Calcified Tissue International

, Volume 83, Issue 3, pp 155–166 | Cite as

Genetic Variation in Candidate Osteoporosis Genes, Bone Mineral Density, and Fracture Risk: The Study of Osteoporotic Fractures

  • Gregory J. Tranah
  • Brent C. Taylor
  • Li-Yung Lui
  • Joseph M. Zmuda
  • Jane A. Cauley
  • Kristine E. Ensrud
  • Teresa A. Hillier
  • Marc C. Hochberg
  • Jia Li
  • Brian K. Rhees
  • Henry A. Erlich
  • Mark D. Sternlicht
  • Gary Peltz
  • Steven R. Cummings
  • For the Study of Osteoporotic Fractures (SOF) Research Group


Candidate osteoporosis gene variants were examined for associations with fracture risk and bone mineral density (BMD). A total of 9704 white women were recruited at four U.S. clinical centers and enrolled into the Study of Osteoporotic Fractures, a longitudinal cohort study. Genotyping of 31 polymorphisms from 18 candidate osteoporosis genes was performed in 6752 women. Incident radiographic fractures were identified at the third and eighth examinations compared with the baseline examination. BMD was measured at the total hip by dual-energy X-ray absorptiometry. Analyses were adjusted for age, clinic site, and self-reported ethnicity. During a mean follow-up of 14.5 years, a total of 849 hip, 658 vertebral, and 2496 nonhip/nonvertebral fractures occurred in 6752 women. Women carrying the ALOX15_G48924T T/T genotype had a higher rate of hip fracture (hazard ratio [HR] = 1.33;95% confidence interval [95% CI] = 1.00–1.77) compared with the G/G genotype. Compared with those carrying the PRL_T228C T/T genotype, women with either the C/C (HR = 0.80; 95% CI = 0.67–0.95) or C/T (HR = 0.81; 95% CI = 0.68–0.97) genotype had a lower rate of nonvertebral/nonhip fractures. Women carrying the BMP2_A125611G G/G genotype had a higher rate of vertebral fracture (odds ratio [OR] = 1.51; 95% CI = 1.03–2.23) compared with the A/A genotype. Women with the ESR1_C1335G G/G genotype had a higher rate of vertebral fracture (OR = 1.64; 95% CI = 1.07–2.50) compared with the C/C genotype. Compared with those with the MMP2_C595T C/C genotype, women with the C/T (OR = 0.79; 95% CI = 0.65–0.96) or T/T (OR = 0.44; 95% CI = 0.27–0.72) genotype had a lower rate of vertebral fracture. In conclusion, polymorphisms in several candidate genes were associated with hip, vertebral, and nonhip/nonvertebral fractures but not with total hip BMD in this large population based cohort study.


Genetics Polymorphism Osteoporosis BMD Fracture 


  1. 1.
    Flicker L, Hopper JL, Rodgers L, Kaymakci B, Green RM, Wark JD (1995) Bone density determinants in elderly women: a twin study. J Bone Miner Res 10:1607–1613PubMedGoogle Scholar
  2. 2.
    Christian JC, Yu PL, Slemenda CW, Johnston CC Jr (1989) Heritability of bone mass: a longitudinal study in aging male twins. Am J Hum Genet 44:429–433PubMedGoogle Scholar
  3. 3.
    Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S (1987) Genetic determinants of bone mass in adults. A twin study. J Clin Invest 80:706–710PubMedCrossRefGoogle Scholar
  4. 4.
    Eisman JA (1999) Genetics of osteoporosis. Endocr Rev 20:788–804PubMedCrossRefGoogle Scholar
  5. 5.
    Deng HW, Mahaney MC, Williams JT, Li J, Conway T, Davies KM, Li JL, Deng H, Recker RR (2002) Relevance of the genes for bone mass variation to susceptibility to osteoporotic fractures and its implications to gene search for complex human diseases. Genet Epidemiol 22:12–25PubMedCrossRefGoogle Scholar
  6. 6.
