Wnt receptors, bone mass, and fractures: gene-wide association analysis of LRP5 and LRP6 polymorphisms with replication

Riancho, José A.; Olmos, José M.; Pineda, Begoña; García-Ibarbia, Carmen; Pérez-Núñez, María Isabel; Nan, Daniel; Velasco, Javier; Cano, Antonio; Garcı́a-Pérez, Miguel A.; Zarrabeitia, Marı́a T.; González‐Macías, Jesús

doi:10.1530/eje-10-0582

Cited by 46 publications

(32 citation statements)

References 36 publications

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“…The Wnt signaling pathway is the key regulator of bone mass. The Wnt co-receptor lipoprotein receptor-related proteins, LRP5 (6)(7)(8)10,11) and LRP6, (19,20) were associated with BMD at the GWAS level, whereas WNT4, a member of the Wnt ligands, was associated with vertebral CSA in older Caucasian men. (22) TNFRSF11A was significantly associated with osteoporotic fracture in the collaborative meta-analysis.…”

Section: Discussionmentioning

confidence: 95%

“…The 113 candidate SNPs from the 16 potential genetic risk loci were selected based on the following criteria: (1) SNPs found to be associated with BMD and/or osteoporotic fracture, including rs11898505 in SPTBN1, (5,7,12,18) rs2229580, rs2229579, rs2502992, and rs2501432 in CNR2, (21,35) rs1801133 in MTHFR, (21,26,36,37) rs7529452 in PLOD, (21) rs2302685 in LRP6, (19) rs3018362 in a region near TNFRSF11A, (5,12) rs11859065, rs16945612, rs11860781, and rs11864477 in ADAMTS18, (16) rs2073618 in TNFRSF11B, (14) rs6993813 near TNFRSF11B, (5,12) rs2234693 (38,39) and rs3798577 (39) in ESR1, rs3736228 near LRP5, (6,12,18,36,40,41) and rs6696981 in ZBTB40 (12,18) ; or (2) tag SNPs of the 16 selected genes based on the HapMap Data Rel 24/phase II Nov08 with r 2 > 0.8.…”

Section: Snp Selectionmentioning

confidence: 99%

“…Another important member of the Wnt signaling pathway, low density lipoprotein receptorrelated protein 6 (LRP6) at 12p13.2, has been identified as being associated with osteoporosis in different ethnic background populations. (19,20) Furthermore, in 2009, Huang and colleagues (21) highlighted procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD), methylenetetrahydrofolate reductase (NAD(P)H) (MTHFR) and cannabinoid receptor 2 (CNR2) at 1p36 as susceptibility loci for osteoporosis in the Chinese population.…”

Section: Introductionmentioning

confidence: 99%

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Susceptibility genes for osteoporotic fracture in postmenopausal chinese women

Wang

Zeng

Zhang

et al. 2012

Journal of Bone and Mineral Research

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To identify the susceptibility genes for osteoporotic fracture in postmenopausal Chinese women, a two-stage case-control association study using joint analysis was conducted in 1046 patients with nontraumatic vertebra, hip, or distal radius fractures and 2303 healthy controls. First, 113 single-nucleotide polymorphisms (SNPs) in 16 potential osteoporosis candidate genes reported in recent genomewide association studies, meta-analyses studies, large-scale association studies, and functional studies were genotyped in a smallsample-size subgroup consisting of 541 patients with osteoporotic fractures and 554 healthy controls. Variants and haplotypes in SPTBN1, TNFRSF11B, CNR2, LRP4, and ESR1 that have been identified as being associated with osteoporotic fractures were further reanalyzed in the entire case-control group. We identified one SNP in TNFRSF11B (rs3102734), three SNPs in ESR1 (rs9397448, rs2234693, and rs1643821), two SNPs in LRP4 (rs17790156 and rs898604), and four SNPs in SPTBN1 (rs2971886, rs2941583, rs2941584, and rs12475342) were associated with all of the broadly defined osteoporotic fractures. The most significant polymorphism was rs3102734, with increased risk of osteoporotic fractures (odds ratio, 1.35; 95% confidence interval [CI], 1.17-1.55, Bonferroni p ¼ 2.6 Â 10 À4 ). Furthermore, rs3102734, rs2941584, rs12475342, rs9397448, rs2234693, and rs898604 exhibited significant allelic, genotypic, and/or haplotypic associations with vertebral fractures. SNPs rs12475342, rs9397448, and rs2234693 showed significant genotypic associations with hip fractures, whereas rs3102734, rs2073617, rs1643821, rs12475342, and rs2971886 exhibited significant genotypic and/or haplotypic associations with distal radius fractures. Accordingly, we suggest that in addition to the clinical risk factors, the variants in TNFRSF11B, SPTBN1, ESR1, and LRP4 are susceptibility genetic loci for osteoporotic fracture in postmenopausal Chinese women. ß

