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Suggestive Linkage of 2p22-25 and 11q12-13 with Low Bone Mineral Density at the Lumbar Spine in the Irish Population

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Abstract

Osteoporosis is a disease characterized by low bone mineral density (BMD) and poor bone quality. Peak bone density is achieved by the third decade of life, after which bone is maintained by a balanced cycle of bone resorption and synthesis. Age-related bone loss occurs as the bone resorption phase outweighs the bone synthesis phase of bone metabolism. Heritability accounts for up to 90% of the variability in BMD. Chromosomal loci including 1p36, 2p22-25, 11q12-13, parathyroid hormone receptor type 1 (PTHR1), interleukin-6 (IL-6), interleukin 1 alpha (IL-1α) and type II collagen A1/vitamin D receptor (COL11A1/VDR) have been linked or shown suggestive linkage with BMD in other populations. To determine whether these loci predispose to low BMD in the Irish population, we investigated 24 microsatellite markers at 7 chromosomal loci by linkage studies in 175 Irish families of probands with primary low BMD (T-score ≤ −1.5). Nonparametric analysis was performed using the maximum likelihood variance estimation and traditional Haseman-Elston tests on the Mapmaker/Sibs program. Suggestive evidence of linkage was observed with lumbar spine BMD at 2p22-25 (maximum LOD score 2.76) and 11q12-13 (MLS 2.55). One region, 1p36, approached suggestive linkage with femoral neck BMD (MLS 2.17). In addition, seven markers achieved LOD scores >1.0, D2S149, D11S1313, D11S987, D11S1314 including those encompassing the PTHR1 (D3S3559, D3S1289) for lumbar spine BMD and D2S149 for femoral neck BMD. Our data suggest that genes within a these chromosomal regions are contributing to a predisposition to low BMD in the Irish population.

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References

  1. LJ Melton (1995) ArticleTitleHow many women have osteoporosis now? J Bone Miner Res 10 175–177 Occurrence Handle7754796

    PubMed  Google Scholar 

  2. NF Ray JK Chan M Thamer LJ Melton III (1997) ArticleTitleMedical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res 12 24–35 Occurrence Handle1:STN:280:ByiA1c3ntl0%3D Occurrence Handle9240722

    CAS  PubMed  Google Scholar 

  3. A Randell PN Sambrook TV Nguyen H Lapsley G Jones PJ Kelly JA Eisman (1995) ArticleTitleDirect clinical and welfare costs of osteoporotic fractures in elderly men and women. Osteoporos Int 5 427–432 Occurrence Handle1:STN:280:BymB2c7islM%3D Occurrence Handle8695963

    CAS  PubMed  Google Scholar 

  4. NA Pocock JA Eisman JL Hopper MG Yeats PM Sambrook S Eberl (1987) ArticleTitleGenetic determinants of bone mass in adults. A twin study. J Clin Invest 80 706–710 Occurrence Handle1:STN:280:BiiA3cfotVM%3D Occurrence Handle3624485

    CAS  PubMed  Google Scholar 

  5. DM Smith WE Nance KW Kang JC Christian CC Johnston Jr (1973) ArticleTitleGenetic factors in determining bone mass. J Clin Invest 52 IssueID11 2800–2808 Occurrence Handle1:STN:280:CSuD387msVA%3D Occurrence Handle4795916

    CAS  PubMed  Google Scholar 

  6. EL Duncan J Sinsheimer K Dymott B Jakobsen AJ Shipman JAH Wass (1997) ArticleTitleBone mineral density of relatives of male and female patients with osteoporosis. J Endocrinol 152 IssueIDsuppl 1 S11

    Google Scholar 

  7. SR Cummings MC Nevitt WS Browner K Stone KM Fox KE Ensrud J Cauley D Black TM Vogt (1995) ArticleTitleRisk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 332 767–773 Occurrence Handle1:STN:280:ByqC28nislE%3D Occurrence Handle7862179