    Ralston SH, de Crombrugghe B (2006) Genetic regulation of bone mass and susceptibility to osteoporosis. Genes Dev 20:2492–2506PubMedCrossRefGoogle Scholar
  7. 7.
    Stewart TL, Ralston SH (2000) Role of genetic factors in the pathogenesis of osteoporosis. J Endocrinol 166:235–245PubMedCrossRefGoogle Scholar
  8. 8.
    Ioannidis JP (2006) Journals should publish all “null” results and should sparingly publish “positive” results. Cancer Epidemiol Biomarkers Prev 15:186PubMedCrossRefGoogle Scholar
  9. 9.
    Nevitt MC, Cummings SR, Lane NE, Hochberg MC, Scott JC, Pressman AR, Genant HK, Cauley JA (1996) Association of estrogen replacement therapy with the risk of osteoarthritis of the hip in elderly white women. Study of Osteoporotic Fractures Research Group. Arch Intern Med 156:2073–2080PubMedCrossRefGoogle Scholar
  10. 10.
    Ensrud KE, Stone K, Cauley JA, White C, Zmuda JM, Nguyen TV, Eisman JA, Cummings SR (1999) Vitamin D receptor gene polymorphisms and the risk of fractures in older women. For the Study of Osteoporotic Fractures Research Group. J Bone Miner Res 14:1637–1645PubMedCrossRefGoogle Scholar
  11. 11.
    Moffett SP, Zmuda JM, Cauley JA, Ensrud KE, Hillier TA, Hochberg MC, Li J, Cayabyab S, Lee JM, Peltz G, Cummings SR (2007) Association of the VDR translation start site polymorphism and fracture risk in older women. J Bone Miner Res 22:730–736PubMedCrossRefGoogle Scholar
  12. 12.
    Moffett SP, Zmuda JM, Cauley JA, Stone KL, Nevitt MC, Ensrud KE, Hillier TA, Hochberg MC, Joslyn G, Morin P, Cummings SR (2004) Association of the G-174C variant in the interleukin-6 promoter region with bone loss and fracture risk in older women. J Bone Miner Res 19:1612–1618PubMedCrossRefGoogle Scholar
  13. 13.
    Moffett SP, Zmuda JM, Oakley JI, Beck TJ, Cauley JA, Stone KL, Lui LY, Ensrud KE, Hillier TA, Hochberg MC, Morin P, Peltz G, Greene D, Cummings SR (2005) Tumor necrosis factor-alpha polymorphism, bone strength phenotypes, and the risk of fracture in older women. J Clin Endocrinol Metab 90:3491–3497PubMedCrossRefGoogle Scholar
  14. 14.
    Taylor BC, Schreiner PJ, Zmuda JM, Li J, Moffett SP, Beck TJ, Cummings SR, Lee JM, Walker K, Ensrud KE (2006) Association of endothelial nitric oxide synthase genotypes with bone mineral density, bone loss, hip structure, and risk of fracture in older women: the SOF study. Bone 39:174–180PubMedCrossRefGoogle Scholar
  15. 15.
    Moffett SP, Oakley JI, Cauley JA, Lui LY, Ensrud KE, Taylor BC, Hillier TA, Hochberg MC, Li J, Cayabyab S, Lee JM, Peltz G, Cummings SR, Zmuda JM (2008) Osteoprotegerin Lys3Asn polymorphism and the risk of fracture in older women. J Clin Endocrinol Metab 93:2002–2008PubMedCrossRefGoogle Scholar
  16. 16.
    Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, Cauley J, Black D, Vogt TM (1995) Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 332:767–773PubMedCrossRefGoogle Scholar
  17. 17.
    Farmer ME, White LR, Brody JA, Bailey KR (1984) Race and sex differences in hip fracture incidence. Am J Public Health 74:1374–1380PubMedCrossRefGoogle Scholar
  18. 18.
    Cheng S, Grow MA, Pallaud C, Klitz W, Erlich HA, Visvikis S, Chen JJ, Pullinger CR, Malloy MJ, Siest G, Kane JP (1999) A multilocus genotyping assay for candidate markers of cardiovascular disease risk. Genome Res 9:936–949PubMedCrossRefGoogle Scholar
  19. 19.
    Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, Cauley J, Black D, Vogt TM (1995) Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 332:767–773PubMedCrossRefGoogle Scholar
  20. 20.
    Nevitt MC, Cummings SR, Stone KL, Palermo L, Black DM, Bauer DC, Genant HK, Hochberg MC, Ensrud KE, Hillier TA, Cauley JA (2005) Risk factors for a first-incident radiographic vertebral fracture in women > or = 65 years of age: the study of osteoporotic fractures. J Bone Miner Res 20:131–140PubMedGoogle Scholar
  21. 21.
    Cauley JA, Hochberg MC, Lui LY, Palermo L, Ensrud KE, Hillier TA, Nevitt MC, Cummings SR (2007) Long-term risk of incident vertebral fractures. JAMA 298:2761–2767PubMedCrossRefGoogle Scholar
  22. 22.
    Nevitt MC, Cummings SR, Browner WS, Seeley DG, Cauley JA, Vogt TM, Black DM (1992) The accuracy of self-report of fractures in elderly women: evidence from a prospective study. Am J Epidemiol 135:490–499PubMedGoogle Scholar
  23. 23.
    Ensrud KE, Palermo L, Black DM, Cauley J, Jergas M, Orwoll ES, Nevitt MC, Fox KM, Cummings SR (1995) Hip and calcaneal bone loss increase with advancing age: longitudinal results from the study of osteoporotic fractures. J Bone Miner Res 10:1778–1787PubMedGoogle Scholar
  24. 24.
    Steiger P, Cummings SR, Black DM, Spencer NE, Genant HK (1992) Age-related decrements in bone mineral density in women over 65. J Bone Miner Res 7:625–632PubMedGoogle Scholar
  25. 25.
    Orwoll ES, Oviatt SK (1991) Longitudinal precision of dual-energy X-ray absorptiometry in a multicenter study. The Nafarelin/Bone Study Group. J Bone Miner Res 6:191–197PubMedGoogle Scholar
  26. 26.
    Black DM, Cummings SR, Genant HK, Nevitt MC, Palermo L, Browner W (1992) Axial and appendicular bone density predict fractures in older women. J Bone Miner Res 7:633–638PubMedGoogle Scholar
  27. 27.
    Cummings SR, Black DM, Nevitt MC, Browner WS, Cauley JA, Genant HK, Mascioli SR, Scott JC, Seeley DG, Steiger P, Vogt TM (1990) Appendicular bone density and age predict hip fracture in women. The Study of Osteoporotic Fractures Research Group. JAMA 263:665–668PubMedCrossRefGoogle Scholar
  28. 28.
    Cummings SR, Black DM, Nevitt MC, Browner W, Cauley J, Ensrud K, Genant HK, Palermo L, Scott J, Vogt TM (1993) Bone density at various sites for prediction of hip fractures. The Study of Osteoporotic Fractures Research Group. Lancet 341:72–75PubMedCrossRefGoogle Scholar
  29. 29.
    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 (1998) First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q. Eur J Hum Genet 6:151–157PubMedCrossRefGoogle Scholar
  30. 30.
    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 87:5151–5159PubMedCrossRefGoogle Scholar
  31. 31.
    Mullin BH, Spector TD, Curtis CC, Ong GN, Hart DJ, Hakim AJ, Worthy T, Wilson SG (2007) Polymorphisms in ALOX12, but not ALOX15, are significantly associated with BMD in postmenopausal women. Calcif Tissue Int 81:10–17PubMedCrossRefGoogle Scholar
  32. 32.
    Ichikawa S, Koller DL, Johnson ML, Lai D, Xuei X, Edenberg HJ, Klein RF, Orwoll ES, Hui SL, Foroud TM, Peacock M, Econs MJ (2006) Human ALOX12, but not ALOX15, is associated with BMD in white men and women. J Bone Miner Res 21:556–564PubMedCrossRefGoogle Scholar
  33. 33.
