AGE

, 36:9635

WNT3A gene polymorphisms are associated with bone mineral density variation in postmenopausal mestizo women of an urban Mexican population: findings of a pathway-based high-density single nucleotide screening

  • Rafael Velázquez-Cruz
  • Humberto García-Ortiz
  • Manuel Castillejos-López
  • Manuel Quiterio
  • Margarita Valdés-Flores
  • Lorena Orozco
  • Teresa Villarreal-Molina
  • Jorge Salmerón
Article

Abstract

Osteoporosis (OP) is a common skeletal disorder characterized by low bone mineral density (BMD) and is a common health problem in Mexico. To date, few genes affecting BMD variation in the Mexican population have been identified. The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) located in genes of the Wnt pathway with BMD variation at various skeletal sites in a cohort of postmenopausal Mexican women. A total of 121 SNPs in or near 15 Wnt signaling pathway genes and 96 ancestry informative markers were genotyped in 425 postmenopausal women using the Illumina GoldenGate microarray SNP genotyping method. BMD was measured by dual-energy X-ray absorptiometry in total hip, femoral neck, Ward’s triangle, and lumbar spine. Associations were tested by linear regression for quantitative traits adjusting for possible confounding factors. SNP rs752107 in WNT3A was strongly associated with decreased total hip BMD showing the highest significance under the recessive model (P = 0.00012). This SNP is predicted to disrupt a binding site for microRNA-149. In addition, a polymorphism of the Wnt antagonist DKK2 was associated with BMD in femoral neck under a recessive model (P = 0.009). Several LRP4, LRP5, and LRP6 gene variants showed site-specific associations with BMD. In conclusion, this is the first report associating Wnt pathway gene variants with BMD in the Mexican population.

Keywords

Bone mineral density Polymorphisms Wnt pathway Postmenopausal Mexican women 

Supplementary material

11357_2014_9635_MOESM1_ESM.doc (306 kb)
ESM 1(DOC 305 kb)

