Calcified Tissue International

, Volume 72, Issue 6, pp 651–658 | Cite as

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

  • F. Wynne
  • F. J. Drummond
  • M. Daly
  • M. Brown
  • F. Shanahan
  • M. G. Molloy
  • K. A. Quane
Clinical Investigations

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.

Keywords

Osteoporosis Osteopenia Linkage Sib-pair Bone mineral density 

Notes

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).

References

  1. 1.
    Melton, LJ 1995How many women have osteoporosis now?J Bone Miner Res10175177PubMedGoogle Scholar
  2. 2.
    Ray, NF, Chan, JK, Thamer, M, Melton III, LJ 1997Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation.J Bone Miner Res122435PubMedGoogle Scholar
  3. 3.
    Randell, A, Sambrook, PN, Nguyen, TV, Lapsley, H, Jones, G, Kelly, PJ, Eisman, JA 1995Direct clinical and welfare costs of osteoporotic fractures in elderly men and women.Osteoporos Int5427432PubMedGoogle Scholar
  4. 4.
    Pocock, NA, Eisman, JA, Hopper, JL, Yeats, MG, Sambrook, PM, Eberl, S 1987Genetic determinants of bone mass in adults. A twin study.J Clin Invest80706710PubMedGoogle Scholar
  5. 5.
    Smith, DM, Nance, WE, Kang, KW, Christian, JC, Johnston Jr, CC 1973Genetic factors in determining bone mass.J Clin Invest5228002808PubMedGoogle Scholar
  6. 6.
    Duncan, EL, Sinsheimer, J, Dymott, K, Jakobsen, B, Shipman, AJ, Wass, JAH 1997Bone mineral density of relatives of male and female patients with osteoporosis.J Endocrinol152S11Google Scholar
  7. 7.
    Cummings, SR, Nevitt, MC, Browner, WS, Stone, K, Fox, KM, Ensrud, KE, Cauley, J, Black, D, Vogt, TM 1995Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.N Engl J Med332767773PubMedGoogle Scholar
  8. 8.
    Torgerson, DJ, Campbell, MK, Thomas, RE, Reid, DM 1996Prediction of perimenopausal fractures by bone mineral density and other risk factors.J Bone Miner Res11293297PubMedGoogle Scholar
  9. 9.
    Efstathiadou, Z, Tsatsoulis, A, Loannidis, J 2001Association of collagen 1α 1 Spl polymorphism with the Risk of prevalent fractures: a meta-analysis.J Bone Miner Res1615861592PubMedGoogle Scholar
  10. 10.
    Gross, C, Eccleshall, TR, Malloy, PJ, Villa, ML, Marcus, R, Feldman, D 1996The 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 Res1118501815PubMedGoogle Scholar
  11. 11.
    Sano, M, Inoue, S, Hosoi, T, Ouchi, Y, Emi, M, Shiraki, M, Orimo, H 1995Association of estrogen receptor dinucleotide repeat polymorphism with osteoporosis.Biochem Biophys Res Commun217378383PubMedGoogle Scholar
  12. 12.
    Ota, N, Nakajima, T, Nakazawa, I, Suzuki, T, Hosoi, T, Orimo, H, Inoue, S, Shirai, Y, Emi, M 2001A nucleotide variant in the promoter region of the interleukin-6 gene associated with decreased bone mineral density.J Hum Genet46267272Google Scholar
  13. 13.
    Tsukamoto, K, Ohta, N, Shirai, Y, Emi, M 1998A highly polymorphic CA repeat marker at the human interleukin 6 receptor (IL6R) locus.J Hum Genet43289290CrossRefPubMedGoogle Scholar
  14. 14.
    Langdahl, BL, Knudsen, JY, Jensen, HK, Gregersen, N, Eriksen, EF 1997A 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.Bone20289294PubMedGoogle Scholar
  15. 15.
    Wynne, F, Drummond, F, O’Sullivan, K, Daly, M, Shannahan, F, Molloy, MG, Quane, KA 2002An investigation of the influence of the OPG gene, VDR (Fok1) and COLIA1 Sp1 polymorphisms on BMD in the Irish population.Calcif Tissue Int712635CrossRefPubMedGoogle Scholar
  16. 16.
