Abstract
Bone mineral density (BMD), an important risk factor for osteoporosis, is a complex trait likely affected by multiple genes. The linkage and/or association of 13 polymorphic loci of seven candidate genes (estrogen receptor alpha [ERα] and beta [ERβ], calcium-sensing receptor, vitamin D receptor, collagen type 1α1, low-density lipoprotein [LDL] receptor-related protein 5 [LRPS], and transforming growth factor β1) were evaluated in 177 southern Chinese pedigrees of 674 subjects, with each pedigree identified through a proband having a BMD Z score of −1.28 or less at the hip or spine. A suggestive linkage was detected between the IVS1-351A/G polymorphism of ERα and spine BMD, and between the 1082G/A, 1730G/A, and D14S1026 polymorphisms of ERβ and BMD at both spine and hip. The quantitative transmission disequilibrium test (QTDT) detected total family association between 1730G/A of ERβ and BMD at spine and hip; between D14S1026 of ERβ and hip BMD; and between the 266A/G and 2220C/T polymorphisms of LRP5 and hip BMD. Similar total family associations were detected when only the females were analyzed. In addition, the IVS1-397T/C polymorphism of ERα was associated with spine BMD, and the 266A/G and 2220C/T polymorphisms of LRP5 were associated with femoral neck BMD in the females. A within-family association was detected with the IVS1-397T/C polymorphism of ERα, and the 266A/G and 2220C/T polymorphisms of LRP5 in the females. The effect of each polymorphism on BMD variance ranged from 1% to 4%. In conclusion, ERα, ERβ and LRP5 are important candidate genes determining BMD variation, especially in females.
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References
SR Cummings LJ Melton (2002) ArticleTitleEpidemiology and outcomes of osteoporotic fractures Lancet 359 1761–1767 Occurrence Handle10.1016/S0140-6736(02)08657-9 Occurrence Handle12049882
CW Slemenda JC Christian CJ Williams JA Norton CC Johnston SuffixJr (1991) ArticleTitleGenetic determinants of bone mass in adult women: a reevaluation of the twin model and the potential importance of gene interaction on heritability estimates J Bone Miner Res 6 561–567 Occurrence Handle1:STN:280:By6A287ovVI%3D Occurrence Handle1887818
R Gueguen P Jouanny F Guillemin C Kuntz J Pourel G Siest (1995) ArticleTitleSegregation analysis and variance components analysis of bone mineral density in healthy families J Bone Miner Res 10 2017–2022 Occurrence Handle1:STN:280:BymC1M3nt1A%3D Occurrence Handle8619384
OM Albagha SH Ralston (2003) ArticleTitleGenetic determinants of susceptibility to osteoporosis Endocrinol Metab Clin North Am 32 65–81 Occurrence Handle10.1016/S0889-8529(02)00059-2 Occurrence Handle1:CAS:528:DC%2BD3sXjtFOjsbw%3D Occurrence Handle12699293
DL Koller LA Rodriguez JC Christian CW Slemenda MJ Econs SL Hui P Morin PM Conneally G Joslyn ME Curran M Peacock CC Johnston T Foroud (1998) ArticleTitleLinkage of a QTL contributing to normal variation in bone mineral density to chromosome 11q12-13 J Bone Miner Res 13 1903–1908 Occurrence Handle1:STN:280:DyaK1M%2Fmt1WqtA%3D%3D Occurrence Handle9844108
