Abstract
Because of the importance of the Wnt pathway in the development and maintenance of both adipose and bone tissue, we wanted to evaluate the involvement of WNT10B, a Wnt pathway activator, in adipogenesis and osteoblastogenesis in humans. Genetic association between WNT10B polymorphisms and adiposity parameters as well as bone mineral density (BMD) measurements was analysed in two independent populations. The first is a population of 1,228 Danish men (702 aged 20–29 years; 532 aged 60–74 years) from the Odense Androgen Study (OAS), which was designed as a cross-sectional, population-based study. The second population, called SIBLOS, includes 922 Belgian men (34 ± 5 years old) and contains siblings selected from over 500 families. Four tagSNPs (rs833840, rs833841, rs10875902 and rs4018511) that capture variation of ten SNPs (MAF > 5 %) in a 15.2 kb region spanning the WNT10B gene and its flanking regions were genotyped. Although no association with body mass index was found, we found all tagSNPs to be associated with BMD parameters (BMD whole body, total hip and femoral neck) and height in the OAS population. The association of rs10875902 was most prominent (nominal p = 0.012) and confirmed a previously shown negative effect on BMD. No significant associations were observed in the SIBLOS population. In the present study, no association between WNT10B polymorphisms and adiposity parameters was found. However, our results clearly illustrate a role for WNT10B variants in determining human BMD. The effect of WNT10B polymorphisms on height should be evaluated in additional populations.
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References
S.E. Ross, N. Hemati, K.A. Longo, C.N. Bennett, P.C. Lucas, R.L. Erickson, O.A. MacDougald, Inhibition of adipogenesis by Wnt signaling. Science 289(5481), 950–953 (2000)
G. Musso, Non-alcoholic fatty liver, adipose tissue, and the bone: a new triumvirate on the block. Endocrine 42(2), 237–239 (2012)
WHO, World Health Organisation-Obesity (2012), http://www.who.int/topics/obesity/en/. Accessed 22 Aug 2012
G.A. Colditz, W.C. Willett, A. Rotnitzky, J.E. Manson, Weight gain as a risk factor for clinical diabetes mellitus in women. Ann. Intern. Med. 122(7), 481–486 (1995)
M. Montaye, D. De Bacquer, G. De Backer, P. Amouyel, Overweight and obesity: a major challenge for coronary heart disease secondary prevention in clinical practice in Europe. Eur. Heart J. 21(10), 808–813 (2000)
L.F. Van Gaal, I.L. Mertens, C.E. De Block, Mechanisms linking obesity with cardiovascular disease. Nature 444(7121), 875–880 (2006)
A. Bergstrom, P. Pisani, V. Tenet, A. Wolk, H.O. Adami, Overweight as an avoidable cause of cancer in Europe. Int. J. Cancer 91(3), 421–430 (2001)
A.J. Stunkard, T.I. Sorensen, C. Hanis, T.W. Teasdale, R. Chakraborty, W.J. Schull, F. Schulsinger, An adoption study of human obesity. N. Engl. J. Med. 314(4), 193–198 (1986)
A.J. Stunkard, J.R. Harris, N.L. Pedersen, G.E. McClearn, The body–mass index of twins who have been reared apart. N. Engl. J. Med. 322(21), 1483–1487 (1990)