    Cheung CL, Chan V, Kung AW (2008) A differential association of ALOX15 polymorphisms with bone mineral density in pre- and post-menopausal women. Hum Hered 65:1–8PubMedCrossRefGoogle Scholar
  34. 34.
    Urano T, Shiraki M, Fujita M, Hosoi T, Orimo H, Ouchi Y, Inoue S (2005) Association of a single nucleotide polymorphism in the lipoxygenase ALOX15 5′-flanking region (-5229G/A) with bone mineral density. J Bone Miner Metab 23:226–230PubMedCrossRefGoogle Scholar
  35. 35.
    Wittwer J, Marti-Jaun J, Hersberger M (2006) Functional polymorphism in ALOX15 results in increased allele-specific transcription in macrophages through binding of the transcription factor SPI1. Hum Mutat 27:78–87PubMedCrossRefGoogle Scholar
  36. 36.
    Wittwer J, Bayer M, Mosandl A, Muntwyler J, Hersberger M (2007) The c.-292C>T promoter polymorphism increases reticulocyte-type 15-lipoxygenase-1 activity and could be atheroprotective. Clin Chem Lab Med 45:487–492PubMedCrossRefGoogle Scholar
  37. 37.
    Bataille-Simoneau N, Gerland K, Chappard D, Basle MF, Mercier L (1996) Expression of prolactin receptors in human osteosarcoma cells. Biochem Biophys Res Commun 229:323–328PubMedCrossRefGoogle Scholar
  38. 38.
    Clement-Lacroix P, Ormandy C, Lepescheux L, Ammann P, Damotte D, Goffin V, Bouchard B, Amling M, Gaillard-Kelly M, Binart N, Baron R, Kelly PA (1999) Osteoblasts are a new target for prolactin: analysis of bone formation in prolactin receptor knockout mice. Endocrinology 140:96–105PubMedCrossRefGoogle Scholar
  39. 39.
    Coss D, Yang L, Kuo CB, Xu X, Luben RA, Walker AM (2000) Effects of prolactin on osteoblast alkaline phosphatase and bone formation in the developing rat. Am J Physiol Endocrinol Metab 279:E1216–E1225PubMedGoogle Scholar
  40. 40.
    Sanfilippo JS (1999) Implications of not treating hyperprolactinemia. J Reprod Med 44:1111–1115PubMedGoogle Scholar
  41. 41.
    Biller BM, Luciano A, Crosignani PG, Molitch M, Olive D, Rebar R, Sanfilippo J, Webster J, Zacur H (1999) Guidelines for the diagnosis and treatment of hyperprolactinemia. J Reprod Med 44:1075–1084PubMedGoogle Scholar
  42. 42.
    Lasco A, Cannavo S, Gaudio A, Morabito N, Basile G, Nicita-Mauro V, Frisina N (2002) Effects of long-lasting raloxifene treatment on serum prolactin and gonadotropin levels in postmenopausal women. Eur J Endocrinol 147:461–465PubMedCrossRefGoogle Scholar
  43. 43.
    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:E69PubMedCrossRefGoogle Scholar
  44. 44.
    Reneland RH, Mah S, Kammerer S, Hoyal CR, Marnellos G, Wilson SG, Sambrook PN, Spector TD, Nelson MR, Braun A (2005) Association between a variation in the phosphodiesterase 4D gene and bone mineral density. BMC Med Genet 6:9PubMedCrossRefGoogle Scholar
  45. 45.
    Medici M, van Meurs JB, Rivadeneira F, Zhao H, Arp PP, Hofman A, Pols HA, Uitterlinden AG (2006) BMP-2 gene polymorphisms and osteoporosis: the Rotterdam Study. J Bone Miner Res 21:845–854PubMedCrossRefGoogle Scholar
  46. 46.
    Inoue K, Mikuni-Takagaki Y, Oikawa K, Itoh T, Inada M, Noguchi T, Park JS, Onodera T, Krane SM, Noda M, Itohara S (2006) A crucial role for matrix metalloproteinase 2 in osteocytic canalicular formation and bone metabolism. J Biol Chem 281:33814–33824PubMedCrossRefGoogle Scholar
  47. 47.
