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01-04-2010

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

Authors: Elke Piters, Wendy Balemans, Torben Leo Nielsen, Marianne Andersen, Eveline Boudin, Kim Brixen, Wim Van Hul

Published in: Calcified Tissue International | Issue 4/2010

Abstract

LRP5 was recently confirmed as an important susceptibility gene for osteoporosis. Our objective was to evaluate the effect of DKK1 polymorphisms on bone mineral density (BMD), hip geometry, and bone turnover. DKK1 is a secreted protein that binds to LRP5/6 receptors and inhibits canonical Wnt signaling. Using HapMap, we selected three SNPs covering the genetic variation in a 13.53-kb region comprising DKK1. The Odense Androgen Study is a population-based study comprising 783 Caucasian men aged 20–29 years. BMD and hip structural parameters were available for study. Bone turnover markers were used as a secondary end point. All analyses were repeated after adjusting for covariables and in subgroups according to physical activity. We found no significant association between DKK1 and BMD or markers of bone turnover; however, a significant association (P = 0.012) was found for rs1569198 with hip axis length (HAL), independent of BMD and height. Moreover, the association seemed to be driven by the nonsedentary subgroup (P = 0.004). Haplotype analysis further confirmed the association of rs1569198 with HAL. Furthermore, we obtained indications for interaction between DKK1 and LRP5 genotypes for different hip geometry parameters. As almost all variance within the DKK1 gene was covered, we conclude that common variation in this gene does not markedly influence BMD or bone turnover markers in young men. In this population, however, a common SNP in DKK1 does have a significant effect on HAL, implying a possible effect on hip fracture risk in the general population. This finding could be of interest but needs replication in independent populations.

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Dennison E, Mohamed MA, Cooper C (2006) Epidemiology of osteoporosis. Rheum Dis Clin North Am 32:617–629CrossRefPubMed

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

Crabtree N, Lunt M, Holt G, Kroger H, Burger H, Grazio S, Khaw KT, Lorenc RS, Nijs J, Stepan J, Falch JA, Miazgowski T, Raptou P, Pols HA, Dequeker J, Havelka S, Hoszowski K, Jajic I, Czekalski S, Lyritis G, Silman AJ, Reeve J (2000) Hip geometry, bone mineral distribution, and bone strength in European men and women: the EPOS study. Bone 27:151–159CrossRefPubMed

Geusens P (1996) Geometric characteristics of the proximal femur and hip fracture risk. Osteoporos Int 6(Suppl 3):27–30CrossRefPubMed

Arden NK, Baker J, Hogg C, Baan K, Spector TD (1996) The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: a study of postmenopausal twins. J Bone Miner Res 11:530–534CrossRefPubMed

Yan L, Crabtree NJ, Reeve J, Zhou B, Dequeker J, Nijs J, Falch JA, Prentice A (2004) Does hip strength analysis explain the lower incidence of hip fracture in the People’s Republic of China? Bone 34:584–588CrossRefPubMed

Gerdhem P, Ivaska KK, Alatalo SL, Halleen JM, Hellman J, Isaksson A, Pettersson K, Vaananen HK, Akesson K, Obrant KJ (2004) Biochemical markers of bone metabolism and prediction of fracture in elderly women. J Bone Miner Res 19:386–393CrossRefPubMed

Meier C, Nguyen TV, Center JR, Seibel MJ, Eisman JA (2005) Bone resorption and osteoporotic fractures in elderly men: the Dubbo Osteoporosis Epidemiology Study. J Bone Miner Res 20:579–587CrossRefPubMed

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 299:1277–1290CrossRefPubMed

10.

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 371:1505–1512CrossRefPubMed

11.

Kiel DP, Ferrari SL, Cupples LA, Karasik D, Manen D, Imamovic A, Herbert AG, Dupuis J (2007) Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men. Bone 40:587–596CrossRefPubMed

12.

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 81:421–429CrossRefPubMed

13.

Sawakami K, Robling AG, Ai M, Pitner ND, Liu D, Warden SJ, Li J, Maye P, Rowe DW, Duncan RL, Warman ML, Turner CH (2006) The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment. J Biol Chem 281:23698–23711CrossRefPubMed

14.

Akhter MP, Wells DJ, Short SJ, Cullen DM, Johnson ML, Haynatzki GR, Babij P, Allen KM, Yaworsky PJ, Bex F, Recker RR (2004) Bone biomechanical properties in LRP5 mutant mice. Bone 35:162–169CrossRefPubMed

15.

Hens JR, Wilson KM, Dann P, Chen X, Horowitz MC, Wysolmerski JJ (2005) TOPGAL mice show that the canonical Wnt signaling pathway is active during bone development and growth and is activated by mechanical loading in vitro. J Bone Miner Res 20:1103–1113CrossRefPubMed

16.