References

  1. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265PubMedCrossRefGoogle Scholar
  2. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:1513–1521PubMedCrossRefGoogle Scholar
  3. Butler JS, Murray DW, Hurson CJ, O’Brien J, Doran PP, O’Byrne JM (2011) The role of Dkk1 in bone mass regulation: correlating serum Dkk1 expression with bone mineral density. J Orthop Res 29:414–418PubMedCrossRefGoogle Scholar
  4. Cardon LR, Palmer LJ (2003) Population stratification and spurious allelic association. Lancet 361:598–604PubMedCrossRefGoogle Scholar
  5. Clark P, Carlos F, Vázquez Martínez JL (2010) Epidemiology, costs and burden of osteoporosis in Mexico. Arch Osteoporos 5:9–17CrossRefGoogle Scholar
  6. de Bakker PI, Yelensky R, Pe’er I, Gabriel SB, Daly MJ, Altshuler D (2005) Efficiency and power in genetic association studies. Nat Genet 37:1217–1223PubMedCrossRefGoogle Scholar
  7. Delezé M, Cons-Molina F, Villa AR, Morales-Torres J, Gonzalez-Gonzalez JG, Calva JJ, Murillo A, Briceño A, Orozco J, Morales-Franco G, Peña-Rios H, Guerrero-Yeo G, Aguirre E, Elizondo J (2000) Geographic differences in bone mineral density of Mexican women. Osteoporos Int 11:562–569PubMedCrossRefGoogle Scholar
  8. Denova-Gutiérrez E, Castañón S, Talavera JO, Flores M, Macías N, Rodríguez-Ramírez S, Flores YN, Salmerón J (2011) Dietary patterns are associated with different indexes of adiposity and obesity in an urban Mexican population. J Nutr 141:921–927PubMedCrossRefGoogle Scholar
  9. Devlin B, Roeder K (1999) Genomic control for association studies. Biometrics 55:997–1004PubMedCrossRefGoogle Scholar
  10. Díaz-Prado S, Cicione C, Muiños-López E, Hermida-Gómez T, Oreiro N, Fernández-López C, Blanco FJ (2012) Characterization of microRNA expression profiles in normal and osteoarthritic human chondrocytes. BMC Musculoskelet Disord 13:144PubMedCentralPubMedCrossRefGoogle Scholar
  11. Duncan EL, Brown MA (2010) Genetic determinants of bone density and fracture risk—state of the art and future directions. J Clin Endocrinol Metab 95:2576–2587PubMedCrossRefGoogle Scholar
  12. Estrada K, Styrkarsdottir U, Evangelou E, Hsu YH, Duncan EL, Ntzani EE, Oei L, Albagha OM, Amin N, Kemp JP, Koller DL, Li G, Liu CT, Minster RL, Moayyeri A, Vandenput L, Willner D, Xiao SM, Yerges-Armstrong LM, Zheng HF, Alonso N, Eriksson J, Kammerer CM, Kaptoge SK, Leo PJ, Thorleifsson G, Wilson SG, Wilson JF, Aalto V, Alen M, Aragaki AK, Aspelund T, Center JR, Dailiana Z, Duggan DJ, Garcia M, Garcia-Giralt N, Giroux S, Hallmans G, Hocking LJ, Husted LB, Jameson KA, Khusainova R, Kim GS, Kooperberg C, Koromila T, Kruk M, Laaksonen M, Lacroix AZ, Lee SH, Leung PC, Lewis JR, Masi L, Mencej-Bedrac S, Nguyen TV, Nogues X, Patel MS, Prezelj J, Rose LM, Scollen S, Siggeirsdottir K, Smith AV, Svensson O, Trompet S, Trummer O, van Schoor NM, Woo J, Zhu K, Balcells S, Brandi ML, Buckley BM, Cheng S, Christiansen C, Cooper C, Dedoussis G, Ford I, Frost M, Goltzman D, González-Macías J, Kähönen M, Karlsson M, Khusnutdinova E, Koh JM, Kollia P, Langdahl BL, Leslie WD, Lips P, Ljunggren Ö, Lorenc RS, Marc J, Mellström D, Obermayer-Pietsch B, Olmos JM, Pettersson-Kymmer U, Reid DM, Riancho JA, Ridker PM, Rousseau F, Slagboom PE, Tang NL, Urreizti R, Van Hul W, Viikari J, Zarrabeitia MT, Aulchenko YS, Castano-Betancourt M, Grundberg E, Herrera L, Ingvarsson T, Johannsdottir H, Kwan T, Li R, Luben R, Medina-Gómez C, Palsson ST, Reppe S, Rotter JI, Sigurdsson G, van Meurs JB, Verlaan D, Williams FM, Wood AR, Zhou Y, Gautvik KM, Pastinen T, Raychaudhuri S, Cauley JA, Chasman DI, Clark GR, Cummings SR, Danoy P, Dennison EM, Eastell R, Eisman JA, Gudnason V, Hofman A, Jackson RD, Jones G, Jukema JW, Khaw KT, Lehtimäki T, Liu Y, Lorentzon M, McCloskey E, Mitchell BD, Nandakumar K, Nicholson GC, Oostra BA, Peacock M, Pols HA, Prince RL, Raitakari O, Reid IR, Robbins J, Sambrook PN, Sham PC, Shuldiner AR, Tylavsky FA, van Duijn CM, Wareham NJ, Cupples LA, Econs MJ, Evans DM, Harris TB, Kung AW, Psaty BM, Reeve J, Spector TD, Streeten EA, Zillikens MC, Thorsteinsdottir U, Ohlsson C, Karasik D, Richards JB, Brown MA, Stefansson K, Uitterlinden AG, Ralston SH, Ioannidis JP, Kiel DP, Rivadeneira F (2012) Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 44:491–501PubMedCentralPubMedCrossRefGoogle Scholar