H.H. Maes, M.C. Neale, L.J. Eaves, Genetic and environmental factors in relative body weight and human adiposity. Behav. Genet. 27(4), 325–351 (1997)
A. Scuteri, S. Sanna, W.M. Chen, M. Uda, G. Albai, J. Strait, S. Najjar, R. Nagaraja, M. Orru, G. Usala, M. Dei, S. Lai, A. Maschio, F. Busonero, A. Mulas, G.B. Ehret, A.A. Fink, A.B. Weder, R.S. Cooper, P. Galan, A. Chakravarti, D. Schlessinger, A. Cao, E. Lakatta, G.R. Abecasis, Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 3(7), e115 (2007)
R.J. Loos, C.M. Lindgren, S. Li, E. Wheeler, J.H. Zhao, I. Prokopenko, M. Inouye, R.M. Freathy, A.P. Attwood, J.S. Beckmann, S.I. Berndt, K.B. Jacobs, S.J. Chanock, R.B. Hayes, S. Bergmann, A.J. Bennett, S.A. Bingham, M. Bochud, M. Brown, S. Cauchi, J.M. Connell, C. Cooper, G.D. Smith, I. Day, C. Dina, S. De, E.T. Dermitzakis, A.S. Doney, K.S. Elliott, P. Elliott, D.M. Evans, I. Sadaf Farooqi, P. Froguel, J. Ghori, C.J. Groves, R. Gwilliam, D. Hadley, A.S. Hall, A.T. Hattersley, J. Hebebrand, I.M. Heid, C. Lamina, C. Gieger, T. Illig, T. Meitinger, H.E. Wichmann, B. Herrera, A. Hinney, S.E. Hunt, M.R. Jarvelin, T. Johnson, J.D. Jolley, F. Karpe, A. Keniry, K.T. Khaw, R.N. Luben, M. Mangino, J. Marchini, W.L. McArdle, R. McGinnis, D. Meyre, P.B. Munroe, A.D. Morris, A.R. Ness, M.J. Neville, A.C. Nica, K.K. Ong, S. O’Rahilly, K.R. Owen, C.N. Palmer, K. Papadakis, S. Potter, A. Pouta, L. Qi, J.C. Randall, N.W. Rayner, S.M. Ring, M.S. Sandhu, A. Scherag, M.A. Sims, K. Song, N. Soranzo, E.K. Speliotes, H.E. Syddall, S.A. Teichmann, N.J. Timpson, J.H. Tobias, M. Uda, C.I. Vogel, C. Wallace, D.M. Waterworth, M.N. Weedon, C.J. Willer, Wraight, X. Yuan, E. Zeggini, J.N. Hirschhorn, D.P. Strachan, W.H. Ouwehand, M.J. Caulfield, N.J. Samani, T.M. Frayling, P. Vollenweider, G. Waeber, V. Mooser, P. Deloukas, M.I. McCarthy, N.J. Wareham, I. Barroso, K.B. Jacobs, S.J. Chanock, R.B. Hayes, C. Lamina, C. Gieger, T. Illig, T. Meitinger, H.E. Wichmann, P. Kraft, S.E. Hankinson, D.J. Hunter, F.B. Hu, H.N. Lyon, B.F. Voight, M. Ridderstrale, L. Groop, P. Scheet, S. Sanna, G.R. Abecasis, G. Albai, R. Nagaraja, D. Schlessinger, A.U. Jackson, J. Tuomilehto, F.S. Collins, M. Boehnke, K.L. Mohlke, Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat. Genet. 40(6), 768–775 (2008)
M. den Hoed, U. Ekelund, S. Brage, A. Grontved, J.H. Zhao, S.J. Sharp, K.K. Ong, N.J. Wareham, R.J. Loos, Genetic susceptibility to obesity and related traits in childhood and adolescence: influence of loci identified by genome-wide association studies. Diabetes 59(11), 2980–2988 (2010)
C.M. Lindgren, I.M. Heid, J.C. Randall, C. Lamina, V. Steinthorsdottir, L. Qi, E.K. Speliotes, G. Thorleifsson, C.J. Willer, B.M. Herrera, A.U. Jackson, N. Lim, P. Scheet, N. Soranzo, N. Amin, Y.S. Aulchenko, J.C. Chambers, A. Drong, J. Luan, H.N. Lyon, F. Rivadeneira, S. Sanna, N.J. Timpson, M.C. Zillikens, J.H. Zhao, P. Almgren, S. Bandinelli, A.J. Bennett, R.N. Bergman, L.L. Bonnycastle, S.J. Bumpstead, S.J. Chanock, L. Cherkas, P. Chines, L. Coin, C. Cooper, G. Crawford, A. Doering, A. Dominiczak, A.S. Doney, S. Ebrahim, P. Elliott, M.R. Erdos, K. Estrada, L. Ferrucci, G. Fischer, N.G. Forouhi, C. Gieger, H. Grallert, C.J. Groves, S. Grundy, C. Guiducci, D. Hadley, A. Hamsten, A.S. Havulinna, A. Hofman, R. Holle, J.W. Holloway, T. Illig, B. Isomaa, L.C. Jacobs, K. Jameson, P. Jousilahti, F. Karpe, J. Kuusisto, J. Laitinen, G.M. Lathrop, D.A. Lawlor, M. Mangino, W.L. McArdle, T. Meitinger, M.A. Morken, A.P. Morris, P. Munroe, N. Narisu, A. Nordstrom, P. Nordstrom, B.A. Oostra, C.N. Palmer, F. Payne, J.F. Peden, I. Prokopenko, F. Renstrom, A. Ruokonen, V. Salomaa, M.S. Sandhu, L.J. Scott, A. Scuteri, K. Silander, K. Song, X. Yuan, H.M. Stringham, A.J. Swift, T. Tuomi, M. Uda, P. Vollenweider, G. Waeber, C. Wallace, G.B. Walters, M.N. Weedon, J.C. Witteman, C. Zhang, W. Zhang, M.J. Caulfield, F.S. Collins, G. Davey Smith, I.N. Day, P.W. Franks, A.T. Hattersley, F.B. Hu, M.R. Jarvelin, A. Kong, J.S. Kooner, M. Laakso, E. Lakatta, V. Mooser, A.D. Morris, L. Peltonen, N.J. Samani, T.D. Spector, D.P. Strachan, T. Tanaka, J. Tuomilehto, A.G. Uitterlinden, C.M. van Duijn, N.J. Wareham, W. Hugh, D.M. Waterworth, M. Boehnke, P. Deloukas, L. Groop, D.J. Hunter, U. Thorsteinsdottir, D. Schlessinger, H.E. Wichmann, T.M. Frayling, G.R. Abecasis, J.N. Hirschhorn, R.J. Loos, K. Stefansson, K.L. Mohlke, I. Barroso, M.I. McCarthy, Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution. PLoS Genet. 5(6), e1000508 (2009)
D. Zegers, S. Beckers, I.L. Mertens, L.F. Van Gaal, W. Van Hul, Association between polymorphisms of the Nesfatin gene, NUCB2, and obesity in men. Mol. Genet. Metab. 103(3), 282–286 (2011)
G. Mazziotti, J. Bilezikian, E. Canalis, D. Cocchi, A. Giustina, New understanding and treatments for osteoporosis. Endocrine 41(1), 58–69 (2012)
P. Bhanot, M. Brink, C.H. Samos, J.C. Hsieh, Y. Wang, J.P. Macke, D. Andrew, J. Nathans, R. Nusse, A new member of the frizzled family from Drosophila functions as a wingless receptor. Nature 382(6588), 225–230 (1996)
A. Bejsovec, Wnt signalling: an embarrassment of receptors. Curr. Biol. 10(24), R919–R922 (2000)
J. Papkoff, B. Rubinfeld, B. Schryver, P. Polakis, Wnt-1 regulates free pools of catenins and stabilizes APC–catenin complexes. Mol. Cell. Biol. 16(5), 2128–2134 (1996)
C.N. Bennett, S.E. Ross, K.A. Longo, L. Bajnok, N. Hemati, K.W. Johnson, S.D. Harrison, O.A. MacDougald, Regulation of Wnt signalling during adipogenesis. J. Biol. Chem. 277(34), 30998–31004 (2002)
C.N. Bennett, K.A. Longo, W.S. Wright, L.J. Suva, T.F. Lane, K.D. Hankenson, O.A. MacDougald, Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc. Natl. Acad. Sci. USA. 102(9), 3324–3329 (2005)
K.A. Longo, W.S. Wright, S. Kang, I. Gerin, S.H. Chiang, P.C. Lucas, M.R. Opp, O.A. MacDougald, Wnt10b inhibits development of white and brown adipose tissues. J. Biol. Chem. 279(34), 35503–35509 (2004)
W.S. Wright, K.A. Longo, V.W. Dolinsky, I. Gerin, S. Kang, C.N. Bennett, S.H. Chiang, T.C. Prestwich, C. Gress, C.F. Burant, V.S. Susulic, O.A. MacDougald, Wnt10b inhibits obesity in ob/ob and agouti mice. Diabetes 56(2), 295–303 (2007)