Robinson JA, Chatterjee-Kishore M, Yaworsky PJ, Cullen DM, Zhao W, Li C, Kharode Y, Sauter L, Babij P, Brown EL, Hill AA, Akhter MP, Johnson ML, Recker RR, Komm BS, Bex FJ (2006) Wnt/beta-catenin signaling is a normal physiological response to mechanical loading in bone. J Biol Chem 281:31720–31728CrossRefPubMed

17.

Urano T, Shiraki M, Ezura Y, Fujita M, Sekine E, Hoshino S, Hosoi T, Orimo H, Emi M, Ouchi Y, Inoue S (2004) Association of a single-nucleotide polymorphism in low-density lipoprotein receptor-related protein 5 gene with bone mineral density. J Bone Miner Metab 22:341–345CrossRefPubMed

18.

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 36:599–606CrossRefPubMed

19.

Saarinen A, Valimaki VV, Valimaki MJ, Loyttyniemi E, Auro K, Uusen P, Kuris M, Lehesjoki AE, Makitie O (2007) The A1330 V polymorphism of the low-density lipoprotein receptor-related protein 5 gene (LRP5) associates with low peak bone mass in young healthy men. Bone 40:1006–1012CrossRefPubMed

20.

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):S14CrossRefPubMed

21.

Nissen N, Madsen JS, Bladbjerg EM, Beck Jensen JE, Jorgensen NR, Langdahl B, Abrahamsen B, Brixen K (2009) No association between hip geometry and four common polymorphisms associated with fracture: the Danish Osteoporosis Prevention Study. Calcif Tissue Int 84:276–285CrossRefPubMed

22.

Yerges LM, Zhang Y, Cauley JA, Kammerer CM, Nestlerode CS, Wheeler VW, Patrick AL, Bunker CH, Moffett SP, Ferrell RE, Zmuda JM (2009) Functional characterization of genetic variation in the Frizzled 1 (FZD1) promoter and association with bone phenotypes: more to the LRP5 story? J Bone Miner Res 24:87–96CrossRefPubMed

23.

Zmuda JM, Yerges LM, Kammerer CM, Cauley JA, Wang X, Nestlerode CS, Wheeler VW, Patrick AL, Bunker CH, Moffett SP, Ferrell RE (2009) Association analysis of WNT10B with bone mass and structure among individuals of African ancestry. J Bone Miner Res 24:437–447CrossRefPubMed

24.

Zhang Y, Wang Y, Li X, Zhang J, Mao J, Li Z, Zheng J, Li L, Harris S, Wu D (2004) The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with Mesd. Mol Cell Biol 24:4677–4684CrossRefPubMed

25.

Morvan F, Boulukos K, Clement-Lacroix P, Roman Roman S, Suc-Royer I, Vayssiere B, Ammann P, Martin P, Pinho S, Pognonec P, Mollat P, Niehrs C, Baron R, Rawadi G (2006) Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 21:934–945CrossRefPubMed

26.

MacDonald BT, Joiner DM, Oyserman SM, Sharma P, Goldstein SA, He X, Hauschka PV (2007) Bone mass is inversely proportional to Dkk1 levels in mice. Bone 41:331–339CrossRefPubMed

27.

Li J, Sarosi I, Cattley RC, Pretorius J, Asuncion F, Grisanti M, Morony S, Adamu S, Geng Z, Qiu W, Kostenuik P, Lacey DL, Simonet WS, Bolon B, Qian X, Shalhoub V, Ominsky MS, Zhu Ke H, Li X, Richards WG (2006) Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 39:754–766CrossRefPubMed

28.

Ohnaka K, Taniguchi H, Kawate H, Nawata H, Takayanagi R (2004) Glucocorticoid enhances the expression of dickkopf-1 in human osteoblasts: novel mechanism of glucocorticoid-induced osteoporosis. Biochem Biophys Res Commun 318:259–264CrossRefPubMed

29.

Ohnaka K, Tanabe M, Kawate H, Nawata H, Takayanagi R (2005) Glucocorticoid suppresses the canonical Wnt signal in cultured human osteoblasts. Biochem Biophys Res Commun 329:177–181CrossRefPubMed

30.

Lee N, Smolarz AJ, Olson S, David O, Reiser J, Kutner R, Daw NC, Prockop DJ, Horwitz EM, Gregory CA (2007) A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies. Br J Cancer 97:1552–1559CrossRefPubMed

31.

Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD Jr (2003) The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349:2483–2494CrossRefPubMed

32.

Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, Shaughnessy JD Jr (2007) Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 109:2106–2111CrossRefPubMed

33.

Hall CL, Kang S, MacDougald OA, Keller ET (2006) Role of Wnts in prostate cancer bone metastases. J Cell Biochem 97:661–672CrossRefPubMed

34.

Voorzanger-Rousselot N, Goehrig D, Journe F, Doriath V, Body JJ, Clezardin P, Garnero P (2007) Increased Dickkopf-1 expression in breast cancer bone metastases. Br J Cancer 97:964–970PubMed

35.

Nielsen TL, Wraae K, Brixen K, Hermann AP, Andersen M, Hagen C (2006) Prevalence of overweight, obesity and physical inactivity in 20- to 29-year-old, Danish men. Relation to sociodemography, physical dysfunction and low socioeconomic status: the Odense Androgen Study. Int J Obes (Lond) 30:805–815CrossRef

36.

