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Genetic Polymorphisms of the Wnt Receptor LRP5 are Differentially Associated with Trochanteric and Cervical Hip Fractures

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Abstract

Epidemiological studies suggest that cervical and trochanteric hip fractures have different pathogenesis. We tested the hypothesis that genetic factors have different influences on both types of fractures. Ten polymorphisms of genes known to play an important role in skeletal homeostasis [estrogen receptor alpha (ESR1), aromatase (CYP19A1), type I collagen (COL1A1), and lipoprotein receptor-related protein 5 (LRP5)] were analyzed in 471 Spanish patients with fragility hip fractures. Two polymorphisms of the LRP5 gene (rs7116604 and rs3781600) were associated with the type of fracture (P = 0.0085 and 0.0047, respectively). The presence of rare alleles at each locus was associated with trochanteric fractures over cervical fractures (OR = 1.7 in individuals with at least one rare allele at rs7116604 or rs3781600 loci in comparison with the common homozygotes). Considering individuals bearing the four common alleles as reference, the OR for trochanteric fractures was 1.6 in those with one or two rare alleles and 7.5 in those with three or four rare alleles (P for trend = 0.0074), which is consistent with an allele-dosage effect. There were no significant differences in the frequency distributions of the ESR1, CYP19A1, and COL1A1 genotypes between trochanteric and cervical fractures in either the original group or an extended group of 818 patients. These results suggest that LRP5 alleles influence the type of hip fractures. They support the view that different genetic factors are involved in cervical and trochanteric fractures, which should be taken into consideration in future genetic association studies.

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References

  1. Armstrong ME, Spencer EA, Cairns BJ, Banks E, Pirie K, Green J, Wright FL, Reeves GK, Beral V (2011) Body mass index and physical activity in relation to the incidence of hip fracture in postmenopausal women. J Bone Miner Res 26:1330–1338

    Article  PubMed  Google Scholar 

  2. Solomon DH, Mogun H, Garneau K, Fischer MA (2011) Risk of fractures in older adults using antihypertensive medications. J Bone Miner Res 26:1561–1567

    Article  PubMed  CAS  Google Scholar 

  3. Peacock M, Turner CH, Econs MJ, Foroud T (2002) Genetics of osteoporosis. Endocr Rev 23:303–326

    Article  PubMed  CAS  Google Scholar 

  4. 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. N Engl J Med 332:767–773

    Article  PubMed  CAS  Google Scholar 

  5. Michaelsson K, Melhus H, Ferm H, Ahlbom A, Pedersen NL (2005) Genetic liability to fractures in the elderly. Arch Intern Med 165:1825–1830

    Article  PubMed  Google Scholar 

  6. Wang JT, Guo Y, Yang TL, Xu XH, Dong SS, Li M, Li TQ, Chen Y, Deng HW (2008) Polymorphisms in the estrogen receptor genes are associated with hip fractures in Chinese. Bone 43:910–914

    Article  PubMed  CAS  Google Scholar 

  7. Velasco J, Hernandez JL, Perez-Castrillon JL, Zarrabeitia MT, Alonso MA, Gonzalez-Macias J, Riancho JA (2010) Haplotypes of intron 4 of the estrogen receptor alpha gene and hip fractures: a replication study in Caucasians. BMC Med Genet 11:16

    Article  PubMed  Google Scholar 

  8. Zhang YP, Liu YZ, Guo Y, Liu XG, Xu XH, Guo YF, Chen Y, Zhang F, Pan F, Zhu XZ, Deng HW (2011) Pathway-based association analyses identified TRAIL pathway for osteoporotic fractures. PLoS ONE 6:e21835

    Article  PubMed  CAS  Google Scholar 

  9. Dragojevic J, Ostanek B, Mencej-Bedrac S, Komadina R, Prezelj J, Marc J (2011) PPARG gene promoter polymorphism is associated with non-traumatic hip fracture risk in the elderly Slovenian population: a pilot study. Clin Biochem 44:1085–1089

    Article  PubMed  CAS  Google Scholar 

  10. Pulkkinen P, Partanen J, Jalovaara P, Jamsa T (2010) BMD T-score discriminates trochanteric fractures from unfractured controls, whereas geometry discriminates cervical fracture cases from unfractured controls of similar BMD. Osteoporos Int 21:1269–1276

    Article  PubMed  CAS  Google Scholar 

  11. Valero C, Perez-Castrillon JL, Zarrabeitia MT, Hernandez JL, Alonso MA, Pino-Montes J, Olmos JM, Gonzalez-Macias J, Riancho JA (2008) Association of aromatase and estrogen receptor gene polymorphisms with hip fractures. Osteoporos Int 19:787–792