DL Koller MJ Econs PA Morin JC Christian SL Hui P Parry ME Curran LA Rodriguez PM Conneally G Joslyn M Peacock CC Johnston T Foroud (2000) ArticleTitleGenome screen for QTLs contributing to normal variation in bone mineral density and osteoporosis J Clin Endocrinol Metab 85 3116–3120 Occurrence Handle10.1210/jc.85.9.3116 Occurrence Handle1:CAS:528:DC%2BD3cXmsVKru7o%3D Occurrence Handle10999795
EL Duncan MA Brown J Sinsheimer J Bell AJ Carr BP Wordsworth JA Wass (1999) ArticleTitleSuggestive linkage of the parathyroid receptor type 1 to osteoporosis J Bone Miner Res 14 1993–1999 Occurrence Handle1:CAS:528:DC%2BD3cXkslWrsw%3D%3D Occurrence Handle10620056
HW Deng FH Xu T Conway XT Deng JL Li KM Davies H Deng M Johnson RR Recker (2001) ArticleTitleIs population bone mineral density variation linked to the marker D11S987 on chromosome 11q12-13? J Clin Endocrinol Metab 86 3735–3741 Occurrence Handle10.1210/jc.86.8.3735 Occurrence Handle1:CAS:528:DC%2BD3MXlvFektbw%3D Occurrence Handle11502804
D Karasik RH Myers LA Cupples MT Hannan DR Gagnon A Herbert DP Kiel (2002) ArticleTitleGenome screen for quantitative trait loci contributing to normal variation in bone mineral density: the Framingham Study J Bone Miner Res 17 1718–1727 Occurrence Handle1:CAS:528:DC%2BD38XntlSrsb8%3D Occurrence Handle12211443
CM Kammerer JL Schneider SA Cole JE Hixson PB Samollow JR O'Connell R Perez TD Dyer L Almasy J Blangero RL Bauer BD Mitchell (2003) ArticleTitleQuantitative trait loci on chromosomes 2p, 4p, and 13q influence bone mineral density of the forearm and hip in Mexican Americans J Bone Miner Res 18 2245–2252 Occurrence Handle1:CAS:528:DC%2BD3sXhtVSqtrzI Occurrence Handle14672361
SG Wilson PW Reed A Bansal M Chiano M Lindersson M Langdown RL Prince D Thompson E Thompson M Bailey PW Kleyn P Sambrook MM Shi TD Spector (2003) ArticleTitleComparison of genome screens for two independent cohorts provides replication of suggestive linkage of bone mineral density to 3p21 and 1p36 Am J Hum Genet 72 144–155 Occurrence Handle10.1086/345819 Occurrence Handle1:CAS:528:DC%2BD3sXis1ygtQ%3D%3D Occurrence Handle12478480
MJ Econs DL Koller SL Hui T Fishburn PM Conneally CC Johnston SuffixJr M Peacock TM Foroud (2004) ArticleTitleConfirmation of linkage to chromosome 1q for peak vertebral bone mineral density in premenopausal white women Am J Hum Genet 74 223–228 Occurrence Handle10.1086/381401 Occurrence Handle1:CAS:528:DC%2BD2cXhtlKiurw%3D Occurrence Handle14730478
SH Ralston N Galwey I Mackey OM Albagha L Cardon JE Compston C Cooper E Duncan R Keen B Langdahl A McLellan J O'Riordan HA Pols DM Reid AG Uitterlinden J Wass ST Bennett (2005) ArticleTitleLoci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS Study Hum Mol Genet 14 943–951 Occurrence Handle10.1093/hmg/ddi088 Occurrence Handle1:CAS:528:DC%2BD2MXis1yjt7Y%3D Occurrence Handle15746152
M Devoto LD Spotila DL Stabley GN Wharton H Rydbeck J Korkko R Kosich D Prockop A Tenenhouse K Sol-Church (2005) ArticleTitleUnivariate and bivariate variance component linkage analysis of a whole-genome scan for loci contributing to bone mineral density Eur J Hum Genet 13 IssueID6 781–788 Occurrence Handle10.1038/sj.ejhg.5201411 Occurrence Handle1:CAS:528:DC%2BD2MXktl2rtrg%3D Occurrence Handle15827564