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Section: Discussionmentioning

confidence: 95%

Section: Snp Selectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Susceptibility genes for osteoporotic fracture in postmenopausal chinese women

Wang

Zeng

Zhang

et al. 2012

Journal of Bone and Mineral Research

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“…Mutations in LRP5 have been shown to influence the differentiation of human mesenchymal stem cells into osteoblasts or adipocytes (140). Moreover, polymorphisms in LRP5 have been associated with osteoporosis and osteoporotic fractures, as well as obesity and metabolic syndrome (116,117,199,200,201). Glucose-induced insulin secretion is impaired in mice deficient in Lrp5 (202).…”

Section: Metabolic Aspects In Relation To a Homeostatic Model Involvimentioning

confidence: 99%

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

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Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

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“…(Arcogen Consortium, 2012;Panoutsopoulou et al, 2011 been related to osteoporosis in genetic association studies (Ralston,90 2010; Riancho et al, 2011;Richards et al, 2009;Styrkarsdottir et al, 91 2009; Valero et al, 2011 …”

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confidence: 99%

Contribution of genetic and epigenetic mechanisms to Wnt pathway activity in prevalent skeletal disorders

García-Ibarbia

Delgado‐Calle

Casafont

et al. 2013

Gene

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Wnt 22 β-Catenin 23 DNA methylation 24 Fractures 25 Bone diseases 26We reported previously that the expression of Wnt-related genes is lower in osteoporotic hip fractures than in 27 osteoarthritis. We aimed to confirm those results by analyzing β-catenin levels and explored potential genetic 28 and epigenetic mechanisms involved. 29 β-Catenin gene expression and nuclear levels were analyzed by real time PCR and confocal immunofluorescence. 30 Increased nuclear β-catenin was found in osteoblasts isolated from patients with osteoarthritis (99 ± 4 31 units vs. 76 ± 12, p = 0.01, n = 10), without differences in gene transcription, which is consistent with 32 a post-translational down-regulation of β-catenin and decreased Wnt pathway activity.33 Twenty four single nucleotide polymorphisms (SNPs) of genes showing differential expression between fractures 34 and osteoarthritis (WNT4, WNT10A, WNT16 and SFRP1) were analyzed in DNA isolated from blood of 853 pa-35 tients. The genotypic frequencies were similar in both groups of patients, with no significant differences. 36 Methylation of Wnt pathway genes was analyzed in bone tissue samples (15 with fractures and 15 with osteo-37 arthritis) by interrogating a CpG-based methylation array. Six genes showed significant methylation differences 38 between both groups of patients: FZD10, TBL1X, CSNK1E, WNT8A, CSNK1A1L and SFRP4. The DNA demethylating 39 agent 5-deoxycytidine up-regulated 8 genes, including FZD10, in an osteoblast-like cell line, whereas it down-40 regulated other 16 genes. 41 In conclusion, Wnt activity is reduced in patients with hip fractures, in comparison with those with osteoarthritis. 42 It does not appear to be related to differences in the allele frequencies of the Wnt genes studied. On the other 43 hand, methylation differences between both groups could contribute to explain the differences in Wnt activity.44

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Wnt receptors, bone mass, and fractures: gene-wide association analysis of LRP5 and LRP6 polymorphisms with replication

Cited by 46 publications

References 36 publications

Susceptibility genes for osteoporotic fracture in postmenopausal chinese women

Susceptibility genes for osteoporotic fracture in postmenopausal chinese women

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Contribution of genetic and epigenetic mechanisms to Wnt pathway activity in prevalent skeletal disorders

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