    Guo LJ, Luo XH, Wu XP, Shan PF, Zhang H, Cao XZ, Xie H, Liao EY (2006) Serum concentrations of MMP-1, MMP-2, and TIMP-1 in Chinese women: age-related changes, and the relationships with bone biochemical markers, bone mineral density. Clin Chim Acta 371:137–142PubMedCrossRefGoogle Scholar
  48. 48.
    Luo XH, Guo LJ, Shan PF, Xie H, Wu XP, Zhang H, Cao XZ, Yuan LQ, Liao EY (2006) Relationship of circulating MMP-2, MMP-1, and TIMP-1 levels with bone biochemical markers and bone mineral density in postmenopausal Chinese women. Osteoporos Int 17:521–526PubMedCrossRefGoogle Scholar
  49. 49.
    Albagha OM, McGuigan FE, Reid DM, Ralston SH (2001) Estrogen receptor alpha gene polymorphisms and bone mineral density: haplotype analysis in women from the United Kingdom. J Bone Miner Res 16:128–134PubMedCrossRefGoogle Scholar
  50. 50.
    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 42:240–246PubMedCrossRefGoogle Scholar
  51. 51.
    Ioannidis JP, Ralston SH, Bennett ST, Brandi ML, Grinberg D, Karassa FB, Langdahl B, van Meurs JB, Mosekilde L, Scollen S, Albagha OM, Bustamante M, Carey AH, Dunning AM, Enjuanes A, van Leeuwen JP, Mavilia C, Masi L, McGuigan FE, Nogues X, Pols HA, Reid DM, Schuit SC, Sherlock RE, Uitterlinden AG (2004) Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA 292:2105–2114PubMedCrossRefGoogle Scholar
  52. 52.
    Jurada S, Marc J, Prezelj J, Kocijancic A, Komel R (2001) Codon 325 sequence polymorphism of the estrogen receptor alpha gene and bone mineral density in postmenopausal women. J Steroid Biochem Mol Biol 78:15–20PubMedCrossRefGoogle Scholar
  53. 53.
    Zavratnik A, Prezelj J, Kocijancic A, Marc J (2007) Exonic, but not intronic polymorphisms of ESR1 gene might influence the hypolipemic effect of raloxifene. J Steroid Biochem Mol Biol 104:22–26PubMedCrossRefGoogle Scholar
  54. 54.
    Turner CH, Roeder RK, Wieczorek A, Foroud T, Liu G, Peacock M (2001) Variability in skeletal mass, structure, and biomechanical properties among inbred strains of rats. J Bone Miner Res 16:1532–1539PubMedCrossRefGoogle Scholar
  55. 55.
    Beamer WG, Shultz KL, Donahue LR, Churchill GA, Sen S, Wergedal JR, Baylink DJ, Rosen CJ (2001) Quantitative trait loci for femoral and lumbar vertebral bone mineral density in C57BL/6J and C3H/HeJ inbred strains of mice. J Bone Miner Res 16:1195–1206PubMedCrossRefGoogle Scholar
  56. 56.
    Sheng MH, Baylink DJ, Beamer WG, Donahue LR, Lau KH, Wergedal JE (2002) Regulation of bone volume is different in the metaphyses of the femur and vertebra of C3H/HeJ and C57BL/6J mice. Bone 30:486–491PubMedCrossRefGoogle Scholar
  57. 57.
    Beamer WG, Donahue LR, Rosen CJ (2002) Genetics and bone. Using the mouse to understand man. J Musculoskelet Neuronal Interact 2:225–231PubMedGoogle Scholar
  58. 58.
    Garcia-Giralt N, Nogues X, Enjuanes A, Puig J, Mellibovsky L, Bay-Jensen A, Carreras R, Balcells S, Diez-Perez A, Grinberg D (2002) Two new single-nucleotide polymorphisms in the COL1A1 upstream regulatory region and their relationship to bone mineral density. J Bone Miner Res 17:384–393PubMedCrossRefGoogle Scholar
  59. 59.