I.C. Kim, M.H. Cha, D.M. Kim, H. Lee, J.S. Moon, S.M. Choi, K.S. Kim, Y. Yoon, A functional promoter polymorphism −607G>C of WNT10B is associated with abdominal fat in Korean female subjects. J. Nutr. Biochem. 22(3), 252–258 (2011)
J.M. Zmuda, L.M. Yerges, C.M. Kammerer, J.A. Cauley, X. Wang, C.S. Nestlerode, V.W. Wheeler, A.L. Patrick, C.H. Bunker, S.P. Moffett, R.E. Ferrell, Association analysis of WNT10B with bone mass and structure among individuals of African ancestry. J. Bone Miner. Res. 24(3), 437–447 (2009)
J.K. Van Camp, S. Beckers, D. Zegers, A. Verrijken, L.F. Van Gaal, W. Van Hul, Genetic association between WNT10B polymorphisms and obesity in a Belgian case–control population is restricted to males. Mol. Genet. Metab. 105(3), 489–493 (2012)
T.L. Nielsen, K. Wraae, K. Brixen, A.P. Hermann, M. Andersen, C. Hagen, 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. 30(5), 805–815 (2006)
M. Frost, K. Wraae, C. Gudex, T. Nielsen, K. Brixen, C. Hagen, M. Andersen, Chronic diseases in elderly men: underreporting and underdiagnosis. Age Ageing 41(2), 177–183 (2012)
B.M. Lapauw, Y. Taes, V. Bogaert, G. Vanbillemont, S. Goemaere, H.G. Zmierczak, D. De Bacquer, J.M. Kaufman, Serum estradiol is associated with volumetric BMD and modulates the impact of physical activity on bone size at the age of peak bone mass: a study in healthy male siblings. J. Bone Miner. Res. 24(6), 1075–1085 (2009)
The International HapMap Consortium, The international HapMap project. Nature 426(6968), 789–796 (2003)
P.I. de Bakker, R. Yelensky, I. Pe’er, S.B. Gabriel, M.J. Daly, D. Altshuler, Efficiency and power in genetic association studies. Nat. Genet. 37(11), 1217–1223 (2005)
J. Ott, Documentation to LINKAGE UTILITY programs, http://linkage.rockefeller.edu/ott/linkutil.htm. Accessed 10 Feb 2011
S. Purcell, B. Neale, K. Todd-Brown, L. Thomas, M.A. Ferreira, D. Bender, J. Maller, P. Sklar, P.I. de Bakker, M.J. Daly, P.C. Sham, PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81(3), 559–575 (2007)
C.N. Bennett, H. Ouyang, Y.L. Ma, Q. Zeng, I. Gerin, K.M. Sousa, T.F. Lane, V. Krishnan, K.D. Hankenson, O.A. MacDougald, Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation. J. Bone Miner. Res. 22(12), 1924–1932 (2007)
S. Ferrari, Human genetics of osteoporosis. Best Pract. Res. 22(5), 723–735 (2008)
F. Rivadeneira, Hunting osteoporosis susceptibility genes: bigger is better but diverse is also welcome. Endocrine (2012). doi:10.1007/s12020-012-9804-y
Acknowledgments
This work was supported by a TOP-research grant from the University of Antwerp to WVH. The study was also funded by a PhD grant of the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen) to DZ and EB. SB holds a postdoctoral fellowship obtained from the Flemish Fund for Scientific Research (F.W.O. Vlaanderen).
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Van Camp, J.K., Beckers, S., Zegers, D. et al. Genetic association study of WNT10B polymorphisms with BMD and adiposity parameters in Danish and Belgian males. Endocrine 44, 247–254 (2013). https://doi.org/10.1007/s12020-012-9869-7
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DOI: https://doi.org/10.1007/s12020-012-9869-7