N Risch K Merikangas (1996) ArticleTitleThe future of genetic studies of complex human diseases Science 273 1516–1517 Occurrence Handle1:CAS:528:DyaK28Xls1Wqs7o%3D Occurrence Handle8801636
RS Spielman RE McGinnis WJ Ewens (1993) ArticleTitleTransmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM) Am J Hum Genet 52 506–516 Occurrence Handle1:STN:280:ByyC1M%2FpvVY%3D Occurrence Handle8447318
GR Abecasis WO Cookson LR Cardon (2000) ArticleTitlePedigree tests of transmission disequilibrium Eur J Hum Genet 8 545–551 Occurrence Handle10.1038/sj.ejhg.5200494 Occurrence Handle1:STN:280:DC%2BD3M%2FgvVCjsw%3D%3D Occurrence Handle10909856
GR Abecasis LR Cardon WO Cookson (2000) ArticleTitleA general test of association for quantitative traits in nuclear families Am J Hum Genet 66 279–292 Occurrence Handle10.1086/302698 Occurrence Handle1:STN:280:DC%2BD3c7gtVKhuw%3D%3D Occurrence Handle10631157
J Mei SS Yeung AW Kung (2001) ArticleTitleHigh dietary phytoestrogen intake is associated with higher bone mineral density in postmenopausal but not premenopausal women J Clin Endocrinol Metab 86 5217–5221 Occurrence Handle10.1210/jc.86.11.5217 Occurrence Handle1:CAS:528:DC%2BD3MXos1Kqs7w%3D Occurrence Handle11701680
AWC Kung SCC Yeung KS Lau (1998) ArticleTitleVitamin D receptor gene polymorphisms and peak bone mass in southern Chinese women Bone 22 389–393 Occurrence Handle10.1016/S8756-3282(97)00301-3 Occurrence Handle1:STN:280:DyaK1c3hsFChtQ%3D%3D Occurrence Handle9556140
AWC Kung KDK Luk LW Chu CWK Tang (1999) ArticleTitleQuantitative ultrasound and sympotomatic vertebral fracture risk in Chinese women Osteoporos Int 10 456–461 Occurrence Handle10.1007/s001980050254 Occurrence Handle1:STN:280:DC%2BD3c7ltlaqsQ%3D%3D Occurrence Handle10663345
AWC Kung AYY Ho PD Ross JY Reginster (2005) ArticleTitleDevelopment of a clinical assessment tool in identifying Asian men with low bone mineral density and comparison of its usefulness to quantitative bone ultrasound Osteoporos Int (Epub ahead of print) 16 849–855
K Tsukamoto H Orimo T Hosoi M Miyao N Ota T Nakajima H Yoshida S Watanabe T Suzuki M Emi (2000) ArticleTitleAssociation of bone mineral density with polymorphism of the human calcium-sensing receptor locus Calcif Tissue Int 66 181–183 Occurrence Handle10.1007/PL00005835 Occurrence Handle1:CAS:528:DC%2BD3cXhslSiur4%3D Occurrence Handle10666491
N Garcia-Giralt X Nogues A Enjuanes J Puig L Mellibovsky A Bay-Jensen R Carreras S Balcells A Diez-Perez D Grinberg (2002) ArticleTitleTwo new single-nucleotide polymorphisms in the COL1A1 upstream regulatory region and their relationship to bone mineral density J Bone Miner Res 17 384–393 Occurrence Handle1:CAS:528:DC%2BD38XitVKht74%3D Occurrence Handle11874231
S Kobayashi S Inoue T Hosoi Y Ouchi M Shiraki H Orimo (1996) ArticleTitleAssociation of bone mineral density with polymorphism of the estrogen receptor gene J Bone Miner Res 11 306–311 Occurrence Handle1:CAS:528:DyaK28Xit1Cgurk%3D Occurrence Handle8852941
C Sundarrajan WX Liao AC Roy SC Ng (2001) ArticleTitleAssociation between estrogen receptor-beta gene polymorphisms and ovulatory dysfunctions in patients with menstrual disorders J Clin Endocrinol Metab 86 135–139 Occurrence Handle10.1210/jc.86.1.135 Occurrence Handle1:CAS:528:DC%2BD3MXhtVGnsrY%3D Occurrence Handle11231990