  13. Falcón-Ramírez E, Casas-Avila L, Miranda A, Diez P, Castro C, Rubio J, Gómez R, Valdés-Flores M (2011) Sp1 polymorphism in collagen I α1 gene is associated with osteoporosis in lumbar spine of Mexican women. Mol Biol Rep 38:2987–2992PubMedCrossRefGoogle Scholar
  14. Falcón-Ramírez E, Casas-Avila L, Cerda-Flores RM, Castro-Hernández C, Rubio-Lightbourn J, Velázquez-Cruz R, Diez-G P, Peñaloza-Espinosa R, Valdés-Flores M (2013) Association of LRP5 haplotypes with osteoporosis in Mexican women. Mol Biol Rep 40:2705–2710PubMedCrossRefGoogle Scholar
  15. Gauderman W, Morrison J (2006) QUANTO 1.1: a computer program for power and sample size calculations for genetic-epidemiology studies. http://hydra.usc.edu/gxe. Accessed June 2013
  16. Gómez R, Magaña JJ, Cisneros B, Pérez-Salazar E, Faugeron S, Véliz D, Castro C, Rubio J, Casas L, Valdés-Flores M (2007) Association of the estrogen receptor alpha gene polymorphisms with osteoporosis in the Mexican population. Clin Genet 72:574–581PubMedCrossRefGoogle Scholar
  17. Hu W, Ye Y, Zhang W, Wang J, Chen A, Guo F (2013) miR-142-3p promotes osteoblast differentiation by modulating Wnt signaling. Mol Med Rep 7:689–693PubMedGoogle Scholar
  18. Korvala J, Löija M, Mäkitie O, Sochett E, Jüppner H, Schnabel D, Mora S, Cole WG, Ala-Kokko L, Männikkö M (2012) Rare variations in WNT3A and DKK1 may predispose carriers to primary osteoporosis. Eur J Med Genet 55:515–519PubMedCrossRefGoogle Scholar
  19. Kosoy R, Nassir R, Tian C, White PA, Butler LM, Silva G, Kittles R, Alarcon-Riquelme ME, Gregersen PK, Belmont JW, De La Vega FM, Seldin MF (2009) Ancestry informative marker sets for determining continental origin and admixture proportions in common populations in America. Hum Mutat 30:69–78PubMedCentralPubMedCrossRefGoogle Scholar
  20. Lazcano-Ponce E, Tamayo J, Díaz R, Burguete AI, Salmerón J (2009) Correlation trends for bone mineral density in Mexican women: evidence of familiar predisposition. Salud Publica Mex 51(Suppl 1):s93–s99PubMedCrossRefGoogle Scholar
  21. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG (2009) Association between the A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 gene and bone mineral density: a meta-analysis. Rheumatol Int 29:539–544PubMedCrossRefGoogle Scholar
  22. Lei SF, Papasian CJ, Deng HW (2011) Polymorphisms in predicted miRNA binding sites and osteoporosis. J Bone Miner Res 26:72–78PubMedCentralPubMedCrossRefGoogle Scholar
  23. Lisker R, López MA, Jasqui S, Ponce De León Rosales S, Correa-Rotter R, Sánchez S, Mutchinick OM (2003) Association of vitamin D receptor polymorphisms with osteoporosis in Mexican postmenopausal women. Hum Biol 75:399–403PubMedCrossRefGoogle Scholar
  24. Liu YJ, Zhang L, Pei Y, Papasian CJ, Deng HW (2013) On genome-wide association studies and their meta-analyses: lessons learned from osteoporosis studies. J Clin Endocrinol Metab 98:E1278–E1282PubMedCentralPubMedCrossRefGoogle Scholar
  25. Magaña JJ, Gómez R, Cisneros B, Casas L, Valdés-Flores M (2008) Association of interleukin-6 gene polymorphisms with bone mineral density in Mexican women. Arch Med Res 39:618–624PubMedCrossRefGoogle Scholar
  26. Mencej-Bedrac S, Prezelj J, Kocjan T, Komadina R, Marc J (2009) Analysis of association of LRP5, LRP6, SOST, DKK1, and CTNNB1 genes with bone mineral density in a Slovenian population. Calcif Tissue Int 85:501–506PubMedCrossRefGoogle Scholar
  27. Monroe DG, McGee-Lawrence ME, Oursler MJ, Westendorf JJ (2012) Update on Wnt signaling in bone cell biology and bone disease. Gene 492:1–18PubMedCentralPubMedCrossRefGoogle Scholar
  28. Nam HS, Kweon SS, Choi JS, Zmuda JM, Leung PC, Lui LY, Hill DD, Patrick AL, Cauley JA (2013) Racial/ethnic differences in bone mineral density among older women. J Bone Miner Metab 31:190–198PubMedCrossRefGoogle Scholar
  29. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy (2001) Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785–795CrossRefGoogle Scholar
  30. Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74:765–769PubMedCentralPubMedCrossRefGoogle Scholar
  31. Patterson N, Price AL, Reich D (2006) Population structure and eigenanalysis. PLoS Genet 2:e190PubMedCentralPubMedCrossRefGoogle Scholar