    CAS  PubMed  Google Scholar 

  8. DJ Torgerson MK Campbell RE Thomas DM Reid (1996) ArticleTitlePrediction of perimenopausal fractures by bone mineral density and other risk factors. J Bone Miner Res 11 293–297 Occurrence Handle1:STN:280:BymH3MblvFI%3D Occurrence Handle8822354

    CAS  PubMed  Google Scholar 

  9. Z Efstathiadou A Tsatsoulis J Loannidis (2001) ArticleTitleAssociation of collagen 1α 1 Spl polymorphism with the Risk of prevalent fractures: a meta-analysis. J Bone Miner Res 16 1586–1592 Occurrence Handle1:CAS:528:DC%2BD3MXmvV2qs7c%3D Occurrence Handle11547828

    CAS  PubMed  Google Scholar 

  10. 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 1850–1815 Occurrence Handle1:CAS:528:DyaK2sXjtVCmtQ%3D%3D Occurrence Handle8970885

    CAS  PubMed  Google Scholar 

  11. 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 Handle1:CAS:528:DyaK2MXpvVWhsb8%3D Occurrence Handle8526937

    CAS  PubMed  Google Scholar 

  12. N Ota T Nakajima I Nakazawa T Suzuki T Hosoi H Orimo S Inoue Y Shirai M Emi (2001) ArticleTitleA nucleotide variant in the promoter region of the interleukin-6 gene associated with decreased bone mineral density. J Hum Genet 46 267–272

    Google Scholar 

  13. K Tsukamoto N Ohta Y Shirai M Emi (1998) ArticleTitleA highly polymorphic CA repeat marker at the human interleukin 6 receptor (IL6R) locus. J Hum Genet 43 289–290 Occurrence Handle10.1007/s100380050095 Occurrence Handle1:CAS:528:DyaK1cXotFSlsbs%3D Occurrence Handle9852689

    Article  CAS  PubMed  Google Scholar 

  14. BL Langdahl JY Knudsen HK Jensen N Gregersen EF Eriksen (1997) ArticleTitleA sequence variation: 713-8delC in the transforming growth factor-beta 1 gene has higher prevalence in osteoporotic women than in normal women and is associated with very low bone mass in osteoporotic women and increased bone turnover in both osteoporotic and normal women. Bone 20 289–294 Occurrence Handle1:CAS:528:DyaK2sXit12qsb0%3D Occurrence Handle9071481

    CAS  PubMed  Google Scholar 

  15. F Wynne F Drummond K O’Sullivan M Daly F Shannahan MG Molloy KA Quane (2002) ArticleTitleAn investigation of the influence of the OPG gene, VDR (Fok1) and COLIA1 Sp1 polymorphisms on BMD in the Irish population. Calcif Tissue Int 71 26–35 Occurrence Handle10.1007/s00223-001-2081-z Occurrence Handle1:CAS:528:DC%2BD38Xms12gtb4%3D Occurrence Handle12073153

    Article  CAS  PubMed  Google Scholar 

  16. M Devoto K Shimoya J Caminis J Ott A Tenenhouse MP Whyte L Sereda S Hall E Considine CJ Williams G Tromp H Kuivaniemi L Ala-Kokko DJ Prockop LD Spotila (1998) ArticleTitleFirst-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4p. Eur J Hum Genet 6 151–157 Occurrence Handle1:CAS:528:DyaK1MXhsFGktbs%3D Occurrence Handle9781060

    CAS  PubMed  Google Scholar 

  17. ML Johnson G Gong W Kimberling SM Recker DB Kimmel R Recker (1997) ArticleTitleLinkage of a gene causing high bone mass to human chromosome 11 (11q12-13). Am J Hum Genet 60 1326–1332 Occurrence Handle1:CAS:528:DyaK2sXktlOqtLg%3D Occurrence Handle9199553

    CAS  PubMed  Google Scholar 

  18. DL Koller J Rodriguez C Christain M Siemenda S Econs P Hui P Morin G Conneally M Joslyn M Curran C Paecock C Johnson 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

