Abstract
The purpose of this study was to identify relationships between single nucleotide polymorphisms (SNPs) in the genes of the Wnt pathway and bone mineral density (BMD) of postmenopausal women. We chose this pathway due to its importance in bone metabolism that was underlined in several studies. DNA samples of 932 Hungarian postmenopausal women were studied. First, their BMD values at different sites (spine, total hip) were measured, using a Lunar Prodigy DXA scanner. Thereafter, T-score values and the patients’ body mass indices (BMIs) were calculated, while information about the fracture history of the sample population was also collected. We genotyped nine SNPs of the following three genes: LRP5, GPR177, and SP7, using a Sequenom MassARRAY Analyzer 4 instrument. The genomic DNA samples used for genotyping were extracted from the buccal mucosa of the subjects. Statistical analyses were carried out using the SPSS 21 and R package. The results of this analysis showed a significant association between SNP rs4988300 of the LRP5 gene and total hip BMD values. We could not reveal any associations between the markers of GPR177, SP7, and bone phenotypes. We found no effect of these genotypes on fracture risk. We could demonstrate a significant gene–gene interaction between two SNPs of LRP5 (rs4988300 and rs634008, p = 0.009) which was lost after Bonferroni correction. We could firmly demonstrate a significant association between rs4988300 of the LRP5 gene and bone density of the hip on the largest homogeneous postmenopausal study group analyzed to date. Our finding corroborates the relationship between LRP5 genotype and bone phenotype in postmenopausal women, however, the complete mechanism of this relationship requires further investigations.
Similar content being viewed by others
References
Zaidi M (2007) Skeletal remodeling in health and disease. Nat Med 13:791–801
Hsu YH, Kiel DP (2012) Clinical review: genome-wide association studies of skeletal phenotypes: what we have learned and where we are headed. J Clin Endocrinol Metab 97:E1958–E1977
Paternoster L, Lorentzon M, Vandenput L et al (2010) Genome-wide association meta-analysis of cortical bone mineral density unravels allelic heterogeneity at the RANKL locus and potential pleiotropic effects on bone. PLoS Genet 6:e1001217
Takacs I, Lazary A, Kosa JP et al (2010) Allelic variations of RANKL/OPG signaling system are related to bone mineral density and in vivo gene expression. Eur J Endocrinol 162:423–431
Lazary A, Kosa JP, Tobias B et al (2008) Single nucleotide polymorphisms in new candidate genes are associated with bone mineral density and fracture risk. Eur J Endocrinol 159:187–196
Kumar J, Swanberg M, McGuigan F, Callreus M, Gerdhem P, Akesson K (2011) LRP4 association to bone properties and fracture and interaction with genes in the Wnt- and BMP signaling pathways. Bone 49:343–348
Li X, Grisanti M, Fan W et al (2011) Dickkopf-1 regulates bone formation in young growing rodents and upon traumatic injury. J Bone Miner Res 26:2610–2621
Wend P, Wend K, Krum SA, Miranda-Carboni GA (2012) The role of WNT10B in physiology and disease. Acta Physiol (Oxf) 204:34–51
Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192
Maeda K, Takahashi N, Kobayashi Y (2013) Roles of Wnt signals in bone resorption during physiological and pathological states. J Mol Med (Berl) 91:15–23
Regard JB, Zhong Z, Williams BO, Yang Y (2012) Wnt signaling in bone development and disease: making stronger bone with Wnts. Cold Spring Harb Perspect Biol 4:a007997
Day TF, Guo X, Garrett-Beal L, Yang Y (2005) Wnt/β-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8:739–750
Gong Y, Slee RB, Fukai N et al (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523
He X, Semenov M, Tamai K, Zeng X (2004) LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: arrows point the way. Development 131:1663–1677
Yadav VK, Ryu JH, Suda N et al (2008) Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135:825–837
Ichikawa S, Koller DL, Padgett LR, Lai D, Hui SL, Peacock M, Foroud T, Econs MJ (2010) Replication of previous genome-wide association studies of bone mineral density in premenopausal American women. J Bone Miner Res 25:1821–1829