HHL Lau AYY Ho KDK Luk AWC Kung (2002) ArticleTitleEstrogen receptor β gene polymorphisms are associated with higher bone mineral density in premenopausal, but not postmenopausal southern Chinese women Bone 31 276–281 Occurrence Handle1:CAS:528:DC%2BD38XlvVWgtL4%3D Occurrence Handle12151079
S Ogawa T Hosoi M Shiraki H Orimo M Emi M Muramatsu Y Ouchi S Inoue (2000) ArticleTitleAssociation of estrogen receptor β gene polymorphism with bone mineral density Biochem Biophys Res Commun 269 537–541 Occurrence Handle10.1006/bbrc.2000.2285 Occurrence Handle1:CAS:528:DC%2BD3cXhsFKitbg%3D Occurrence Handle10708589
M Okubo A Horinishi DH Kim TT Yamamoto T Murase (2002) ArticleTitleSeven novel sequence variants in the human low density lipoprotein receptor related protein 5 (LRP5) gene Hum Mutat 19 186–188 Occurrence Handle10.1002/humu.9012 Occurrence Handle11793484
E Ziv A Kahn J Cauley P Morin R Saiz W Browner (2003) ArticleTitleNo association between the TGF-beta 1 Leu10Pro polymorphism and osteoporosis among white women in the United States Am J Med 114 227–231 Occurrence Handle1:CAS:528:DC%2BD3sXhvFequr4%3D Occurrence Handle12637138
C Gross TR Eccleshall PJ Malloy ML Villa R Marcus D Feldman (1996) ArticleTitleThe presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal Mexican-American women J Bone Miner Res 11 1850–1855 Occurrence Handle1:CAS:528:DyaK2sXjtVCmtQ%3D%3D Occurrence Handle8970885
GR Abecasis SS Cherny WO Cookson LR Cardon (2002) ArticleTitleMerlin – rapid analysis of dense genetic map using sparse gene flow trees Nat Genet 30 97–101 Occurrence Handle10.1038/ng786 Occurrence Handle1:CAS:528:DC%2BD38XivVGjtg%3D%3D Occurrence Handle11731797
LM McIntyre ER Martin KL Simonsen NL Kaplan (2000) ArticleTitleCircumventing multiple testing: a multilocus Monte Carlo approach to testing for association Genet Epidemiol 19 18–29 Occurrence Handle10.1002/1098-2272(200007)19:1<18::AID-GEPI2>3.0.CO;2-Y Occurrence Handle1:STN:280:DC%2BD3cvht1egsg%3D%3D Occurrence Handle10861894
M Sano S Inoue T Hosoi Y Ouchi M Emi M Shiraki H Orimo (1995) ArticleTitleAssociation of estrogen receptor dinucleotide repeat polymorphism with osteoporosis Biochem Biophys Res Commun 217 378–383 Occurrence Handle10.1006/bbrc.1995.2787 Occurrence Handle1:CAS:528:DyaK2MXpvVWhsb8%3D Occurrence Handle8526937
OM Albagha FE McGuigan DM Reid SH Ralston (2001) ArticleTitleEstrogen receptor alpha gene polymorphisms and bone mineral density: haplotype analysis in women from the United Kingdom J Bone Miner Res 16 128–134 Occurrence Handle1:CAS:528:DC%2BD3MXitlChug%3D%3D Occurrence Handle11149476
YJ Qin H Shen QR Huang LJ Zhao Q Zhou MX Li JW He XY Mo JH Lu RR Recker HW Deng (2003) ArticleTitleEstrogen receptor alpha gene polymorphisms and peak bone density in Chinese nuclear families J Bone Miner Res 18 1028–1035 Occurrence Handle1:CAS:528:DC%2BD3sXkslOhsb8%3D Occurrence Handle12817755
S Khosla BL Riggs EJ Atkinson AL Oberg C Mavilia F Del Monte LJ Melton Suffix3rd ML Brandi (2004) ArticleTitleRelationship of estrogen receptor genotypes to bone mineral density and to rates of bone loss in men J Clin Endocrinol Metab 89 1808–1816 Occurrence Handle10.1210/jc.2003-031448 Occurrence Handle1:CAS:528:DC%2BD2cXjt1elt7o%3D Occurrence Handle15070949