    CAS  PubMed  Google Scholar 

  19. C Heaney H Shaley K Elbedour R Carmi JB Staack VC Sheffield DR Beier (1998) ArticleTitleHuman autosomal recessive osteopetrosis maps to 11q13, a position predicted by comparative mapping of the murine osteosclerosis (oc) mutation. Hum Mol Genet 7 1407–1410 Occurrence Handle10.1093/hmg/7.9.1407 Occurrence Handle1:CAS:528:DyaK1cXmtVSls70%3D Occurrence Handle9700194

    Article  CAS  PubMed  Google Scholar 

  20. Y Gong M Vikkula L Boon J Liu P Beighton R Ramesar L Peltonen H Somer T Hirose B Dallapiccola A De Paepe W Swoboda B Zabel A Superti-Furga B Steinmann HG Brunner A Jans RG Boles W Adkins MJ van den Boogaard BR Olsen ML Warman (1996) ArticleTitleOsteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13. Am J Hum Genet 59 146–151 Occurrence Handle1:CAS:528:DyaK28XksFSitr4%3D Occurrence Handle8659519

    CAS  PubMed  Google Scholar 

  21. E Van Hul J Gram J Bollerslev L Van Wesenbeeck D Mathysen PE Andersen F Vanhoenacker W Van Hul (2002) ArticleTitleLocalization of the gene causing autosomal dominant osteopetrosis type 1 to chromosome 11q12-13. J Bone Miner Res 17 IssueID6 1111–1117 Occurrence Handle1:CAS:528:DC%2BD38Xks1Wktbg%3D Occurrence Handle12054167

    CAS  PubMed  Google Scholar 

  22. RD Little JP Carulli RG Del Mastro et al. (2002) ArticleTitleA mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 70 11–19 Occurrence Handle10.1086/338450 Occurrence Handle1:CAS:528:DC%2BD38XlvVKhtw%3D%3D Occurrence Handle11741193

    Article  CAS  PubMed  Google Scholar 

  23. Y Gong RB Slee N Fukai G Rawadi et al. (2001) ArticleTitleLDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107 513–523 Occurrence Handle1:CAS:528:DC%2BD3MXovVCnsb4%3D Occurrence Handle11719191

    CAS  PubMed  Google Scholar 

  24. A Frattini PJ Orchard C Sobacchi S Giliani M Abinun JP Mattsson DJ Keeling AK Andersson P Wallbrandt L Zecca LD Notarangelo P Vezzoni A Villa (2000) ArticleTitleDefects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet 25 IssueID3 343–346 Occurrence Handle1:CAS:528:DC%2BD3cXkvFKktLo%3D Occurrence Handle10888887

    CAS  PubMed  Google Scholar 

  25. 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

    CAS  PubMed  Google Scholar 

  26. T Niu C Cehn H Cordell J Yang B Wang Z Wang Z Fang NJ Schork CJ Rosen X Xu (1999) ArticleTitleA genome-wide scan for loci linked to forearm bone mineral density. Hum Genet 104 226–233 Occurrence Handle10.1007/s004390050940 Occurrence Handle1:CAS:528:DyaK1MXit1Shu74%3D Occurrence Handle10323246

    Article  CAS  PubMed  Google Scholar 

  27. M Devoto C Specchia L Hui-Hua J Caminis A Tenenhouse H Rodriguez L Spotila (2001) ArticleTitleVariance component linkage analysis indicates a QTL for femoral neck bone mineral density on chromosome 1p36. Hum Mol Gen 10 2447–2452 Occurrence Handle10.1093/hmg/10.21.2447 Occurrence Handle1:CAS:528:DC%2BD3MXos1aqsbo%3D Occurrence Handle11689491

