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Genetics and the Individualized Prediction of Fracture

  • Bone Genetics (S Ferrari, Section Editor)
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Abstract

Recent genome-wide association studies have identified many genetic variants associated with fracture risk. These genetic variants are common in the general population but have very modest effect sizes. A remaining challenge is to translate these genetic variant discoveries to better predict the risk of fracture based on an individual’s genetic profile (ie, individualized risk assessment). Empirical and simulation studies have shown that 1) the utility of a single genetic variant for fracture risk assessment is very limited; but 2) a profile of 50 genetic variants, each with odds ratio ranging from 1.02 to 1.15, can improve the accuracy of fracture prediction and classification beyond that obtained by conventional clinical risk factors. These results are consistent with the view that genetic profiling, when integrated in existing risk assessment models, can inform a more accurate prediction of fracture risk in an individual.

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References

  1. Nguyen ND, Ahlborg HG, Center JR, Eisman JA, Nguyen TV. Residual lifetime risk of fractures in women and men. J Bone Miner Res. 2007;22(6):781–8.

    Article  PubMed  Google Scholar 

  2. Cummings SR, Black DM, Rubin SM. Lifetime risks of hip, Colles', or vertebral fracture and coronary heart disease among white postmenopausal women. Arch Intern Med. 1989;149(11):2445–8.

    Article  PubMed  CAS  Google Scholar 

  3. Shortt NL, Robinson CM. Mortality after low-energy fractures in patients aged at least 45 years old. J Orthop Trauma. 2005;19(6):396–400.

    Article  PubMed  Google Scholar 

  4. Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA. 2009;301(5):513–21.

    Article  PubMed  CAS  Google Scholar 

  5. Center JR, Bliuc D, Nguyen TV, Eisman JA. Risk of subsequent fracture after low-trauma fracture in men and women. Jama. 2007;297(4):387–94.

    Article  PubMed  CAS  Google Scholar 

  6. Center JR, Nguyen TV, Schneider D, Sambrook PN, Eisman JA. Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet. 1999;353(9156):878–82.

    Article  PubMed  CAS  Google Scholar 

  7. Seeman E. Reduced bone density in women with fractures: contribution of low peak bone density and rapid bone loss. Osteoporos Int. 1994;4 Suppl 1:15–25.

    Article  PubMed  Google Scholar 

  8. Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med. 1995;332(12):767–73.

    Article  PubMed  CAS  Google Scholar 

  9. Deng HW, Chen WM, Recker S, Stegman MR, Li JL, Davies KM, et al. Genetic determination of Colles' fracture and differential bone mass in women with and without Colles' fracture. J Bone Miner Res. 2000;15(7):1243–52.

    Article  PubMed  CAS  Google Scholar 

  10. Michaelsson K, Melhus H, Ferm H, Ahlbom A, Pedersen NL. Genetic liability to fractures in the elderly. Arch Intern Med. 2005;165(16):1825–30.

    Article  PubMed  Google Scholar 

  11. Nguyen TV, Howard GM, Kelly PJ, Eisman JA. Bone mass, lean mass, and fat mass: same genes or same environments? Am J Epidemiol. 1998;147(1):3–16.

    Article  PubMed  CAS  Google Scholar 

  12. Makovey J, Nguyen TV, Naganathan V, Wark JD, Sambrook PN. Genetic effects on bone loss in peri- and postmenopausal women: a longitudinal twin study. J Bone Miner Res. 2007;22(11):1773–80.

    Article  PubMed  Google Scholar 

  13. Howard GM, Nguyen TV, Harris M, Kelly PJ, Eisman JA. Genetic and environmental contributions to the association between quantitative ultrasound and bone mineral density measurements: a twin study. J Bone Miner Res. 1998;13(8):1318–27.

    Article  PubMed  CAS  Google Scholar 

  14. Tokita A, Kelly PJ, Nguyen TV, Qi JC, Morrison NA, Risteli L, et al. Genetic influences on type I collagen synthesis and degradation: further evidence for genetic regulation of bone turnover. J Clin Endocrinol Metab. 1994;78(6):1461–6.

    Article  PubMed  CAS  Google Scholar 

  15. Nguyen TV, Blangero J, Eisman JA. Genetic epidemiological approaches to the search for osteoporosis genes. J Bone Miner Res. 2000;15(3):392–401.

    Article  PubMed  CAS  Google Scholar 

  16. Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nat Rev Genet. 2005;6(2):95–108.

    Article  PubMed  CAS  Google Scholar 

  17. Ralston SH, de Crombrugghe B. Genetic regulation of bone mass and susceptibility to osteoporosis. Genes Dev. 2006;20(18):2492–506.

    Article  PubMed  CAS  Google Scholar 

  18. Huang QY, Recker RR, Deng HW. Searching for osteoporosis genes in the post-genome era: progress and challenges. Osteoporos Int. 2003;14(9):701–15.

    Article  PubMed  Google Scholar 

  19. Nguyen TV. Pharmacogenetics of anti-resorptive therapy efficacy: a Bayesian interpretation. Osteoporos Int. 2005;16(8):857–60.

