Human Genetics

, Volume 118, Issue 5, pp 568–577 | Cite as

Variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are associated with bone mineral density at different skeletal sites in men

  • Yi-Hsiang Hsu
  • Tianhua Niu
  • Henry A. Terwedow
  • Xin Xu
  • Yan Feng
  • Zhiping Li
  • Joseph D. Brain
  • Cliff J. Rosen
  • Nan Laird
  • Xiping Xu
Original Investigations

Abstract

In order to assess the contribution of polymorphisms in the RANKL (TNFSF11), RANK (TNFRSF11A) and OPG (TNFRSF11B) genes to variations in bone mineral density (BMD), a population-based cohort with 1,120 extreme low hip BMD cases or extreme high hip BMD controls was genotyped on five SNPs. We further explored the associations between these genetic variations and forearm BMDs by genotyping 266 offspring and 309 available parents from 160 nuclear families. A family-based association test was used. Significantly positive associations were found for A163G polymorphisms in the promoter regions of the OPG gene, a missense substitution in exon 7 (Ala192Val) of the RANK gene and rs9594782 SNP in the 5′ UTR of the RANKL gene with BMD in men only. Men with TC/CC genotypes of the rs9594782 SNP had a 2.1 times higher risk of extremely low hip BMD (P=0.004), and lower whole body BMD (P<0.001). Subjects with the TC genotype of the Ala192Val polymorphism had a 40% reduced risk of having extremely low hip BMD (P<0.01), and higher whole body BMD (P<0.01). Subjects with the GG genotype of the A163G polymorphism had a 70% reduced risk of having extremely low hip BMD (P<0.05), and higher whole body BMD (P<0.01). Significant gene–gene interactions were also observed among the OPG, RANK and RANKL genes. Our findings suggest that genetic variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are strongly associated with BMD at different skeletal sites in adult men, but not in women.