    Grant SF, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH (1996) Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene. Nat Genet 14:203–205PubMedCrossRefGoogle Scholar
  60. 60.
    Mann V, Hobson EE, Li B, Stewart TL, Grant SF, Robins SP, Aspden RM, Ralston SH (2001) A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. J Clin Invest 107:899–907PubMedCrossRefGoogle Scholar
  61. 61.
    McGuigan FE, Armbrecht G, Smith R, Felsenberg D, Reid DM, Ralston SH (2001) Prediction of osteoporotic fractures by bone densitometry and COLIA1 genotyping: a prospective, population-based study in men and women. Osteoporos Int 12:91–96PubMedCrossRefGoogle Scholar
  62. 62.
    Uitterlinden AG, Burger H, Huang Q, Yue F, McGuigan FE, Grant SF, Hofman A, van Leeuwen JP, Pols HA, Ralston SH (1998) Relation of alleles of the collagen type Ialpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women. N Engl J Med 338:1016–1021PubMedCrossRefGoogle Scholar
  63. 63.
    Stewart TL, Jin H, McGuigan FE, Albagha OM, Garcia-Giralt N, Bassiti A, Grinberg D, Balcells S, Reid DM, Ralston SH (2006) Haplotypes defined by promoter and intron 1 polymorphisms of the COLIA1 gene regulate bone mineral density in women. J Clin Endocrinol Metab 91:3575–3583PubMedCrossRefGoogle Scholar
  64. 64.
    Ralston SH, Uitterlinden AG, Brandi ML, Balcells S, Langdahl BL, Lips P, Lorenc R, Obermayer-Pietsch B, Scollen S, Bustamante M, Husted LB, Carey AH, Diez-Perez A, Dunning AM, Falchetti A, Karczmarewicz E, Kruk M, van Leeuwen JP, van Meurs JB, Mangion J, McGuigan FE, Mellibovsky L, del Monte F, Pols HA, Reeve J, Reid DM, Renner W, Rivadeneira F, van Schoor NM, Sherlock RE, Ioannidis JP (2006) Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study. PLoS Med 3:e90PubMedCrossRefGoogle Scholar
  65. 65.
    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 74:866–875PubMedCrossRefGoogle Scholar
  66. 66.
    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 (2004) Influence of LRP5 polymorphisms on normal variation in BMD. J Bone Miner Res 19:1619–1627PubMedCrossRefGoogle Scholar
  67. 67.
    Koh JM, Jung MH, Hong JS, Park HJ, Chang JS, Shin HD, Kim SY, Kim GS (2004) Association between bone mineral density and LDL receptor-related protein 5 gene polymorphisms in young Korean men. J Korean Med Sci 19:407–412PubMedCrossRefGoogle Scholar
  68. 68.
    Mizuguchi T, Furuta I, Watanabe Y, Tsukamoto K, Tomita H, Tsujihata M, Ohta T, Kishino T, Matsumoto N, Minakami H, Niikawa N, Yoshiura K (2004) LRP5, low-density-lipoprotein-receptor-related protein 5, is a determinant for bone mineral density. J Hum Genet 49:80–86PubMedCrossRefGoogle Scholar
  69. 69.
    van Meurs JB, Trikalinos TA, Ralston SH, Balcells S, Brandi ML, Brixen K, Kiel DP, Langdahl BL, Lips P, Ljunggren O, Lorenc R, Obermayer-Pietsch B, Ohlsson C, Pettersson U, Reid DM, Rousseau F, Scollen S, Van Hul W, Agueda L, Akesson K, Benevolenskaya LI, Ferrari SL, Hallmans G, Hofman A, Husted LB, Kruk M, Kaptoge S, Karasik D, Karlsson MK, Lorentzon M, Masi L, McGuigan FE, Mellstrom D, Mosekilde L, Nogues X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Weber K, Ioannidis JP, Uitterlinden AG (2008) Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA 299:1277–1290PubMedCrossRefGoogle Scholar
  70. 70.