    Article  PubMed  Google Scholar 

  20. Gong Y, Vikkula M, Boon L, Liu J, Beighton P, Ramesar R, et al. Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13. Am J Hum Genet. 1996;59(1):146–51.

    PubMed  CAS  Google Scholar 

  21. Johnson ML, Gong G, Kimberling W, Recker SM, Kimmel DB, Recker RB. Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13). Am J Hum Genet. 1997;60(6):1326–32.

    Article  PubMed  CAS  Google Scholar 

  22. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107(4):513–23.

    Article  PubMed  CAS  Google Scholar 

  23. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002;70(1):11–9.

    Article  PubMed  CAS  Google Scholar 

  24. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002;346(20):1513–21.

    Article  PubMed  CAS  Google Scholar 

  25. Kiel DP, Demissie S, Dupuis J, Lunetta KL, Murabito JM, Karasik D. Genome-wide association with bone mass and geometry in the Framingham Heart Study. BMC Med Genet. 2007;8 Suppl 1:S14.

    Google Scholar 

  26. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, et al. Multiple genetic loci for bone mineral density and fractures. N Engl J Med. 2008;358(22):2355–65.

    Article  PubMed  CAS  Google Scholar 

  27. Richards JB, Rivadeneira F, Inouye M, Pastinen TM, Soranzo N, Wilson SG, et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet. 2008;371(9623):1505–12.

    Article  PubMed  CAS  Google Scholar 

  28. Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson BV, Hsu YH, Richards JB, et al. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet. 2009;41(11):1199–206.

    Article  PubMed  CAS  Google Scholar 

  29. Richards JB, Kavvoura FK, Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson BV, et al. Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med. 2009;151(8):528–37.

    PubMed  Google Scholar 

  30. Estrada K, Styrkarsdottir U, Evangelou E, Hsu YH, Duncan EL, Ntzani EE, et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. 2012;44(5):491–501.

    Article  Google Scholar 

  31. Pepe MS, Janes H, Longton G, Leisenring W, Newcomb P. Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker. Am J Epidemiol. 2004;159(9):882–90.

    Article  PubMed  Google Scholar 

  32. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143(1):29–36.

    PubMed  CAS  Google Scholar 

  33. Schoonmaker MM, Bernhardt BA, Holtzman NA. Factors influencing health insurers' decisions to cover new genetic technologies. Int J Technol Assess Health Care. 2000;16(1):178–89.

    Article  PubMed  CAS  Google Scholar 

  34. Pencina MJ, D'Agostino Sr RB, D'Agostino Jr RB, Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med. 2008;27(2):157–72. discussion 207-12.

    Article  PubMed  Google Scholar 

  35. Cook NR. Statistical evaluation of prognostic versus diagnostic models: beyond the ROC curve. Clin Chem. 2008;54(1):17–23.

    Article  PubMed  CAS  Google Scholar 

  36. Pepe MS, Gu JW, Morris DE. The potential of genes and other markers to inform about risk. Cancer Epidemiol Biomarkers Prev. 2010;19(3):655–65.

    Article  PubMed  CAS  Google Scholar 

  37. Tran BN, Nguyen ND, Center JR, Eisman JA, Nguyen TV. Enhancement of absolute fracture risk prognosis with genetic marker: the collagen I alpha 1 gene. Calcif Tissue Int. 2009;85(5):379–88.

    Article  PubMed  CAS  Google Scholar 

  38. Nguyen ND, Frost SA, Center JR, Eisman JA, Nguyen TV. Development of a nomogram for individualizing hip fracture risk in men and women. Osteoporos Int. 2007;18(8):1109–17.

    Article  PubMed  CAS  Google Scholar 

  39. Nguyen ND, Frost SA, Center JR, Eisman JA, Nguyen TV. Development of prognostic nomograms for individualizing 5-year and 10-year fracture risks. Osteoporos Int. 2008.

  40. Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19(4):385–97.

    Article  PubMed  CAS  Google Scholar 

  41. Tran BN, Nguyen ND, Center JR, Eisman JA, Nguyen TV. Enhancement of absolute fracture risk prognosis with genetic marker: the collagen I alpha 1 gene. Calcif Tissue Int. 2009;85(5):379–88.

    Article  PubMed  Google Scholar 

  42. Reich DE, Lander ES. On the allelic spectrum of human disease. Trends Genet. 2001;17(9):502–10.

    Article  PubMed  CAS  Google Scholar 

  43. Nguyen TV. Individualization of osteoporosis risk. Osteoporos Int. 2007;18(9):1153–6.

    Article  PubMed  CAS  Google Scholar 

  44. Holtzman NA, Marteau TM. Will genetics revolutionize medicine? N Engl J Med. 2000;343(2):141–4.

    Article  PubMed  CAS  Google Scholar 

  45. Wray NR, Yang J, Goddard ME, Visscher PM. The genetic interpretation of area under the ROC curve in genomic profiling. PLoS Genet. 2010;6(2):e1000864.

    Article  PubMed  Google Scholar 

  46. Nguyen TV, Eisman JA. Individualized prognosis of fracture in men. In: Orwoll ES, Bilezikian JP, Vanderschueren D, editors. Osteoporosis in men: the effects of gender on skeletal health. 2nd ed. London: Elsevier; 2010. p. 361–373.