Supplementary material

439_2005_62_MOESM1_ESM.pdf (132 kb)
Supplementary material

References

  1. Albagha OM, Pettersson U, Stewart A, McGuigan FE, MacDonald HM, Reid DM, Ralston SH (2005) Association of oestrogen receptor alpha gene polymorphisms with postmenopausal bone loss, bone mass, and quantitative ultrasound properties of bone. J Med Genet 42(3):240–246CrossRefPubMedGoogle Scholar
  2. Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L (1997) A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390(6656):175–179CrossRefPubMedGoogle Scholar
  3. Arko B, Prezelj J, Komel R, Kocijancic A, Hudler P, Marc J (2002) Sequence variations in the osteoprotegerin gene promoter in patients with postmenopausal osteoporosis. J Clin Endocrinol Metab 87(9):4080–4084CrossRefPubMedGoogle Scholar
  4. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265CrossRefPubMedGoogle Scholar
  5. Bekker PJ, Holloway D, Nakanishi A, Arrighi M, Leese PT, Dunstan CR (2001) The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res 16(2):348–360PubMedCrossRefGoogle Scholar
  6. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS (1998) Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12(9):1260–1268PubMedGoogle Scholar
  7. Crisafulli A, Altavilla D, Squadrito G, Romeo A, Adamo EB, Marini R, Inferrera MA, Marini H, Bitto A, D’Anna R, Corrado F, Bartolone S, Frisina N, Squadrito F (2004) Effects of the phytoestrogen genistein on the circulating soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin system in early postmenopausal women. J Clin Endocrinol Metab 89(1):188–192CrossRefPubMedGoogle Scholar
  8. Cummings SR, Black D (1995) Bone mass measurements and risk of fracture in Caucasian women: a review of findings from prospective studies. Am J Med 98(2A):24S–28SCrossRefPubMedGoogle Scholar
  9. Daroszewska A, Hocking LJ, McGuigan FE, Langdahl B, Stone MD, Cundy T, Nicholson GC, Fraser WD, Ralston SH (2004) Susceptibility to Paget’s disease of bone is influenced by a common polymorphic variant of osteoprotegerin. J Bone Miner Res 19(9):1506–1511PubMedCrossRefGoogle Scholar
  10. Deng HW, Chen WM, Conway T, Zhou Y, Davies KM, Stegman MR, Deng H, Recker R (2000) Determination of bone mineral density of the hip and spine in human pedigrees by genetic and life-style factors. Genetic Epi 19:160–177CrossRefGoogle Scholar
  11. Deng HW, Xu FH, Huang QY, Shen H, Deng H, Conway T, Liu YJ, Liu YZ, Li JL, Zhang HT, Davies KM, Recker RR (2002) A whole-genome linkage scan suggests several genomic regions potentially containing quantitative trait loci for osteoporosis. J Clin Endocrinol Metab 87:5151–5159CrossRefPubMedGoogle Scholar
  12. Duncan EL, Cardon LR, Sinsheimer JS, Wass JA, Brown MA (2003) Site and gender specificity of inheritance of bone mineral density. J Bone Miner Res 18:1531–1538PubMedCrossRefGoogle Scholar
  13. Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927PubMedGoogle Scholar
  14. Ferrari SL, Deutsch S, Choudhury U, Chevalley T, Bonjour JP, Dermitzakis ET, Rizzoli R, Antonarakis SE (2004) 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 74(5):866–875CrossRefPubMedGoogle Scholar
  15. Han JH, Choi SJ, Kurihara N, Koide M, Oba Y, Roodman GD (2001) Macrophage inflammatory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand. Blood 97(11):3349–3353CrossRefPubMedGoogle Scholar
  16. Hao K, Niu T, Sangokoya C, Li J, Xu X (2002) SNPkit: an efficient approach to systematic evaluation of candidate single nucleotide polymorphisms in public databases. Biotechniques 33(4):822, 824–826, 828 passimGoogle Scholar
  17. Hoh J, Wille A, Ott J (2001) Trimming, weighting, and grouping SNPs in human case-control association studies. Genome Res 11(12):2115–2119CrossRefPubMedGoogle Scholar
  18. Honore P, Luger NM, Sabino MA, Schwei MJ, Rogers SD, Mach DB, O’keefe PF, Ramnaraine ML, Clohisy DR, Mantyh PW (2000) Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat Med 6(5):521–528CrossRefPubMedGoogle Scholar
  19. Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, Tan HL, Elliott G, Kelley MJ, Sarosi I, Wang L, Xia XZ, Elliott R, Chiu L, Black T, Scully S, Capparelli C, Morony S, Shimamoto G, Bass MB, Boyle WJ (1999) Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 96(7):3540–3545CrossRefPubMedGoogle Scholar
  20. Hsu YH, Venners SA, Terwedow H, Feng Y, Niu T, Li Z, Laird N, Brain J, Cummings S, Bouxsein ML, Rosen CJ, Xu X (2005) Relationship of body composition, fat mass and serum lipids to osteoporotic fractures and bone mineral density in Chinese men and women. Am J Clin Nutr (in press)Google Scholar
  21. Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RG, van Hul W, Whyte MP, Nakatsuka K, Hovy L, Anderson DM (2000) Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 24(1):45–48PubMedCrossRefGoogle Scholar
  22. Kammerer CM, Schneider JL, Cole SA, Hixson JE, Samollow PB, O’Connell JR, Perez R, Dyer TD, Almasy L, Blangero J, Bauer RL, Mitchell BD (2003) Quantitative 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(12):2245–2252PubMedCrossRefGoogle Scholar
  23. Karasik D, Myers RH, Cupples LA, Hannan MT, Gagnon DR, Herbert A, Kiel DP (2002) Genome screen for quantitative trait loci contributing to normal variation in bone mineral density: the Framingham study. J Bone Miner Res 17(9):1718–1727PubMedCrossRefGoogle Scholar
  24. Kim N, Odgren PR, Kim DK, Marks SC Jr, Choi Y (2000) Diverse roles of the tumor necrosis factor family member TRANCE in skeletal physiology revealed by TRANCE deficiency and partial rescue by a lymphocyte-expressed TRANCE transgene. Proc Natl Acad Sci USA 97(20):10905–10910CrossRefPubMedGoogle Scholar
  25. Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S, Wong T, Campagnuolo G, Moran E, Bogoch ER, Van G, Nguyen LT, Ohashi PS, Lacey DL, Fish E, Boyle WJ, Penninger JM (1999) Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402(6759):304–309PubMedCrossRefGoogle Scholar