    Article  PubMed  CAS  Google Scholar 

  12. Riancho JA, Olmos JM, Pineda B, Garcia-Ibarbia C, Perez-Nunez MI, Nan DN, Velasco J, Cano A, Garcia-Perez MA, Zarrabeitia MT, Gonzalez-Macias J (2011) Wnt receptors, bone mass, and fractures: gene-wide association analysis of LRP5 and LRP6 polymorphisms with replication. Eur J Endocrinol 164:123–131

    Article  PubMed  CAS  Google Scholar 

  13. Riancho JA, Valero C, Naranjo A, Morales DJ, Sanudo C, Zarrabeitia MT (2007) Identification of an aromatase haplotype that is associated with gene expression and postmenopausal osteoporosis. J Clin Endocrinol Metab 92:660–665

    Article  PubMed  CAS  Google Scholar 

  14. 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:e90

    Article  PubMed  Google Scholar 

  15. Jin H, Evangelou E, Ioannidis JP, Ralston SH (2011) Polymorphisms in the 5′ flank of COL1A1 gene and osteoporosis: meta-analysis of published studies. Osteoporos Int 22:911–921

    Article  PubMed  CAS  Google Scholar 

  16. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575

    Article  PubMed  CAS  Google Scholar 

  17. Li J, Ji L (2005) Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity 95:221–227

    Article  PubMed  CAS  Google Scholar 

  18. Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74:765–769

    Article  PubMed  CAS  Google Scholar 

  19. Michaelsson K, Weiderpass E, Farahmand BY, Baron JA, Persson PG, Ziden L, Zetterberg C, Ljunghall S (1999) Differences in risk factor patterns between cervical and trochanteric hip fractures. Swedish Hip Fracture Study Group. Osteoporos Int 10:487–494

    Article  PubMed  CAS  Google Scholar 

  20. Fox KM, Cummings SR, Williams E, Stone K (2000) Femoral neck and intertrochanteric fractures have different risk factors: a prospective study. Osteoporos Int 11:1018–1023

    Article  PubMed  CAS  Google Scholar 

  21. Karagas MR, Lu-Yao GL, Barrett JA, Beach ML, Baron JA (1996) Heterogeneity of hip fracture: age, race, sex, and geographic patterns of femoral neck and trochanteric fractures among the US elderly. Am J Epidemiol 143:677–682

    PubMed  CAS  Google Scholar 

  22. Tanner DA, Kloseck M, Crilly RG, Chesworth B, Gilliland J (2010) Hip fracture types in men and women change differently with age. BMC Geriatr 10:12

    Article  PubMed  Google Scholar 

  23. Schott AM, Hans D, Duboeuf F, Dargent-Molina P, Hajri T, Breart G, Meunier PJ (2005) Quantitative ultrasound parameters as well as bone mineral density are better predictors of trochanteric than cervical hip fractures in elderly women. Results from the EPIDOS study. Bone 37:858–863

    Article  PubMed  CAS  Google Scholar 

  24. Szulc P, Duboeuf F, Schott AM, Dargent-Molina P, Meunier PJ, Delmas PD (2006) Structural determinants of hip fracture in elderly women: re-analysis of the data from the EPIDOS study. Osteoporos Int 17:231–236

    Article  PubMed  CAS  Google Scholar 

  25. Di Monaco M, Di Monaco R, Mautino F, Cavanna A (2002) Femur bone mineral density, age and fracture type in 300 hip-fractured women. Aging Clin Exp Res 14:47–51

    PubMed  CAS  Google Scholar 

  26. Maeda Y, Sugano N, Saito M, Yonenobu K (2011) Comparison of femoral morphology and bone mineral density between femoral neck fractures and trochanteric fractures. Clin Orthop Relat Res 469:884–889

    Article  PubMed  Google Scholar 

  27. Partanen J, Jamsa T, Jalovaara P (2001) Influence of the upper femur and pelvic geometry on the risk and type of hip fractures. J Bone Miner Res 16:1540–1546

    Article  PubMed  CAS  Google Scholar 

  28. Duboeuf F, Hans D, Schott AM, Kotzki PO, Favier F, Marcelli C, Meunier PJ, Delmas PD (1997) Different morphometric and densitometric parameters predict cervical and trochanteric hip fracture: the EPIDOS study. J Bone Miner Res 12:1895–1902

    Article  PubMed  CAS  Google Scholar 

  29. Gnudi S, Ripamonti C, Lisi L, Fini M, Giardino R, Giavaresi G (2002) Proximal femur geometry to detect and distinguish femoral neck fractures from trochanteric fractures in postmenopausal women. Osteoporos Int 13:69–73

