen P, Kuris M, Lehesjoki AE, Makitie O: The a1330v polymorphism of the low-density lipoprotein receptor-related protein 5 gene (lrp5) associates with low peak bone mass in young healthy men. Bone 2007;40:1006–1012.
  27. Bollerslev J, Wilson SG, Dick IM, Islam FM, Ueland T, Palmer L, Devine A, Prince RL: Lrp5 gene polymorphisms predict bone mass and incident fractures in elderly australian women. Bone 2005;36:599–606.
  28. Xiong DH, Shen H, Zhao LJ, Xiao P, Yang TL, Guo Y, Wang W, Guo YF, Liu YJ, Recker RR, Deng HW: Robust and comprehensive analysis of 20 osteoporosis candidate genes by very high-density single-nucleotide polymorphism screen among 405 white nuclear families identified significant association and gene-gene interaction. J Bone Miner Res 2006;21:1678–1695.
  29. Mizuguchi T, Furuta I, Watanabe Y, Tsukamoto K, Tomita H, Tsujihata M, Ohta T, Kishino T, Matsumoto N, Minakami H, Niikawa N, Yoshiura K: Lrp5, low-density-lipoprotein-receptor-related protein 5, is a determinant for bone mineral density. J Hum Genet 2004;49:80–86.
  30. Mei J, Yeung SS, Kung AW: High dietary phytoestrogen intake is associated with higher bone mineral density in postmenopausal but not premenopausal women. J Clin Endocrinol Metab 2001;86:5217–5221.
  31. Cheung CL, Chan V, Kung AW: A differential association of alox15 polymorphisms with bone mineral density in pre- and post-menopausal women. Hum Hered 2008;65:1–8.
  32. Barrett JC, Fry B, Maller J, Daly MJ: Haploview: Analysis and visualization of ld and haplotype maps. Bioinformatics 2005;21:263–265.
  33. Abecasis GR, Cookson WO: Gold – graphical overview of linkage disequilibrium. Bioinformatics 2000;16:182–183.
  34. Purcell S, Cherny SS, Sham PC: Genetic power calculator: Design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003;19:149–150.
  35. Cartharius K, Frech K, Grote K, Klocke B, Haltmeier M, Klingenhoff A, Frisch M, Bayerlein M, Werner T: Matinspector and beyond: Promoter analysis based on transcription factor binding sites. Bioinformatics 2005;21:2933–2942.
  36. Twells RC, Mein CA, Phillips MS, Hess JF, Veijola R, Gilbey M, Bright M, Metzker M, Lie BA, Kingsnorth A, Gregory E, Nakagawa Y, Snook H, Wang WY, Masters J, Johnson G, Eaves I, Howson JM, Clayton D, Cordell HJ, Nutland S, Rance H, Carr P, Todd JA: Haplotype structure, ld blocks, and uneven recombination within the lrp5 gene. Genome Res 2003;13:845–855.
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