Gardner JC, van Bezooijen RL, Mervis B, Hamdy NA, Lowik CW, Hamersma H, Beighton P, Papapoulos SE (2005) Bone mineral density in sclerosteosis; affected individuals and gene carriers. J Clin Endocrinol Metab 90:6392–6395CrossRefPubMed

37.

Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265CrossRefPubMed

38.

Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229CrossRefPubMed

39.

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 81:559–575CrossRefPubMed

40.

Ralston SH, Galwey N, MacKay I, Albagha OM, 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 14:943–951CrossRefPubMed

41.

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

42.

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 74:866–875CrossRefPubMed

43.

Kryukov GV, Pennacchio LA, Sunyaev SR (2007) Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am J Hum Genet 80:727–739CrossRefPubMed

44.

Pritchard JK (2001) Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet 69:124–137CrossRefPubMed

45.

Pritchard JK, Cox NJ (2002) The allelic architecture of human disease genes: common disease-common variant… or not? Hum Mol Genet 11:2417–2423CrossRefPubMed

46.

Pagani F, Baralle FE (2004) Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet 5:389–396CrossRefPubMed

47.

Ai M, Holmen SL, Van Hul W, Williams BO, Warman ML (2005) Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Mol Cell Biol 25:4946–4955CrossRefPubMed

48.

Balemans W, Devogelaer JP, Cleiren E, Piters E, Caussin E, Van Hul W (2007) Novel LRP5 missense mutation in a patient with a high bone mass phenotype results in decreased DKK1-mediated inhibition of Wnt signaling. J Bone Miner Res 22:708–716CrossRefPubMed

49.

Bhat BM, Allen KM, Liu W, Graham J, Morales A, Anisowicz A, Lam HS, McCauley C, Coleburn V, Cain M, Fortier E, Bhat RA, Bex FJ, Yaworsky PJ (2007) Structure-based mutation analysis shows the importance of LRP5 beta-propeller 1 in modulating Dkk1-mediated inhibition of Wnt signaling. Gene 391:103–112CrossRefPubMed

50.

Chen L, Wang K, Shao Y, Huang J, Li X, Shan J, Wu D, Zheng JJ (2008) Structural insight into the mechanisms of Wnt signaling antagonism by Dkk. J Biol Chem 283:23364–23370CrossRefPubMed

51.

Sims AM, Shephard N, Carter K, Doan T, Dowling A, Duncan EL, Eisman J, Jones G, Nicholson G, Prince R, Seeman E, Thomas G, Wass JA, Brown MA (2008) Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes. J Bone Miner Res 23:499–506CrossRefPubMed

52.

Seeman E (2001) Clinical review 137. Sexual dimorphism in skeletal size, density, and strength. J Clin Endocrinol Metab 86:4576–4584CrossRefPubMed

53.

Beck TJ, Looker AC, Ruff CB, Sievanen H, Wahner HW (2000) Structural trends in the aging femoral neck and proximal shaft: analysis of the Third National Health and Nutrition Examination Survey dual-energy X-ray absorptiometry data. J Bone Miner Res 15:2297–2304CrossRefPubMed

54.

Beck TJ, Oreskovic TL, Stone KL, Ruff CB, Ensrud K, Nevitt MC, Genant HK, Cummings SR (2001) Structural adaptation to changing skeletal load in the progression toward hip fragility: the study of osteoporotic fractures. J Bone Miner Res 16:1108–1119CrossRefPubMed

55.

Devlin MJ, Stetter CM, Lin HM, Beck TJ, Legro RS, Petit MA, Lieberman DE, Lloyd T (2009) Peripubertal estrogen levels and physical activity affect femur geometry in young adult women. Osteoporos Int. doi:10.1007/s00198-009-1000-4

56.

Burr DB (1997) Muscle strength, bone mass, and age-related bone loss. J Bone Miner Res 12:1547–1551CrossRefPubMed

57.

Duda GN, Heller M, Albinger J, Schulz O, Schneider E, Claes L (1998) Influence of muscle forces on femoral strain distribution. J Biomech 31:841–846CrossRefPubMed

58.

Brownbill RA, Ilich JZ (2003) Hip geometry and its role in fracture: what do we know so far? Curr Osteoporos Rep 1:25–31CrossRefPubMed

59.

Reid IR, Chin K, Evans MC, Jones JG (1994) Relation between increase in length of hip axis in older women between 1950s and 1990s and increase in age specific rates of hip fracture. BMJ 309:508–509PubMed

Title: 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
Authors: Elke Piters
Wendy Balemans
Torben Leo Nielsen
Marianne Andersen
Eveline Boudin
Kim Brixen
Wim Van Hul
Publication date: 01-04-2010
Publisher: Springer-Verlag
Published in: Calcified Tissue International / Issue 4/2010
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI: https://doi.org/10.1007/s00223-010-9334-7

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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

Abstract

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