    Devoto, M, Shimoya, K, Caminis, J, Ott, J, Tenenhouse, A, Whyte, MP, Sereda, L, Hall, S, Considine, E, Williams, CJ, Tromp, G, Kuivaniemi, H, Ala-Kokko, L, Prockop, DJ, Spotila, LD 1998First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4p.Eur J Hum Genet6151157PubMedGoogle Scholar
  17. 17.
    Johnson, ML, Gong, G, Kimberling, W, Recker, SM, Kimmel, DB, Recker, R 1997Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13).Am J Hum Genet6013261332PubMedGoogle Scholar
  18. 18.
    Koller, DL, Rodriguez, J, Christain, C, Siemenda, M, Econs, S, Hui, P, Morin, P, Conneally, G, Joslyn, M, Curran, M, Paecock, C, Johnson, C, Foroud, T 1998Linkage of a QTL contributing to normal variation in bone mineral density to chromosome 11q12-13.J Bone Miner Res1319031908PubMedGoogle Scholar
  19. 19.
    Heaney, C, Shaley, H, Elbedour, K, Carmi, R, Staack, JB, Sheffield, VC, Beier, DR 1998Human autosomal recessive osteopetrosis maps to 11q13, a position predicted by comparative mapping of the murine osteosclerosis (oc) mutation.Hum Mol Genet714071410CrossRefPubMedGoogle Scholar
  20. 20.
    Gong, Y, Vikkula, M, Boon, L, Liu, J, Beighton, P, Ramesar, R, Peltonen, L, Somer, H, Hirose, T, Dallapiccola, B, De Paepe, A, Swoboda, W, Zabel, B, Superti-Furga, A, Steinmann, B, Brunner, HG, Jans, A, Boles, RG, Adkins, W, van den Boogaard, MJ, Olsen, BR, Warman, ML 1996Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13.Am J Hum Genet59146151PubMedGoogle Scholar
  21. 21.
    Van Hul, E, Gram, J, Bollerslev, J, Van Wesenbeeck, L, Mathysen, D, Andersen, PE, Vanhoenacker, F, Van Hul, W 2002Localization of the gene causing autosomal dominant osteopetrosis type 1 to chromosome 11q12-13.J Bone Miner Res1711111117PubMedGoogle Scholar
  22. 22.
    Little, RD, Carulli, JP, Del Mastro, RG,  et al. 2002A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait.Am J Hum Genet701119CrossRefPubMedGoogle Scholar
  23. 23.
    Gong, Y, Slee, RB, Fukai, N, Rawadi, G,  et al. 2001LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.Cell107513523PubMedGoogle Scholar
  24. 24.
    Frattini, A, Orchard, PJ, Sobacchi, C, Giliani, S, Abinun, M, Mattsson, JP, Keeling, DJ, Andersson, AK, Wallbrandt, P, Zecca, L, Notarangelo, LD, Vezzoni, P, Villa, A 2000Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis.Nat Genet25343346PubMedGoogle Scholar
  25. 25.
    Duncan, EL, Brown, MA, Sinsheimer, J, Bell, J, Carr, AJ, Wordsworth, BP, Wass, JA 1999Suggestive linkage of the parathyroid receptor type 1 to osteoporosis.J Bone Miner Res1419931999PubMedGoogle Scholar
  26. 26.
    Niu, T, Cehn, C, Cordell, H, Yang, J, Wang, B, Wang, Z, Fang, Z, Schork, NJ, Rosen, CJ, Xu, X 1999A genome-wide scan for loci linked to forearm bone mineral density.Hum Genet104226233CrossRefPubMedGoogle Scholar
  27. 27.
    Devoto, M, Specchia, C, Hui-Hua, L, Caminis, J, Tenenhouse, A, Rodriguez, H, Spotila, L 2001Variance component linkage analysis indicates a QTL for femoral neck bone mineral density on chromosome 1p36.Hum Mol Gen1024472452CrossRefPubMedGoogle Scholar
  28. 28.
    Kanis, JA, Melton Jr, L, Christiansen, C, Johnston, CC, Khaltaev, N 1994The diagnosis of osteoporosis.J Bone Miner Res911371141PubMedGoogle Scholar
  29. 29.
    Old, JM 1983Methods in haematology.Churchill-LivingstonEdinburgGoogle Scholar
  30. 30.
    O’Connell, JR, Weeks, DE 1998Pedcheck: a program for identification of genotype incompatibilities in linkage analysis.Am J Hum Genet63259266PubMedGoogle Scholar
  31. 31.