    Article  CAS  PubMed  Google Scholar 

  28. JA Kanis L Melton Jr C Christiansen CC Johnston N Khaltaev (1994) ArticleTitleThe diagnosis of osteoporosis. J Bone Miner Res 9 1137–1141 Occurrence Handle1:STN:280:ByqD28jgtFY%3D Occurrence Handle7976495

    CAS  PubMed  Google Scholar 

  29. JM Old (1983) Methods in haematology. Churchill-Livingston Edinburg

    Google Scholar 

  30. JR O’Connell DE Weeks (1998) ArticleTitlePedcheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63 259–266 Occurrence Handle1:STN:280:DyaK1c3pvFyhsA%3D%3D Occurrence Handle9634505

    CAS  PubMed  Google Scholar 

  31. J Haseman R Elston (1972) ArticleTitleThe investigation of linkage between a quantitative trait and a marker locus. Behav Genet 2 3–19 Occurrence Handle1:STN:280:CSyB3Mzgs1w%3D Occurrence Handle4157472

    CAS  PubMed  Google Scholar 

  32. L Kruglyak E Lander (1995) ArticleTitleComplete multipoint sib-pair analysis of qualitative and quantitative traits. Am J Hum Genet 57 439–454 Occurrence Handle1:STN:280:ByqA1Mjot1w%3D Occurrence Handle7668271

    CAS  PubMed  Google Scholar 

  33. L Almasy J Blangero (1998) ArticleTitleMultipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62 1198–1211 Occurrence Handle1:STN:280:DyaK1c3htlGrtg%3D%3D Occurrence Handle9545414

    CAS  PubMed  Google Scholar 

  34. S Slager V Vieland (1997) ArticleTitleInvestigating the numerical effect of ascertainment bias in linkage analysis: development of methods and primary results. Genet Epididemiol 14 1119–1124 Occurrence Handle10.1002/(SICI)1098-2272(1997)14:6<1119::AID-GEPI93>3.0.CO;2-J Occurrence Handle1:STN:280:DyaK1c%2FpsFCgsA%3D%3D

    Article  CAS  Google Scholar 

  35. S Lyengar F Calafell K Kidd (1997) ArticleTitleDetection of major genes underlying several quantitative traits associated with a common disease using different ascertainment schemes. Genet Epid 14 809–814 Occurrence Handle10.1002/(SICI)1098-2272(1997)14:6<809::AID-GEPI41>3.3.CO;2-I

    Article  Google Scholar 

  36. E Lander L Kruglyak (1995) ArticleTitleGenetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet 11 241–247 Occurrence Handle1:CAS:528:DyaK2MXptlSjs74%3D Occurrence Handle7581446

    CAS  PubMed  Google Scholar 

  37. S Nicole CS Davoine H Topaloglu et al. (2000) ArticleTitlePerlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia). Nat Genet 26 IssueID4 480–483

    Google Scholar 

  38. R Kumar JD Haugen (1994) ArticleTitleHuman and rat osteoblast-like cells express stathmin, a growth-regulatory protein. Biochem Biophys Res Commun 201 861–865 Occurrence Handle10.1006/bbrc.1994.1780 Occurrence Handle1:CAS:528:DyaK2cXkt1Oruro%3D Occurrence Handle8003023

    Article  CAS  PubMed  Google Scholar 

  39. T Cook B Gebelein K Mesa A Mladek R Urrutia (1998) ArticleTitleMolecular cloning and characterisation of TIEG2 reveals a new subfamily of transforming growth factor-beta-inducible Sp1-like zinc finger-encoding genes involved in the regulation of cell growth. J Biol Chem 273 25929–25936 Occurrence Handle10.1074/jbc.273.40.25929 Occurrence Handle1:CAS:528:DyaK1cXms1egtL4%3D Occurrence Handle9748269

    Article  CAS  PubMed  Google Scholar 

  40. H Krude H Biebermann W Luck R Horn G Brabant A Gruters (1998) ArticleTitleSevere early-onset obesity, adrenal insufficiency and red pigmentation caused by POMC mutations in humans. Nat Genet 19 155–157 Occurrence Handle10.1038/509 Occurrence Handle1:CAS:528:DyaK1cXls1Crt7o%3D Occurrence Handle9620771

