Association of LRP5 Ala1330Val polymorphism with fracture risk: a meta-analysis

Peng, Jiayuan; Lu, Yiming; Yj, Liu; Yl, Zhan

doi:10.4238/gmr.15017552

Cited by 4 publications

(3 citation statements)

References 18 publications

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“…Another key finding is the high prevalence of variants in LRP5 , a main co‐receptor that triggers the Wnt pathway and osteoblast activity. Several studies and a meta‐analysis failed to show an association between fractures or low BMD and the p.Ala1330Val polymorphism, so this polymorphism is not considered a risk factor for low BMD or fracture . The frequency of 14.5% of the variation in our cohort is lower than the 22% previously reported in white population‐based cohorts with ExAc.…”

Section: Discussioncontrasting

confidence: 76%

Primary Osteoporosis in Young Adults: Genetic Basis and Identification of Novel Variants in Causal Genes

et al. 2017

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Genetic determinants contribute to osteoporosis and enhance the risk of fracture. Genomewide association studies of unselected population‐based individuals or families have identified polymorphisms in several genes related to low bone density, but not in osteoporotic patients with Z‐score < −2.0 SD with fragility fracture(s). The aim of this study was to determine the causal genes of idiopathic osteoporosis in the adulthood. Also, we used next‐generation sequencing of candidate genes in a cohort of 123 young or middle‐aged adults with idiopathic osteoporosis. All patients were included if they had a low bone mineral density (Z‐score < −2 SD), a diagnosis before age 55 years (mean ± SD, 48.4 ± 10.6 years; mean ± SD age at first fracture, 30.4 ± 17.4 years) and fracture or not. We found that 11 patients carried rare or novel variants in COL1A2 (n = 4), PLS3 (n = 2), WNT1 (n = 4), or DKK1 (n = 1). We showed a high prevalence of pathogenic variants in LRP5: 22 patients (17.8%) had the p.Val667Met variant, including three at the homozygous level and 16 (13%) carrying a novel or very rare variant. Functional analysis revealed that the LRP5 missense variants resulted in reduced luciferase activity, which indicates reduced activation of canonical WNT signaling. The clinical phenotype of patients carrying causal gene variants was indistinguishable. In conclusion, molecular screening of young osteoporotic adults revealed several variants and could be useful to characterize susceptibility genes for personalizing treatment, in particular for the new anabolic drugs.© 2017 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

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Section: Discussioncontrasting

confidence: 76%

Primary Osteoporosis in Young Adults: Genetic Basis and Identification of Novel Variants in Causal Genes

et al. 2017

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“…LRP5 encodes a transmembrane protein in the WNT signaling pathway and regulates bone mass in humans and mice [40]. Several studies have shown that LRP5 polymorphisms are a determining factor of bone mass [41].…”

Section: Discussionmentioning

confidence: 99%

Case Control Association Study of WNT Signaling Pathway-related Genes and Osteoporosis Risk Among Chinese Postmenopausal Women

Yang

Liu

et al. 2020

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Background: The WNT signaling pathway is involved in the regulation of bone homeostasis, and the effects of WNT signaling pathway related genes (WLS, WNT16 and LRP5) on osteoporosis risk among Chinese postmenopausal women is still unknown. Hence, we performed a case-control study to assess the association of WNT signaling pathway related genes and osteoporosis risk.Methods: This study involved 1026 women (515 osteoporosis patients and 511 controls) of postmenopausal age who were randomly sampled from Xi'an 630 Hospital, Shaanxi Province, China. Eleven genetic polymorphisms in WLS (rs2566755, rs12407028, rs2566752 and rs7554551), WNT16 (rs3779381, rs3801387, rs917727 and rs7776725) and LRP5 (rs2291467, rs11228240 and rs12272917) were selected and genotyped using the Agena MassARRAY iPLEX system. The association of the genetic polymorphisms and osteoporosis risk was assessed by odds ratios and 95% confidence intervals. The Multifactor Dimensionality Reduction (MDR) method was conducted to analyze SNP-SNP interaction.Results: We found that LRP5 polymorphisms (rs2291467, rs11228240 and rs12272917) were significantly associated with a decreased risk of osteoporosis in homozygotes, both in recessive and additive models (P < 0.05). Stratification analysis showed that LRP5 polymorphisms (rs2291467, rs11228240 and rs12272917) significantly decreased the osteoporosis risk in the subgroup of BMI ≤ 24 (P < 0.05) and that individuals carrying a heterozygote genotype of WNT16 polymorphisms (rs3779381, rs3801387, rs917727 and rs7776725) had a higher osteoporosis risk in the subgroup of BMI > 24 (P < 0.05). We observed that three blocks (block 1: rs2566755 and rs12407028, block 2: rs3779381, rs3801387, rs917727 and rs7776725, block 3: rs2291467 and rs11228240), Trs2291467Trs11228240 and Crs2291467Crs11228240 had a strong association with a lower risk of osteoporosis. Additionally, MDR analysis revealed that a four-locus model (rs2566752 and rs2566755 in WLS, rs7776725 in WNT16, rs12272917 in LRP5) was significantly associated with osteoporosis risk. Conclusions: Our findings suggested that WLS, WNT16 and LRP5 genetic polymorphisms were associated with osteoporosis risk among Chinese postmenopausal women.