  26. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93(2):165–176CrossRefPubMedGoogle Scholar
  27. Laird NM, Horvath S, Xu X (2000) Implementing a unified approach to family-based tests of association. Genet Epidemiol 19(Suppl 1):S36–S42CrossRefPubMedGoogle Scholar
  28. Langdahl BL, Carstens M, Stenkjaer L, Eriksen EF (2002) Polymorphisms in the osteoprotegerin gene are associated with osteoporotic fractures. J Bone Miner Res 17(7):1245–1255PubMedCrossRefGoogle Scholar
  29. Lange C, Silverman EK, Xu X, Weiss ST, Laird NM (2003) A multivariate family-based association test using generalized estimating equations: FBAT–GEE. Biostatistics 4(2):195–206CrossRefPubMedGoogle Scholar
  30. Lange C, Blacker D, Laird NM (2004) Family-based association tests for survival and times-to-onset analysis. Stat Med 23(2):179–189CrossRefPubMedGoogle Scholar
  31. Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, McCabe S, Elliott R, Scully S, Van G, Kaufman S, Juan SC, Sun Y, Tarpley J, Martin L, Christensen K, McCabe J, Kostenuik P, Hsu H, Fletcher F, Dunstan CR, Lacey DL, Boyle WJ (2000) RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 97(4):1566–1571CrossRefPubMedGoogle Scholar
  32. Liu YZ, Liu YJ, Recker R, Deng HW (2003) Molecular studies of identification of genes for osteoporosis: the 2002 update. J Endocrinol 177:147–196CrossRefPubMedGoogle Scholar
  33. Morinaga T, Nakagawa N, Yasuda H, Tsuda E, Higashio K (1998) Cloning and characterization of the gene encoding human osteoprotegerin/osteoclastogenesis-inhibitory factor. Eur J Biochem 254(3):685–691CrossRefPubMedGoogle Scholar
  34. Niu T, Qin ZS, Xu X, Liu JS (2002) Bayesian haplotype inference for multiple linked single-nucleotide polymorphisms. Am J Hum Genet 70:157–169CrossRefPubMedGoogle Scholar
  35. Rabinowitz D, Laird N (2000) A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 50(4):211–223CrossRefPubMedGoogle Scholar
  36. Ralston SH, Galwey N, MacKay I, Albagha OME, Cardon L, Compston JE, Cooper C, Duncan E, Keen R, Langdahl B, McLellan A, O’Riordan J, Pols HA, Reid DM, Uitterlinden AG, Wass J, Bennett ST (2005) Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study. Hum Mol Genet 14(7):943–951CrossRefPubMedGoogle Scholar
  37. Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. In: Krawetz S, Misener S (eds) Bioinformatics methods and protocols in the series methods in molecular biology. Humana Press, Totowa, pp 365–386Google Scholar
  38. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Amgen EST Program, Boyle WJ (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89(2):309–319Google Scholar
  39. Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS, Bagger Y, Christiansen C, Reynisdottir I, Grant SF, Jonasson K, Frigge ML, Gulcher JR, Sigurdsson G, Stefansson K (2003) Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS Biol 1(3):E69CrossRefPubMedGoogle Scholar
  40. Thirunavukkarasu K, Halladay DL, Miles RR, Yang X, Galvin RJ, Chandrasekhar S, Martin TJ, Onyia JE (2000) The osteoblast-specific transcription factor Cbfa1 contributes to the expression of osteoprotegerin, a potent inhibitor of osteoclast differentiation and function. J Biol Chem 275(33):25163–25172CrossRefPubMedGoogle Scholar
  41. Wan M, Shi X, Feng X, Cao X (2001) Transcriptional mechanisms of bone morphogenetic protein-induced osteoprotegerin gene expression. J Biol Chem 276(13):10119–10125CrossRefPubMedGoogle Scholar
  42. Wang MW, Wei S, Faccio R, Takeshita S, Tebas P, Powderly WG, Teitelbaum SL, Ross FP (2004) The HIV protease inhibitor ritonavir blocks osteoclastogenesis and function by impairing RANKL-induced signaling. J Clin Invest (2):206–213CrossRefGoogle Scholar
  43. Wilson SG, Reed PW, Bansal A, Chiano M, Lindersson M, Langdown M, Prince RL, Thompson D, Thompson E, Bailey M, Kleyn PW, Sambrook P, Shi MM, Spector TD (2003) Comparison 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(1):144–155CrossRefPubMedGoogle Scholar
  44. Xu X, Niu T, Christiani DC, Weiss ST, Zhou Y, Chen C, Yang J, Fang Z, Jiang Z, Liang W, Zhang F (1996) Environmental and occupational determinants of blood pressure in rural communities in China. Ann Epidemiol 7:95–106CrossRefGoogle Scholar
  45. Xu X, Niu T, Chen C, Kuo AY, Rosen CJ (1998) Forearm bone mineral density in Chinese women: a community-based study. J Clin Densitometry 1:149–156CrossRefGoogle Scholar
  46. Yamada Y, Ando F, Niino N, Shimokata H (2003) Association of polymorphisms of the osteoprotegerin gene with bone mineral density in Japanese women but not men. Mol Genet Metab 80(3):344–349CrossRefPubMedGoogle Scholar
  47. Yano K, Tsuda E, Washida N, Kobayashi F, Goto M, Harada A, Ikeda K, Higashio K, Yamada Y (1999) Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: increased serum concentrations in postmenopausal women with osteoporosis. J Bone Miner Res 14(4):518–527PubMedCrossRefGoogle Scholar
  48. Zhang YH, Heulsmann A, Tondravi MM, Mukherjee A, Abu-Amer Y (2001) Tumor necrosis factor-alpha (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways. J Biol Chem 276(1):563–568CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Yi-Hsiang Hsu
    • 1
  • Tianhua Niu
    • 2
  • Henry A. Terwedow
    • 1
  • Xin Xu
    • 1
  • Yan Feng
    • 1
  • Zhiping Li
    • 3
  • Joseph D. Brain
    • 1
  • Cliff J. Rosen
    • 4
  • Nan Laird
    • 5
  • Xiping Xu
    • 1
    • 3
  1. 1.Program for Population GeneticsHarvard School of Public HealthBostonUSA
  2. 2.Division of Preventive Medicine, Department of MedicineBrigham and Women Hospital, Harvard Medical SchoolBostonUSA
  3. 3.Institute of MedicineAnhui Medical UniversityAnhuiChina
  4. 4.Maine Center for Osteoporosis Research and EducationSt. Joseph HospitalBangorUSA
  5. 5.Department of BiostatisticsHarvard School of Public HealthBostonUSA

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