TNFRSF11B gene variants and bone mineral density in postmenopausal women in Malta

Vidal, Christopher; Brincat, Mark; Xuereb-Anastasi, Angela

doi:10.1016/j.maturitas.2005.11.003

Cited by 46 publications

(43 citation statements)

References 40 publications

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“…Previous studies have reported association between rs2073618 and urinary levels of two other bone resorption markers, N-terminal cross-linking telopeptide of type I collagen (NTX-1) (26) and deoxypyridinoline (DPD). (27) In contrast, other studies did not find any significant association between rs2073618 and bone turnover markers, but these studies were relatively small. (15,19,28) The other five SNPs have not been tested previously in association with bone turnover markers.…”

Section: Discussionmentioning

confidence: 84%

“…Interestingly, the same alleles also were associated with higher levels of CTX-I, which remained significant even after correction for multiple testing, suggesting that the negative effect of the SNP on LS BMD a may be due to an accelerating effect on bone resorption. Two OPG SNPs, rs2073617 (27) and rs3134069, (18) have been associated previously with LS BMD a in postmenopausal women. However, we could not confirm these associations in our male population.…”

Section: Discussionmentioning

confidence: 93%

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Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men

Roshandel

Holliday

Pye

et al. 2010

Journal of Bone and Mineral Research

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The aim of this study was to determine if single-nucleotide polymorphisms (SNPs) in RANKL, RANK, and OPG influence bone turnover and bone mineral density (BMD) in men. Pairwise tag SNPs (r 2 ! 0.8) were selected for RANKL, RANK, and OPG and their 10-kb flanking regions. Selected tag SNPs plus five SNPs near RANKL and OPG, associated with BMD in published genome-wide association studies (GWAS), were genotyped in 2653 men aged 40 to 79 years of age recruited for participation in a population-based study of male aging, the European Male Ageing Study (EMAS). N-terminal propeptide of type I procollagen (PINP) and C-terminal cross-linked telopeptide of type I collagen (CTX-I) serum levels were measured in all men. BMD at the calcaneus was estimated by quantitative ultrasound (QUS) in all men. Lumbar spine and total-hip areal BMD (BMD a ) was measured by dual-energy X-ray absorptiometry (DXA) in a subsample of 620 men. Multiple OPG, RANK, and RANKL SNPs were associated with bone turnover markers. We also identified a number of SNPs associated with BMD, including rs2073618 in OPG and rs9594759 near RANKL. The minor allele of rs2073618 (C) was associated with higher levels of both PINP rs9594759 (C) was associated with lower PINP (b ¼ À1.84, p ¼ .003) and CTX-I (b ¼ À27.02, p ¼ 6.06 Â 10 À8 ) and higher ultrasound BMD at the calcaneus (b ¼ 0.01, p ¼ .037). Our findings suggest that genetic variation in the RANKL/RANK/OPG signaling pathway influences bone turnover and BMD in European men. ß

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 93%

Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men

Roshandel

Holliday

Pye

et al. 2010

Journal of Bone and Mineral Research

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“…In a previous study, we reported a significantly higher frequency of haplotype A-T-G within the TNFRSF11B gene promoter in postmenopausal women with low BMD (Vidal et al 2006). Genotype distribution was significantly different for the C950T polymorphism, with TT genotype found in 83% of postmenopausal women with low BMD and an odds ratio of 2 .…”

Section: Introductionmentioning

confidence: 80%

Functional polymorphisms within the TNFRSF11B (osteoprotegerin) gene increase the risk for low bone mineral density