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“…The most unexpected result obtained in our study is the absence of statistically significant association of the genetic marker LRP5 rs3736228 with the response to BPs treatment. Studies on various populations have shown that this missense substitution is associated with both the risk of developing osteoporosis [13,31] and with the effectiveness of its antiresorptive therapy with BPs [32]. It is located in exon 18 of LRP5 gene and leads to alanine substitution by valine (p.Ala1330Val) in the extracellular region of LPR5, responsible for mediating the interactions of LRP5 and its ligands.…”

Section: Discussionmentioning

confidence: 99%

Bone metabolism genes variation and response to bisphosphonate treatment in women with postmenopausal osteoporosis

et al. 2019

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Introduction Long-term treatment is used in patients with osteoporosis, and bisphosphonates (BPs) are the most commonly prescribed medications. However, in some patients this therapy is not effective, cause different side effects and complications. Unfortunately, at least one year is needed to identify and confirm an ineffectiveness of BPs therapy on bone mineral density (BMD). Among other factors, a response to BPs therapy may also be explained by genetic factors. The aim of this study was to analyze the influence of SOST , PTH , FGF2 , FDPS , GGPS1 , and LRP5 gene variants on the response to treatment with aminobisphosphonates. Materials and methods Women with postmenopausal osteoporosis were included to this study if they used aminobisphosphonates for at least 12 months. Exclusion criteria were: persistence on BPs therapy less than 80%, bone metabolic diseases, diseases deemed to affect bone metabolism, malignant tumours, using of any medications influencing BMD. The study protocol was approved by the local ethics committee. The BMD at the lumbar spine and femoral neck were measured using dual x-ray absorptiometry (GE Lunar) before and at least 12 months after treatment with BPs. According to BMD change, patients were divided in two groups–responders and non-responders to BPs terapy. Polymorphic variants in SOST , PTH , FGF2 , FDPS , GGPS1 , and LRP5 genes were determined using PCR analysis with TaqMan probes (Thermo Scientific). Results In total, 201 women with BPs therapy were included in the study. No statistically significant differences were observed in age, age at menopause, weight, height, BMI and baseline BMD levels between responders (122 subjects) and non-responders (79 subjects). As single markers, the SOST rs1234612 T/T (OR = 2.3; P = 0.02), PTH rs7125774 T/T (OR = 2.8, P = 0.0009), FDPS rs2297480 G/G (OR = 29.3, P = 2.2×10 −7 ), and GGPS1 rs10925503 C/C+C/T (OR = 2.9; P = 0.003) gene variants were over-represented in non-responders group. No significant association between FGF2 rs6854081 and LRP5 rs3736228 gene variants and response to BPs treatment was observed. The carriers of T-T-G-C allelic combination (constructed from rs1234612, rs7125774, rs2297480, and rs10925503) were predisposed to negative response to BPs treatment (OR = 4.9, 95% CI 1.7–14.6, P = 0.005). The C-C-T-C combination was significantly over-represented in responders (OR = 0.1, 95% CI 0.1–0.5, P = 0.006). Conclusions ...

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Association of LRP5 Ala1330Val polymorphism with fracture risk: a meta-analysis

Cited by 4 publications

References 18 publications

Primary Osteoporosis in Young Adults: Genetic Basis and Identification of Novel Variants in Causal Genes

Primary Osteoporosis in Young Adults: Genetic Basis and Identification of Novel Variants in Causal Genes

Case Control Association Study of WNT Signaling Pathway-related Genes and Osteoporosis Risk Among Chinese Postmenopausal Women

Bone metabolism genes variation and response to bisphosphonate treatment in women with postmenopausal osteoporosis

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