    Richards JB, Rivadeneira F, Inouye M, Pastinen TM, Soranzo N, Wilson SG, Andrew T, Falchi M, Gwilliam R, Ahmadi KR, Valdes AM, Arp P, Whittaker P, Verlaan DJ, Jhamai M, Kumanduri V, Moorhouse M, van Meurs JB, Hofman A, Pols HA, Hart D, Zhai G, Kato BS, Mullin BH, Zhang F, Deloukas P, Uitterlinden AG, Spector TD (2008) Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371:1505–1512PubMedCrossRefGoogle Scholar
  71. 71.
    Giroux S, Elfassihi L, Cole DE, Rousseau F (2008) Replication of associations between LRP5 and ESRRA variants and bone density in premenopausal women. Osteoporos Int (in press)Google Scholar
  72. 72.
    Lorentzon M, Lorentzon R, Lerner UH, Nordstrom P (2001) Calcium sensing receptor gene polymorphism, circulating calcium concentrations and bone mineral density in healthy adolescent girls. Eur J Endocrinol 144:257–261PubMedCrossRefGoogle Scholar
  73. 73.
    Zofkova I, Zajickova K, Hill M, Krepelova A (2003) Does polymorphism C1377T of the calcitonin receptor gene determine bone mineral density in postmenopausal women? Exp Clin Endocrinol Diabetes 111:447–449PubMedCrossRefGoogle Scholar
  74. 74.
    Abrahamsen B, Madsen JS, Tofteng CL, Stilgren L, Bladbjerg EM, Kristensen SR, Brixen K, Mosekilde L (2003) A common methylenetetrahydrofolate reductase (C677T) polymorphism is associated with low bone mineral density and increased fracture incidence after menopause: longitudinal data from the Danish osteoporosis prevention study. J Bone Miner Res 18:723–729PubMedCrossRefGoogle Scholar
  75. 75.
    Bathum L, n Hjelmborg J, Christiansen L, Madsen JS, Skytthe A, Christensen K (2004) Evidence for an association of methylene tetrahydrofolate reductase polymorphism C677T and an increased risk of fractures: results from a population-based Danish twin study. Osteoporos Int 15:659–664PubMedCrossRefGoogle Scholar
  76. 76.
    Hong X, Hsu YH, Terwedow H, Tang G, Liu X, Jiang S, Xu X, Xu X (2007) Association of the methylenetetrahydrofolate reductase C677T polymorphism and fracture risk in Chinese postmenopausal women. Bone 40:737–742PubMedCrossRefGoogle Scholar
  77. 77.
    Jorgensen HL, Madsen JS, Madsen B, Saleh MM, Abrahamsen B, Fenger M, Lauritzen JB (2002) Association of a common allelic polymorphism (C677T) in the methylene tetrahydrofolate reductase gene with a reduced risk of osteoporotic fractures. A case control study in Danish postmenopausal women. Calcif Tissue Int 71:386–392PubMedCrossRefGoogle Scholar
  78. 78.
    Kiel DP, Demissie S, Dupuis J, Lunetta KL, Murabito JM, Karasik D (2007) Genome-wide association with bone mass and geometry in the Framingham Heart Study. BMC Med Genet 8(Suppl 1):S14PubMedCrossRefGoogle Scholar
  79. 79.
    Miyao M, Morita H, Hosoi T, Kurihara H, Inoue S, Hoshino S, Shiraki M, Yazaki Y, Ouchi Y (2000) Association of methylenetetrahydrofolate reductase (MTHFR) polymorphism with bone mineral density in postmenopausal Japanese women. Calcif Tissue Int 66:190–194PubMedCrossRefGoogle Scholar
  80. 80.
    Valero C, Alonso MA, Zarrabeitia MT, Viadero C, Hernandez JL, Riancho JA (2007) MTHFR C677T polymorphism and osteoporotic fractures. Horm Metab Res 39:543–547PubMedCrossRefGoogle Scholar
  81. 81.
    Villadsen MM, Bunger MH, Carstens M, Stenkjaer L, Langdahl BL (2005) Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with osteoporotic vertebral fractures, but is a weak predictor of BMD. Osteoporos Int 16:411–416PubMedCrossRefGoogle Scholar
  82. 82.
