Polymorphisms within RANKL and Osteoprotegerin Genes in Low Bone Mass among Postmenopausal Indonesian Women (original) (raw)
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Association of TNFSF11 gene promoter polymorphisms with bone mineral density in postmenopausal women
Maturitas, 2006
Objectives: The receptor activator of nuclear factor-B ligand (RANKL) is recognized as one of the important regulators of osteoclastogenesis. The expression of the tumour necrosis factor superfamily, member 11 (TNFSF11) gene, which encodes for RANKL protein, is increased relative to the expression of osteoprotegrin in cases of senile osteoporosis with hip bone fracture. Our aim was to find polymorphisms in the TNFSF11 gene promoter and to investigate their possible association with bone mineral density (BMD). Methods: The TNFSF11 gene promoter region was screened for the presence of new sequence variations by direct sequencing. DNA sequencing revealed the presence of four sequence variations: −290C > T, −643C > T, −693G > C and −1594G > A. Association of the discovered polymorphisms with BMD was investigated in 115 Slovenian postmenopausal women, using restriction fragment length polymorphism analysis. After a year, bone loss in the association with the identified sequence variations was evaluated in 43 postmenopausal women. Results: Three of the discovered sequence variations (−290C > T, −643C > T, −693G > C) proved to be polymorphic, whereas variation −1594G > A was only found in one patient. The frequencies of genotypes were as follows: CC (27.8%), CT (43.5%), TT (28.7%) for −290C > T polymorphism; CC (23.5%), CT (47.8%), TT (28.7%) for −643C > T polymorphism; and GG (22.6%), GC (51.3%), CC (26.1%) for −693G > C polymorphism. A statistically significant association of genotype with BMD at the femoral neck was observed only in the −290C > T polymorphism. Genotype CC was associated with lower BMD than the TT genotype (P = 0.022). In polymorphism −693G > C, a significant difference in bone loss rate was observed in total hip (P = 0.011) and femoral neck BMD (P = 0.037). Conclusions: Four sequence variations were identified in the studied region of TNFSF11 gene promoter. Our results of preliminary clinical evaluation suggest that the −290C > T polymorphism in the TNFSF11 gene promoter could contribute to the genetic regulation of BMD.
VDR and TNFSF11 polymorphisms are associated with osteoporosis in Thai patients
Biomedical Reports
Determining molecular markers for osteoporosis may be valuable for improving the quality of life of affected elderly patients by aiding in early detection and disease management. In the present study, the association between single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) and tumour necrosis factor superfamily number 11 (TNFSF11) genes and the susceptibility of developing osteoporosis was investigated in a Thai female cohort. The study group consisted of 105 Thai postmenopausal patients diagnosed with osteoporosis and 132 healthy Thai postmenopausal female volunteers. DNA extracted from blood samples was used to genotype the VDR and TNFSF11 genes using polymerase chain reaction-restriction fragment length polymorphism and sequencing analysis. For VDR, the frequencies of the genotypes TT, CT and CC for the TaqI SNP (rs731236) were 87.88, 11.36 and 0.76%, respectively, in the control group, while in the osteoporosis cohort were 92.38, 5.71 and 1.91%, respectively. For the FokI SNP (rs2228570), the frequencies of the genotypes CC, CT and TT were 31.06, 55.30 and 13.64%, respectively, in the control group, and in the osteoporosis group were 29.52, 43.81 and 26.67%, respectively. For BsmI SNP (rs1544410), the frequencies of the genotypes GG, GA and AA were 78.03, 18.94 and 3.03%, respectively, in control group, and in the osteoporosis group were 80.95, 18.10 and 0.95%, respectively. The significant risk of osteoporosis associated with the FokI SNP was determined. The odds ratio (95% confidence interval) was 2.30 (1.14-4.69; P= 0.01) among patients with osteoporosis with TT as the susceptibility genotype. For TNFSF11, the frequencies of the genotypes TT, CT and CC for the-290C>T SNP (rs9525641) in the control group were 36.36, 50.76 and 12.88%, respectively, while in the osteoporosis group were 31.43, 56.19 and 12.38%, respectively. For the-643C>T SNP (rs9533156), the frequencies of the genotypes TT, CT and CC in the control group were 35.61, 48.48 and 15.91%, respectively, while in the osteoporosis group were 32.38, 55.24 and 12.38%, respectively. For the-693G>C SNP (rs9533155), the frequencies of the genotypes CC, CG, and GG in the control group were 39.39, 46.97 and 13.64%, respectively, and in the osteoporosis group were 36.19, 53.33 and 10.48%, respectively. No significant associations of the TNFSF11 SNPs with osteoporosis were determined; however, it was notable that the GCT haplotype of TNFSF11 may be a protective haplotype for osteoporosis. Therefore, it was concluded that the SNP FokI of VDR may be a potential molecular biomarker for the development of osteoporosis in Thai females.