Vidal

Formosa²,

Xuereb-Anastasi³

2011

Journal of Molecular Endocrinology

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Polymorphisms within the TNFRSF11B gene have been studied and associated with osteoporosis and fracture risk. Osteoprotegerin (OPG), the product of this gene, is a key negative regulator of osteoclastogenesis and is secreted by osteoblasts/stromal cells. A previous study in Maltese postmenopausal women showed positive association of low bone mineral density (BMD) with a polymorphism found within the promoter region of this gene (C950T). In this study, direct DNA sequencing revealed 12 variants with polymorphisms C950T, G1181C and rs4876869 observed to be in strong linkage disequilibrium. The constructed haplotype T-G-T was found to increase the risk for a low BMD, while C-G-T and C-C-C have a protective role; thus, we investigated the functional role of both C950T and rs4876869 in vitro. The promoter region, including the C950T alleles, was amplified by PCR, cloned into pGL3 enhancer vector and transfected into HeLa, COS-7 and RAW264.7 cell lines. After incubation, luciferase activity was measured. The T/C (rs4876869) change was tested for its possible effect on pre-mRNA splicing, using an exon-trapping vector. A statistical significant difference in gene expression was observed between the alleles for T950C, with the T allele showing a lower luciferase expression in all cell lines (P!0 . 01). For rs4876869, exon skipping was observed for the C allele, while only one transcript harbouring the whole exon was observed for the T allele. Our findings suggest that the T-G-T haplotype might be increasing the risk for osteoporosis due to lower quantities of the full OPG transcript being expressed resulting in a higher bone resorption.

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“…These families were recruited from the Department of Obstetrics and Gynaecology, St Luke's Hospital, Malta and selected from probands that already participated in previous association studies. 17,18 These two probands were observed to be severely osteoporotic according to WHO criteria (t-scoreoÀ2.50), where both probands had t-scores of À3.50, were relatively young in age when diagnosed (50 and 55 years, respectively) and have a known family history of osteoporosis. A total of 27 family members were recruited, nine of whom came from pedigree 1 and 18 from pedigree 2 ( Table 1).…”

Section: Subjectsmentioning

confidence: 99%

“…Sequence variants identified were analysed in all family members and a cohort of unrelated postmenopausal women, 17,18 either by direct sequencing or by restriction fragment length polymorphism (RFLP). PCR products (10 ml) were digested using appropriate restriction enzymes according to the manufacturer's instructions (New England Biolabs, Beverly, MA, USA).…”

Section: Analysis Of Candidate Genementioning

confidence: 99%

Linkage to chromosome 11p12 in two Maltese families with a highly penetrant form of osteoporosis

et al. 2007

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Osteoporosis is a metabolic bone disease with a strong genetic component. Family-based linkage studies were performed by a number of investigators to try to identify loci that might contain genes responsible for an increased susceptibility to osteoporosis. A whole-genome linkage scan using 400 microsatellite markers was performed in 27 members from two Maltese families with a highly penetrant form of osteoporosis. The phenotype was defined by lumbar and femoral z-scores calculated after measurement of bone mineral density by DEXA. Both males and females were among the affected individuals. Multipoint parametric and non-parametric linkage analyses were performed by EasyLinkage v4.01 using GENEHUNTER v2.1, assuming dominant and recessive modes of inheritance with variable penetrance. Evidence of linkage was observed to a marker at 11p12 where a non-parametric LOD score of 5.77 (P ¼ 0.0006) was obtained. A maximum heterogeneity LOD score of 2.55 for this region was obtained for the dominant mode of inheritance with 90% penetrance and a phenocopy rate of 1%. Following fine mapping, the critical interval was narrowed to a region that is 52.94 cM from 11p-telomere. In this region, the gene for tumour necrosis factor receptor-associated factor 6 (TRAF6) is located approximately 1 cM away from the indicated marker. Sequencing of the promoter region and exons of the TRAF6 gene revealed three sequence variants, one of which was found in three affected members within one family.

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TNFRSF11B gene variants and bone mineral density in postmenopausal women in Malta

Cited by 46 publications

References 40 publications

Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men

Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men

Functional polymorphisms within the TNFRSF11B (osteoprotegerin) gene increase the risk for low bone mineral density

Linkage to chromosome 11p12 in two Maltese families with a highly penetrant form of osteoporosis

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