Estrada K, Styrkarsdottir U, Evangelou E et al (2012) Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 44:491–501
Bartscherer K, Pelte N, Ingelfinger D, Boutros M (2006) Secretion of Wnt ligands requires Evi, a conserved transmembrane protein. Cell 125:523–533
Maruyama T, Jiang M, Hsu W (2013) Gpr177, a novel locus for bone mineral density and osteoporosis, regulates osteogenesis and chondrogenesis in skeletal development. J Bone Miner Res 28:1150–1159
Rivadeneira F, Styrkársdottir U, Estrada K et al (2009) Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41:1199–1206
Chen D, Li Y, Zhou Z, Xing Y, Zhong Y, Zou X, Tian W, Zhang C (2012) Synergistic inhibition of Wnt pathway by HIF-1alpha and osteoblast-specific transcription factor osterix (Osx) in osteoblasts. PLoS ONE 7:e52948
Kobayashi T, Kronenberg H (2005) Minireview: transcriptional regulation in development of bone. Endocrinology 146:1012–1017
Dalle Carbonare L, Valenti MT, Zanatta M, Donatelli L, Lo Cascio V (2009) Circulating mesenchymal stem cells with abnormal osteogenic differentiation in patients with osteoporosis. Arthritis Rheum 60:3356–3365
Gonzalez JR, Armengol L, Sole X, Guino E, Mercader JM, Estivill X, Moreno V (2007) SNPassoc: an R package to perform whole genome association studies. Bioinformatics 23:644–645
Riancho JA, Olmos JM, Pineda B et al (2011) Wnt receptors, bone mass, and fractures: gene-wide association analysis of LRP5 and LRP6 polymorphisms with replication. Eur J Endocrinol 164:123–131
Tuysuz B, Bursali A, Alp Z, Suyugul N, Laine CM, Makitie O (2012) Osteoporosis-pseudoglioma syndrome: three novel mutations in the LRP5 gene and response to bisphosphonate treatment. Horm Res Paediatr 77:115–120
Laine CM, Chung BD, Susic M et al (2011) Novel mutations affecting LRP5 splicing in patients with osteoporosis-pseudoglioma syndrome (OPPG). Eur J Hum Genet 19:875–881
Boyden LM, Mao J, Belsky J et al (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:1513–1521
Hill TP, Später D, Taketo MM, Birchmeier W, Hartmann C (2005) Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell 8:727–738
Hu H, Hilton MJ, Tu X, Yu K, Ornitz DM, Long F (2005) Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development 132:49–60
Xiong DH, Shen H, Zhao LJ et al (2006) Robust and comprehensive analysis of 20 osteoporosis candidate genes by very high-density single-nucleotide polymorphism screen among 405 white nuclear families identified significant association and gene-gene interaction. J Bone Miner Res 21:1678–1695
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):S14
Cefalu CA (2004) Is bone mineral density predictive of fracture risk reduction? Curr Med Res Opin 20:341–349
Yu HM, Jin Y, Fu J, Hsu W (2010) Expression of Gpr177, a Wnt trafficking regulator, in mouse embryogenesis. Dev Dyn 239:2102–2109
Jin J, Morse M, Frey C, Petko J, Levenson R (2010) Expression of GPR177 (Wntless/Evi/Sprinter), a highly conserved Wnt-transport protein, in rat tissues, zebrafish embryos, and cultured human cells. Dev Dyn 239:2426–2434
Fu J, Jiang M, Mirando AJ, Yu HM, Hsu W (2009) Reciprocal regulation of Wnt and Gpr177/mouse Wntless is required for embryonic axis formation. Proc Natl Acad Sci USA 106:18598–18603
Roshandel D, Thomson W, Pye SR et al (2011) Polymorphisms in genes involved in the NF-kappaB signalling pathway are associated with bone mineral density, geometry and turnover in men. PLoS One 6:e28031
Chauveau C, Broux O, Delecourt C, Hardouin P, Jeanfils J, Devedjian JC (2008) Gene expression in normotopic and heterotopic human bone: increased level of SP7 mRNA in pathological tissue. Mol Cell Biochem 318:81–87
Mendez JP, Rojano-Mejia D, Coral-Vazquez RM et al (2013) Impact of genetic variants of IL-6, IL6R, LRP5, ESR1 and SP7 genes on bone mineral density in postmenopausal Mexican-Mestizo women with obesity. Gene 528:216–220
Conflict of interest
All authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Horváth, P., Balla, B., Kósa, J.P. et al. Strong effect of SNP rs4988300 of the LRP5 gene on bone phenotype of Caucasian postmenopausal women. J Bone Miner Metab 34, 79–85 (2016). https://doi.org/10.1007/s00774-014-0645-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00774-014-0645-z