TNFRSF11B gene polymorphisms, bone mineral density, and fractures in Slovak postmenopausal women
Journal of Applied Genetics, 2014
Osteoporosis is a common disease that is characterized by low bone mineral density (BMD), deterioration in bone microarchitecture, and increased fracture risk. Due to its important role in bone biology, the TNFRSF11B gene, coding for OPG, has been considered as a candidate gene for osteoporosis. In this study, single nucleotide polymorphisms (SNPs) A163G, T245G, and G1181C (rs3102735, rs3134069, and rs2073618, respectively) within the TNFRSF11B gene were studied for association with BMD and fracture incidence in a cohort of 327 postmenopausal Slovak women. Genomic DNA was extracted and purified from peripheral blood leukocytes by the commercial kit JetQuick (Genomed GmbH, Germany) using a standard protocol. Genotyping was performed using the Custom TaqMan® SNP Genotyping Assays. The lumbar L 1-L 4 spine BMD (g/cm 2) and T-score in the subgroup of Slovak postmenopausal women with osteoporotic fractures were significantly lower than those in the subgroup of women without fracture (p=0.0025; p=0.0009). We identified the T245G (rs3134069) polymorphism in the TNFRSF11B gene associated with osteoporotic fractures (vertebral fractures: p=0.0320; non-vertebral fractures: p=0.0005; all fractures: 0.0000). The polymorphism T245G (rs3134069) in the TNFRSF11B gene could be used together with other genetic markers to identify individuals at high risk of osteoporotic fractures. The results from the present study provided more evidence to reveal the role of TNFRSF11B gene polymorphisms in BMD and the risk of osteoporotic fractures.
Human Molecular Genetics, 2002
Osteoporosis is a multifactorial disease with a strong genetic component characterized by reduced bone density and increased fracture risk. A candidate locus for regulation of hip bone mineral density (BMD) has been identified on chromosome 1p36 by linkage analysis. One of the positional and functional candidate genes located within this region is the tumour necrosis factor receptor superfamily member 1B (TNFRSF1B). In order to investigate whether allelic variation in TNFRSF1B contributes to regulation of bone mass, we studied several polymorphisms of this gene in a population based cohort study of 1240 perimenopausal women from the UK. We studied a T676G change in exon 6 (196: Met-Arg) and three SNPs (G593A, T598G, and T620C) in the 3 0 UTR of the gene. The 3 0 UTR SNPs were in strong linkage disequilibrium (LD) with each other (P < 0.00001), and the exon 6 SNP was in LD with G593A and T598G (P < 0.00001). We found no association between T676G alleles and BMD at the spine or hip. However, haplotype analysis showed that subjects homozygous for the A593-T598-C620 haplotype (n ¼ 85) had femoral neck BMD values 5.7% lower than those who did not carry the haplotype (n ¼ 1155; P < 0.00008) and this remained significant after correcting for confounding factors and multiple testing (P < 0.0009). Regression analysis showed that the ATC haplotype accounted for 1.2% of the population variance in hip BMD and was the second strongest predictor after body weight. In summary, our work supports the view that allelic variation in the 3 0 UTR of TNFRSF1B gene contributes to the genetic regulation of bone mass, with effects that are specific for femoral neck BMD.
Journal of Molecular Endocrinology, 2011
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 activi...