    Article  CAS  PubMed  Google Scholar 

  41. C Sobacchi A Frattini P Orchard O Porras et al. (2001) ArticleTitleThe mutational spectrum of human malignant autosomal recessive osteopetrosis. Hum Mol Genet 10 IssueID17 1767–1773 Occurrence Handle1:CAS:528:DC%2BD3MXntFCitLY%3D Occurrence Handle11532986

    CAS  PubMed  Google Scholar 

  42. RS Johnson BM Spiegelman V Papaioannou (1992) ArticleTitlePleiotropic effects of a null mutation in the c-fos proto-oncogene. Cell 71 IssueID4 577–586 Occurrence Handle1:CAS:528:DyaK3sXlslGjuw%3D%3D Occurrence Handle1423615

    CAS  PubMed  Google Scholar 

  43. K Matsuo JM Owens M Tonko C Elliott TJ Chambers EF Wagner (2000) ArticleTitleFos11 is a transcriptional target of c-Fos during osteoclast differentiation. Nat Genet 24 IssueID2 184–187 Occurrence Handle10.1038/72855 Occurrence Handle1:CAS:528:DC%2BD3cXhtFCgtr0%3D Occurrence Handle10655067

    Article  CAS  PubMed  Google Scholar 

  44. E Schipani C Landman A Parfitt G Jansen S Kikuchi S Kooh W Cole H Juppner (1996) ArticleTitleConstitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen’s metaphyseal chondrodysplasia. N Engl J Med 335 708–714 Occurrence Handle1:CAS:528:DyaK28XlvVOns7k%3D Occurrence Handle8703170

    CAS  PubMed  Google Scholar 

  45. K Kruse C Schutz (1993) ArticleTitleCalcium metabolism in the Jansen type of metaphyseal dysphyseal. Eur J Pediatr 152 912–915 Occurrence Handle1:STN:280:ByuC3c3jtVI%3D Occurrence Handle8276022

    CAS  PubMed  Google Scholar 

  46. RYL Zee RH Myers MT Hannan PWF Wilson JM Ordovas EJ Schaefer K Lindpaintner DP Kiel (2000) ArticleTitleAbsence of linkage for bone mineral density to chromosome 12q12-14 in the region of the vitamin D receptor gene. Calcif Tissue Int 67 434–439 Occurrence Handle10.1007/s002230001175 Occurrence Handle1:CAS:528:DC%2BD3MXhvVOrtb8%3D Occurrence Handle11289690

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to Dr. Marcella Devoto for her informative advice and discussion during this study. We would also like to thank Ms. M. Twohy, Ms. A. O’Connell and Ms. C. Tait and those general practitioners who helped in the recruitment and bleeding of individuals for the study. In addition, we would like to express our gratitude to all the patients and their families who participated in this study. Work submitted in the paper was funded by the Irish Centre for Arthritis Research and Education and an International Osteoporosis Foundation (IOF)-Servier Young Investigator Research Fellowship 2000 (FW).

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Authors and Affiliations

  1. Department of Rheumatology, National University of Ireland, Cork, Ireland

    F. Wynne, F. J. Drummond, M. Daly, M. G. Molloy & K. A. Quane

  2. Department of Medicine, National University of Ireland, Cork, Ireland

    F. Wynne, F. J. Drummond, F. Shanahan & K. A. Quane

  3. Spondyloarthritis and Bone Disease Research Group, Oxford, England

    M. Brown

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  1. F. Wynne
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Correspondence to F. J. Drummond.

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Wynne, F., Drummond, F., Daly, M. et al. Suggestive Linkage of 2p22-25 and 11q12-13 with Low Bone Mineral Density at the Lumbar Spine in the Irish Population . Calcif Tissue Int 72, 651–658 (2003). https://doi.org/10.1007/s00223-002-2086-2

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