  32. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909PubMedCrossRefGoogle Scholar
  33. Price AL, Patterson N, Yu F, Cox DR, Waliszewska A, McDonald GJ, Tandon A, Schirmer C, Neubauer J, Bedoya G, Duque C, Villegas A, Bortolini MC, Salzano FM, Gallo C, Mazzotti G, Tello-Ruiz M, Riba L, Aguilar-Salinas CA, Canizales-Quinteros S, Menjivar M, Klitz W, Henderson B, Haiman CA, Winkler C, Tusie-Luna T, Ruiz-Linares A, Reich D (2007) A genome wide admixture map for Latino populations. Am J Hum Genet 80:1024–1036PubMedCentralPubMedCrossRefGoogle Scholar
  34. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC (2007) PLINK: a toolset for whole-genome association and population-based linkage analysis. Am J Hum Genet 81:559–575PubMedCentralPubMedCrossRefGoogle Scholar
  35. Qiu W, Chen L, Kassem M (2011) Activation of non-canonical Wnt/JNK pathway by Wnt3a is associated with differentiation fate determination of human bone marrow stromal (mesenchymal) stem cells. Biochem Biophys Res Commun 413:98–104PubMedCrossRefGoogle Scholar
  36. Ralston SH, de Crombrugghe B (2006) Genetic regulation of bone mass and susceptibility to osteoporosis. Genes Dev 20:2492–2506PubMedCrossRefGoogle Scholar
  37. 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 371:1505–1512PubMedCentralPubMedCrossRefGoogle Scholar
  38. Rivadeneira F, Styrkársdottir U, Estrada K, Halldórsson BV, Hsu YH, Richards JB, Zillikens MC, Kavvoura FK, Amin N, Aulchenko YS, Cupples LA, Deloukas P, Demissie S, Grundberg E, Hofman A, Kong A, Karasik D, van Meurs JB, Oostra B, Pastinen T, Pols HA, Sigurdsson G, Soranzo N, Thorleifsson G, Thorsteinsdottir U, Williams FM, Wilson SG, Zhou Y, Ralston SH, van Duijn CM, Spector T, Kiel DP, Stefansson K, Ioannidis JP, Uitterlinden AG, Genetic Factors for Osteoporosis (GEFOS) Consortium (2009) Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41:1199–1206PubMedCentralPubMedCrossRefGoogle Scholar
  39. Rojano-Mejía D, Coral-Vázquez RM, Espinosa LC, López-Medina G, Aguirre-García MC, Coronel A, Canto P (2013) JAG1 and COL1A1 polymorphisms and haplotypes in relation to bone mineral density variations in postmenopausal Mexican-Mestizo Women. Age (Dordr) 35:471–478CrossRefGoogle Scholar
  40. Silva-Zolezzi I, Hidalgo-Miranda A, Estrada-Gil J, Fernandez-Lopez JC, Uribe-Figueroa L, Contreras A, Balam-Ortiz E, del Bosque-Plata L, Velazquez-Fernandez D, Lara C, Goya R, Hernandez-Lemus E, Davila C, Barrientos E, March S, Jimenez-Sanchez G (2009) Analysis of genomic diversity in Mexican Mestizo populations to develop genomic medicine in Mexico. Proc Natl Acad Sci U S A 106:8611–8616PubMedCentralPubMedCrossRefGoogle Scholar
  41. 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 23:499–506PubMedCrossRefGoogle Scholar
  42. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Center JR, Nguyen TV, Bagger Y, Gulcher JR, Eisman JA, Christiansen C, Sigurdsson G, Kong A, Thorsteinsdottir U, Stefansson K (2008) Multiple genetic loci for bone mineral density and fractures. N Engl J Med 358:2355–2365PubMedCrossRefGoogle Scholar
  43. Tran BN, Nguyen ND, Eisman JA, Nguyen TV (2008) Association between LRP5 polymorphism and bone mineral density: a Bayesian meta-analysis. BMC Med Genet 9:55PubMedCentralPubMedCrossRefGoogle Scholar
  44. 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, Mellström D, Mosekilde L, Nogues X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Weber K, Ioannidis JP, Uitterlinden AG, GENOMOS Study (2008) Large scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA 299:1277–1290PubMedCentralPubMedCrossRefGoogle Scholar
  45. Wu S, Liu Y, Zhang L, Han Y, Lin Y, Deng HW (2013) Genome-wide approaches for identifying genetic risk factors for osteoporosis. Genome Med 5:44PubMedCentralPubMedCrossRefGoogle Scholar
  46. Yerges LM, Klei L, Cauley JA, Roeder K, Kammerer CM, Ensrud KE, Nestlerode CS, Lewis C, Lang TF, Barrett-Connor E, Moffett SP, Hoffman AR, Ferrell RE, Orwoll ES, Zmuda JM (2010) Candidate gene analysis of femoral neck trabecular and cortical volumetric bone mineral density in older men. J Bone Miner Res 25:330–338PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© American Aging Association 2014