    Article  PubMed  CAS  Google Scholar 

  30. Gnudi S, Ripamonti C, Gualtieri G, Malavolta N (1999) Geometry of proximal femur in the prediction of hip fracture in osteoporotic women. Br J Radiol 72:729–733

    PubMed  CAS  Google Scholar 

  31. Panula J, Savela M, Jaatinen PT, Aarnio P, Kivela SL (2008) The impact of proximal femur geometry on fracture type—a comparison between cervical and trochanteric fractures with two parameters. Scand J Surg 97:266–271

    PubMed  CAS  Google Scholar 

  32. Riggs BL, Khosla S, Melton LJ III (2002) Sex steroids and the construction and conservation of adult skeleton. Endocr Rev 23:279–302

    Article  PubMed  CAS  Google Scholar 

  33. Balemans W, Van Hul W (2007) The genetics of low-density lipoprotein receptor-related protein 5 in bone: a story of extremes. Endocrinology 148:2622–2629

    Article  PubMed  CAS  Google Scholar 

  34. 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 299:1277–1290

    Article  PubMed  Google Scholar 

  35. 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 371:1505–1512

    Article  PubMed  CAS  Google Scholar 

  36. Agueda L, Bustamante M, Jurado S, Garcia-Giralt N, Ciria M, Salo G, Carreras R, Nogues X, Mellibovsky L, Diez-Perez A, Grinberg D, Balcells S (2008) A haplotype-based analysis of the LRP5 gene in relation to osteoporosis phenotypes in Spanish postmenopausal women. J Bone Miner Res 23:1954–1963

    Article  PubMed  CAS  Google Scholar 

  37. Bollerslev J, Wilson SG, Dick IM, Islam FM, Ueland T, Palmer L, Devine A, Prince RL (2005) LRP5 gene polymorphisms predict bone mass and incident fractures in elderly Australian women. Bone 36:599–606

    Article  PubMed  CAS  Google Scholar 

  38. Brixen K, Beckers S, Peeters A, Piters E, Balemans W, Nielsen TL, Wraae K, Bathum L, Brasen C, Hagen C, Andersen M, Van Hul W, Abrahamsen B (2007) Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with peak bone mass in non-sedentary men: results from the Odense Androgen Study. Calcif Tissue Int 81:421–429

    Article  PubMed  CAS  Google Scholar 

  39. 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 19:1619–1627

    Article  PubMed  CAS  Google Scholar 

  40. Koay MA, Tobias JH, Leary SD, Steer CD, Vilarino-Guell C, Brown MA (2007) The effect of LRP5 polymorphisms on bone mineral density is apparent in childhood. Calcif Tissue Int 81:1–9

    Article  PubMed  CAS  Google Scholar 

  41. Piters E, Balemans W, Nielsen TL, Andersen M, Boudin E, Brixen K, Van Hul W (2010) Common genetic variation in the DKK1 gene is associated with hip axis length but not with bone mineral density and bone turnover markers in young adult men: results from the odense androgen study. Calcif Tissue Int 86:271–281

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by grants from Instituto de Salud Carlos III-Fondo de Investigaciones Sanitarias (PI06/0034, PS09/00539). We thank the staff at the Centro Nacional de Genotipado, particularly Maria Torres, for their help in genotyping. We also acknowledge the excellent technical assistance of Verónica Mijares and Jana Arozamena.

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Authors and Affiliations

  1. Department of Internal Medicine, Hospital U.M. Valdecilla-IFIMAV, Universidad de Cantabria, RETICEF, 39008, Santander, Spain

    Javier Riancho, Carmen García-Ibarbia, Teresa Díaz & José A. Riancho

  2. Service of Traumatology and Orthopedic Surgery, Hospital U.M. Valdecilla-IFIMAV, Universidad de Cantabria, Santander, Spain

    María I. Pérez-Núñez & María A. Alonso

  3. Service of Internal Medicine, Hospital U. Río Hortega, Universidad de Valladolid, RETICEF, Valladolid, Spain

    José L. Pérez-Castrillón

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  1. Javier Riancho
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  2. Carmen García-Ibarbia
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Correspondence to José A. Riancho.

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Riancho, J., García-Ibarbia, C., Pérez-Núñez, M.I. et al. Genetic Polymorphisms of the Wnt Receptor LRP5 are Differentially Associated with Trochanteric and Cervical Hip Fractures. Calcif Tissue Int 90, 137–143 (2012). https://doi.org/10.1007/s00223-011-9557-2

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