    Haseman, J, Elston, R 1972The investigation of linkage between a quantitative trait and a marker locus.Behav Genet2319PubMedGoogle Scholar
  32. 32.
    Kruglyak, L, Lander, E 1995Complete multipoint sib-pair analysis of qualitative and quantitative traits.Am J Hum Genet57439454PubMedGoogle Scholar
  33. 33.
    Almasy, L, Blangero, J 1998Multipoint quantitative-trait linkage analysis in general pedigrees.Am J Hum Genet6211981211PubMedGoogle Scholar
  34. 34.
    Slager, S, Vieland, V 1997Investigating the numerical effect of ascertainment bias in linkage analysis: development of methods and primary results.Genet Epididemiol1411191124CrossRefGoogle Scholar
  35. 35.
    Lyengar, S, Calafell, F, Kidd, K 1997Detection of major genes underlying several quantitative traits associated with a common disease using different ascertainment schemes.Genet Epid14809814CrossRefGoogle Scholar
  36. 36.
    Lander, E, Kruglyak, L 1995Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.Nature Genet11241247PubMedGoogle Scholar
  37. 37.
    Nicole, S, Davoine, CS, Topaloglu, H,  et al. 2000Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia).Nat Genet26480483Google Scholar
  38. 38.
    Kumar, R, Haugen, JD 1994Human and rat osteoblast-like cells express stathmin, a growth-regulatory protein.Biochem Biophys Res Commun201861865CrossRefPubMedGoogle Scholar
  39. 39.
    Cook, T, Gebelein, B, Mesa, K, Mladek, A, Urrutia, R 1998Molecular 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 Chem2732592925936CrossRefPubMedGoogle Scholar
  40. 40.
    Krude, H, Biebermann, H, Luck, W, Horn, R, Brabant, G, Gruters, A 1998Severe early-onset obesity, adrenal insufficiency and red pigmentation caused by POMC mutations in humans.Nat Genet19155157CrossRefPubMedGoogle Scholar
  41. 41.
    Sobacchi, C, Frattini, A, Orchard, P, Porras, O,  et al. 2001The mutational spectrum of human malignant autosomal recessive osteopetrosis.Hum Mol Genet1017671773PubMedGoogle Scholar
  42. 42.
    Johnson, RS, Spiegelman, BM, Papaioannou, V 1992Pleiotropic effects of a null mutation in the c-fos proto-oncogene.Cell71577586PubMedGoogle Scholar
  43. 43.
    Matsuo, K, Owens, JM, Tonko, M, Elliott, C, Chambers, TJ, Wagner, EF 2000Fos11 is a transcriptional target of c-Fos during osteoclast differentiation.Nat Genet24184187CrossRefPubMedGoogle Scholar
  44. 44.
    Schipani, E, Landman, C, Parfitt, A, Jansen, G, Kikuchi, S, Kooh, S, Cole, W, Juppner, H 1996Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen’s metaphyseal chondrodysplasia.N Engl J Med335708714PubMedGoogle Scholar
  45. 45.
    Kruse, K, Schutz, C 1993Calcium metabolism in the Jansen type of metaphyseal dysphyseal.Eur J Pediatr152912915PubMedGoogle Scholar
  46. 46.
    Zee, RYL, Myers, RH, Hannan, MT, Wilson, PWF, Ordovas, JM, Schaefer, EJ, Lindpaintner, K, Kiel, DP 2000Absence of linkage for bone mineral density to chromosome 12q12-14 in the region of the vitamin D receptor gene.Calcif Tissue Int67434439CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • F. Wynne
    • 1
    • 2
  • F. J. Drummond
    • 1
    • 2
  • M. Daly
    • 1
  • M. Brown
    • 3
  • F. Shanahan
    • 2
  • M. G. Molloy
    • 1
  • K. A. Quane
    • 1
    • 2
  1. 1.Department of RheumatologyNational University of Ireland, CorkIreland
  2. 2.Department of MedicineNational University of Ireland, CorkIreland
  3. 3.Spondyloarthritis and Bone Disease Research Group, OxfordEngland

Personalised recommendations