TNFRSF11B gene variants and bone mineral density in postmenopausal women in Malta
Maturitas, 2006
A number of polymorphisms in various genes have been identified and associated with bone mineral density (BMD) and with an increased risk of osteoporosis. Objective: In this study, three single nucleotide polymorphisms (SNPs) within the TNFRSF11B gene were studied for association with an increased risk of osteoporosis in postmenopausal Maltese women (n = 126). Methodology: Analysis was performed by PCR restriction fragment length polymorphism (RFLP) while BMD at the lumbar spine, femoral neck, Ward's triangle and trochanter was measured by DEXA. Results: No significant association was observed between genotypes and BMD for all polymorphisms studied within this gene. Homozygotes CC (T 950 -C) were observed to have the highest BMD at all anatomical sites although statistical significance was not reached when comparing the three genotypes. A statistical significant difference was observed in the distribution of genotype frequencies for this polymorphism between normal individuals and those that were either osteopenic or osteoporotic at one or both anatomical sites, with the TT genotype associated more frequently with low BMD. The T 950 -C and G 1181 -C polymorphisms were in strong linkage disequilibrium with each other but not with the A 163 -G polymorphism further upstream in the OPG promoter. Statistical significance was reached when constructing haplotypes, where the A-T-G haplotype was found to be more frequent in individuals with low BMD. Conclusions: These results indicate the possible role of TNFRSF11B gene variants in postmenopausal bone loss in women in Malta.
Advances in Medical Sciences, 2020
We aimed to examine the polymorphism of the promoter and exon 5 of the TNFSF11 gene and their impact on bone mineral density (BMD) and the frequency of bone fractures. TNFSF11 encodes the receptor activator of the NF-kB ligand (RANKL), a key regulator of bone metabolism and osteoporosis drug targets. BMD is an essential measure in diagnosing osteoporosis and assessing the risk of fractures. In vivo, RANKL expression research suggests that promoter TNFSF11 variants influence BMD. Moreover, exon 5 polymorphism of a linear epitope sequence for a denosumab could be related to the effectiveness of biological therapy. Patients and methods: The study included 114 postmenopausal osteoporosis patients. BMD was measured in the lumbar spine and the femoral neck. Genetic analysis was performed using Sanger sequencing. Genotypes data for 263 female European population group were obtained from the 1000Genomes database. Results: We identified six promoter polymorphisms (rs9525641, rs9533155, rs9533156, rs11839112, rs28926171, rs183599708) and one silent TNFSF11 variant in exon 5 (rs9562415). Three of the sequence variants detected (rs9525641, rs9533155, rs9533156) proved to be polymorphic, whereas the others four occurred at a frequency below 2%. The statistical analysis demonstrated no significant differences between polymorphisms and BMD, and bone fractures. However, variant rs9533156 was relevant with the lumbar spine T-score (p = 0.0273), and no association with BMD was of borderline significance (p = 0.0529). Conclusions: Variant rs9533156 may contribute to the genetic regulation of BMD in Polish postmenopausal osteoporosis, while the exon 5 sequence of the TNFSF11 gene is very conservative.
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.
Journal of Molecular Endocrinology, 2008
Tumour necrosis factor superfamily member 11 (TNFSF11) gene, that codes for receptor activator of nuclear factor-κB ligand, is one of the candidate genes for the genetic susceptibility to osteoporosis. As variations in the TNFSF11 gene promoter could alter its expression, the aim of the study was to evaluate the functional influence of three polymorphisms in the promoter and to investigate their association with bone mineral density (BMD) and biochemical markers in postmenopausal women. A total of 404 postmenopausal women were genotyped for the presence of TNFSF11 gene promoter polymorphisms −290C>T, −643C>T and −693G>C. Two common haplotypes, CCG and TTC, which occur in 44.3 and 49.3% of subjects respectively, were subjected to functional analysis. Amplified fragments were cloned into pGL3-basic reporter plasmid, which was co-transfected with pRL-TK plasmid into HEK293 cells. Dual luciferase reporter assay was performed. BMD and biochemical markers were measured. Reporter ...