Authors and Affiliations

  • Rafael Velázquez-Cruz
    • 1
  • Humberto García-Ortiz
    • 2
  • Manuel Castillejos-López
    • 3
  • Manuel Quiterio
    • 4
  • Margarita Valdés-Flores
    • 5
  • Lorena Orozco
    • 2
  • Teresa Villarreal-Molina
    • 6
  • Jorge Salmerón
    • 7
  1. 1.Laboratorio de Genómica del Metabolismo ÓseoInstituto Nacional de Medicina GenómicaMéxicoMéxico
  2. 2.Laboratorio de Inmunogenómica y Enfermedades MetabolicasInstituto Nacional de Medicina GenómicaMéxicoMéxico
  3. 3.Unidad de Vigilancia Epidemiológica HospitalariaInstituto Nacional de Enfermedades RespiratoriasMéxicoMéxico
  4. 4.Centro de Investigación en Salud PoblacionalInstituto Nacional de salud PúblicaCuernavacaMéxico
  5. 5.Servicio de GenéticaInstituto Nacional de RehabilitaciónMéxicoMéxico
  6. 6.Laboratorio de Enfermedades CardiovascularesInstituto Nacional de Medicina GenómicaMéxicoMéxico
  7. 7.Unidad de Investigación Epidemiológica y en Servicios de SaludInstituto Mexicano del Seguro SocialCuernavacaMéxico

Personalised recommendations