JP Ioannidis I Stavrou TA Trikalinos C Zois ML Brandi L Gennari O Albagha SH Ralston A Tsatsoulis (2002) ArticleTitleER-alpha genetics meta-analysis association of polymorphisms of the estrogen receptor alpha gene with bone mineral density and fracture risk in women: a meta-analysis J Bone Miner Res 17 2048–2060 Occurrence Handle1:CAS:528:DC%2BD38Xoslems7Y%3D Occurrence Handle12412813
JP Ioannidis SH Ralston ST Bennett ML Brandi D Grinberg et al. (2004) ArticleTitleDifferential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes JAMA 292 2105–2114 Occurrence Handle10.1001/jama.292.17.2105 Occurrence Handle1:CAS:528:DC%2BD2cXpsVeku7g%3D Occurrence Handle15523071
B Arko J Prezelj R Komel A Kocijancic J Marc (2002) ArticleTitleNo major effect of estrogen receptor beta gene RsaI polymorphism on bone mineral density and response to alendronate therapy in postmenopausal osteoporosis J Steroid Biochem Mol Biol 81 147–152 Occurrence Handle10.1016/S0960-0760(02)00061-4 Occurrence Handle1:CAS:528:DC%2BD38Xls1WhsrY%3D Occurrence Handle12137804
AM Shearman D Karasik KM Gruenthal S Demissie LA Cupples DE Housman DP Kiel (2004) ArticleTitleEstrogen receptor beta polymorphisms are associated with bone mass in women and men: the Framingham Study J Bone Miner Res 19 773–781 Occurrence Handle1:CAS:528:DC%2BD2cXktFGks78%3D Occurrence Handle15068501
LJ Zhao PY Liu JR Long Y Lu FH Xu YY Zhang H Shen P Xiao L Elze RR Recker HW Deng (2004) ArticleTitleTest of linkage and/or association between the estrogen receptor alpha gene with bone mineral density in Caucasian nuclear families Bone 35 395–402 Occurrence Handle10.1016/j.bone.2004.04.013 Occurrence Handle1:CAS:528:DC%2BD2cXmtVWitrc%3D Occurrence Handle15268889
DM Herrington TD Howard KB Brosnihan DP McDonnell X Li GA Hawkins DM Reboussin J Xu SL Zheng DA Meyers ER Bleecker (2002) ArticleTitleCommon estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein Circulation 105 1879–1882 Occurrence Handle1:CAS:528:DC%2BD38XktFajtbg%3D Occurrence Handle11997270
E Enmark M Pelto-Huikko K Grandien S Lagercrantz J Lagercrantz G Fried M Nordenskjold JA Gustafsson (1997) ArticleTitleHuman estrogen receptor beta-gene structure, chromosomal localization, and expression pattern J Clin Endocrinol Metab 82 4258–4265 Occurrence Handle10.1210/jc.82.12.4258 Occurrence Handle1:CAS:528:DyaK2sXnvFyrtL0%3D Occurrence Handle9398750
HW Deng FH Xu QY Huang H Shen H Deng T Conway YZ Liu JL Li HT Zhang KM Davies RR Recker (2002) ArticleTitleA whole-genome linkage scan suggests several genomeic regions potentially containing quantitative trait loci for osteoporosis J Clin Endocrinol Metab 87 5151–5159 Occurrence Handle10.1210/jc.2002-020474 Occurrence Handle1:CAS:528:DC%2BD38Xos1ynt7s%3D Occurrence Handle12414886
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Lau, H., Ng, M., Cheung, W. et al. Assessment of linkage and association of 13 genetic loci with bone mineral density. J Bone Miner Metab 24, 226–234 (2006). https://doi.org/10.1007/s00774-005-0676-6
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DOI: https://doi.org/10.1007/s00774-005-0676-6