    Uitterlinden AG, Ralston SH, Brandi ML, Carey AH, Grinberg D, Langdahl BL, Lips P, Lorenc R, Obermayer-Pietsch B, Reeve J, Reid DM, Amedei A, Bassiti A, Bustamante M, Husted LB, Diez-Perez A, Dobnig H, Dunning AM, Enjuanes A, Fahrleitner-Pammer A, Fang Y, Karczmarewicz E, Kruk M, van Leeuwen JP, Mavilia C, van Meurs JB, Mangion J, McGuigan FE, Pols HA, Renner W, Rivadeneira F, van Schoor NM, Scollen S, Sherlock RE, Ioannidis JP (2006) The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis. Ann Intern Med 145:255–264PubMedGoogle Scholar
  83. 83.
    Langdahl BL, Uitterlinden AG, Ralston SH, Trikalinos TA, Balcells S, Brandi ML, Scollen S, Lips P, Lorenc R, Obermayer-Pietsch B, Reid DM, Armas JB, Arp PP, Bassiti A, Bustamante M, Husted LB, Carey AH, Perez Cano R, Dobnig H, Dunning AM, Fahrleitner-Pammer A, Falchetti A, Karczmarewicz E, Kruk M, van Leeuwen JP, Masi L, van Meurs JB, Mangion J, McGuigan FE, Mellibovsky L, Mosekilde L, Nogues X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Ioannidis JP (2008) Large-scale analysis of association between polymorphisms in the transforming growth factor beta 1 gene (TGFB1) and osteoporosis: the GENOMOS study. Bone 42:969–981PubMedCrossRefGoogle Scholar
  84. 84.
    Ioannidis JP (2005) Why most published research findings are false. PLoS Med 2:e124PubMedCrossRefGoogle Scholar
  85. 85.
    Rebbeck TR, Martinez ME, Sellers TA, Shields PG, Wild CP, Potter JD (2004) Genetic variation and cancer: improving the environment for publication of association studies. Cancer Epidemiol Biomarkers Prev 13:1985–1986PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Gregory J. Tranah
    • 1
    • 2
  • Brent C. Taylor
    • 3
    • 4
  • Li-Yung Lui
    • 1
  • Joseph M. Zmuda
    • 5
  • Jane A. Cauley
    • 5
  • Kristine E. Ensrud
    • 3
    • 4
    • 6
  • Teresa A. Hillier
    • 7
  • Marc C. Hochberg
    • 8
  • Jia Li
    • 9
  • Brian K. Rhees
    • 9
  • Henry A. Erlich
    • 9
  • Mark D. Sternlicht
    • 10
  • Gary Peltz
    • 11
  • Steven R. Cummings
    • 1
    • 12
  • For the Study of Osteoporotic Fractures (SOF) Research Group
    • 13
  1. 1.CPMC Research InstituteSan FranciscoUSA
  2. 2.California Pacific Medical Center Research Institute, San Francisco Coordinating Center UCSFSan FranciscoUSA
  3. 3.Center for Chronic Disease Outcomes ResearchMinneapolis VA Medical CenterMinneapolisUSA
  4. 4.Division of Epidemiology and Community HealthUniversity of MinnesotaMinneapolisUSA
  5. 5.Department of EpidemiologyUniversity of PittsburghPittsburgUSA
  6. 6.Department of MedicineUniversity of MinnesotaMinneapolisUSA
  7. 7.Kaiser Permanente Center for Health Research Northwest/HawaiiPortlandUSA
  8. 8.Department of Medicine and Epidemiology and Preventative MedicineUniversity of Maryland School of Medicine UniversityBaltimoreUSA
  9. 9.Department of Human GeneticsRoche Molecular SystemsAlamedaUSA
  10. 10.Department of AnatomyUniversity of CaliforniaSan FranciscoUSA
  11. 11.Department of Genetics and GenomicsRoche Palo AltoPalo AltoUSA
  12. 12.Department of EpidemiologyUniversity of CaliforniaSan FranciscoUSA
  13. 13.San FranciscoUSA

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