  47. Kattan MW, Reuter V, Motzer RJ, Katz J, Russo P. A postoperative prognostic nomogram for renal cell carcinoma. J Urol. 2001;166(1):63–7.

    Article  PubMed  CAS  Google Scholar 

  48. Johnell O, Kanis JA, Oden A, Johansson H, De Laet C, Delmas P, et al. Predictive value of BMD for hip and other fractures. J Bone Miner Res. 2005;20(7):1185–94.

    Article  PubMed  Google Scholar 

  49. Nguyen ND, Pongchaiyakul C, Center JR, Eisman JA, Nguyen TV. Identification of high-risk individuals for hip fracture: a 14-year prospective study. J Bone Miner Res. 2005;20(11):1921–8.

    Article  PubMed  Google Scholar 

  50. Leslie WD, Lix LM, Tsang JF, Caetano PA. Single-site vs multisite bone density measurement for fracture prediction. Arch Intern Med. 2007;167(15):1641–7.

    Article  PubMed  Google Scholar 

  51. Kanis JA, Johnell O, De Laet C, Johansson H, Oden A, Delmas P, et al. A meta-analysis of previous fracture and subsequent fracture risk. Bone. 2004;35(2):375–82.

    Article  PubMed  CAS  Google Scholar 

  52. Dargent-Molina P, Douchin MN, Cormier C, Meunier PJ, Breart G. Use of clinical risk factors in elderly women with low bone mineral density to identify women at higher risk of hip fracture: the EPIDOS prospective study. Osteoporos Int. 2002;13(7):593–9.

    Article  PubMed  CAS  Google Scholar 

  53. Nguyen ND, Eisman JA, Center JR, Nguyen TV. Risk factors for fracture in nonosteoporotic men and women. J Clin Endocrinol Metab. 2007;92(3):955–62.

    Article  PubMed  CAS  Google Scholar 

  54. Borgstrom F, Johnell O, Kanis JA, Jonsson B, Rehnberg C. At what hip fracture risk is it cost-effective to treat? International intervention thresholds for the treatment of osteoporosis. Osteoporos Int. 2006;17(10):1459–71.

    Article  PubMed  CAS  Google Scholar 

  55. Delmas PD, Rizzoli R, Cooper C, Reginster JY. Treatment of patients with postmenopausal osteoporosis is worthwhile. The position of the International Osteoporosis Foundation. Osteoporos Int. 2005;16(1):1–5.

    Article  PubMed  Google Scholar 

  56. Nguyen ND, Eisman JA, Nguyen TV. Anti-hip fracture efficacy of bisphosphonates: a Bayesian analysis of clinical trials. J Bone Miner Res. 2006;21(1):340–9.

    PubMed  CAS  Google Scholar 

  57. McCloskey E, Johansson H, Oden A, Aropuu A, Jalava T, Kanis J. Efficacy of clodronate on fracture risk in women selected by 10-year fracture probability. J Bone Miner Res. 2007;22(10):S131.

    Google Scholar 

  58. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461(7265):747–53.

    Article  PubMed  CAS  Google Scholar 

  59. Zuk O, Hechter E, Sunyaev SR, Lander ES. The mystery of missing heritability: genetic interactions create phantom heritability. Proc Natl Acad Sci U S A. 2012;109(4):1193–8.

    Article  PubMed  CAS  Google Scholar 

  60. Center JR, Nguyen TV, Sambrook PN, Eisman JA. Hormonal and biochemical parameters in the determination of osteoporosis in elderly men. J Clin Endocrinol Metab. 1999;84(10):3626–35.

    Article  PubMed  CAS  Google Scholar 

  61. Nguyen TV, Center JR, Sambrook PN, Eisman JA. Risk factors for proximal humerus, forearm, and wrist fractures in elderly men and women: the Dubbo Osteoporosis Epidemiology Study. Am J Epidemiol. 2001;153(6):587–95.

    Article  PubMed  CAS  Google Scholar 

  62. Nguyen TV, Kelly PJ, Sambrook PN, Gilbert C, Pocock NA, Eisman JA. Lifestyle factors and bone density in the elderly: implications for osteoporosis prevention. J Bone Miner Res. 1994;9(9):1339–46.

    Article  PubMed  CAS  Google Scholar 

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Disclosure

Conflicts of interest: T.V. Nguyen and J.A. Eisman have no conflict of interest in relation to this paper. T.V. Nguyen is supported by a senior fellowship from the Australian National Health and Medical Research Council. J.A. Eisman received support from the MBF Living Well Foundation; the Ernst Heine Foundation; and untied grants from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Servier, and Novartis.

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  1. Osteoporosis and Bone Biology Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia

    Tuan V. Nguyen & John A. Eisman

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  1. Tuan V. Nguyen
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Correspondence to Tuan V. Nguyen.

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Nguyen, T.V., Eisman, J.A. Genetics and the Individualized Prediction of Fracture. Curr Osteoporos Rep 10, 236–244 (2012). https://doi.org/10.1007/s11914-012-0113-4

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