Polymorphism rs2073618 of the TNFRSF11B (OPG) Gene and Bone Mineral Density in Mexican Women with Rheumatoid Arthritis.
ABSTRACT: Osteoporosis (OP) is highly prevalent in rheumatoid arthritis (RA) and is influenced by genetic factors. Single-nucleotide polymorphism (SNP) rs2073618 in the TNFRSF11B osteoprotegerin (OPG) gene has been related to postmenopausal OP although, to date, no information has been described concerning whether this polymorphism is implied in abnormalities of bone mineral density (BMD) in RA. We evaluated, in a case-control study performed in Mexican-Mestizo women with RA, whether SNP rs2073618 in the TNFRSF11B gene is associated with a decrease in BMD. RA patients were classified as follows: (1) low BMD and (2) normal BMD. All patients were genotyped for the rs2073618 polymorphism by PCR-RFLP. The frequency of low BMD was 74.4%. Higher age was observed in RA with low BMD versus normal BMD (62 and 54 years, resp.; p < 0.001). Worse functioning and lower BMI were observed in RA with low BMD (p = 0.003 and p = 0.002, resp.). We found similar genotype frequencies in RA with low BMD versus RA with normal BMD (GG genotype 71% versus 64.4%, GC 26% versus 33%, and CC 3% versus 2.2%, resp.; p = 0.6). We concluded that in Mexican-Mestizo female patients with RA, the rs2073618 polymorphism of the TNRFS11B gene is not associated with low BMD.
Project description:The etiology of otosclerosis is unknown. The etiopathogenesis of otosclerosis seems similar to that occurring in Paget's disease of bone, for which mutations or polymorphisms in several genes have been identified. Among these, TNFRSF11B gene encoding the osteoprotegerin is produced at high levels in the normal inner ear and at low level in active otosclerotic stapes footplates. The aim of this work was to verify the presence of a correlation between the rs2073618 (N3K) polymorphism in the TNFRSF11B gene and otosclerosis. Mutational screening in the TNFRSF11B gene was performed by direct sequencing. SNPs analysis was performed by PCR and by specific restriction enzyme assay with HpaI. The significance of the association was analyzed by statistical specific software. No causative mutation has been identified but the data suggested a strong correlation between the rs2073618 (N3K) polymorphism and otosclerosis. This correlation, however, has been excluded in a case-control study. This study excluded the association between the N3K polymorphism and otosclerosis in Campania region population.
Project description:Patients with rheumatoid arthritis (RA) have accelerated atherosclerosis, but there is limited information about the genetic contribution to atherosclerosis in this population. Therefore, we examined the association between selected genetic polymorphisms and coronary atherosclerosis in patients with RA.Genotypes for single-nucleotide polymorphisms (SNPs) in 152 candidate genes linked with autoimmune or cardiovascular risk were measured in 140 patients with RA. The association between the presence of coronary artery calcium (CAC) and SNP allele frequency was assessed by logistic regression with adjustment for age, sex, and race. To adjust for multiple comparisons, a false discovery rate (FDR) threshold was set at 20%.Patients with RA were 54±11 years old and predominantly Caucasian (89%) and female (69%). CAC was present in 70 patients (50%). A variant in rs2073618 that encodes an Asn3Lys missense substitution in the osteoprotegerin gene (OPG, TNFRSF11B) was significantly associated with the presence of CAC (OR=4.09, p<0.00026) and withstands FDR correction.Our results suggest that a polymorphism of the TNFRSF11B gene, which encodes osteoprotegerin, is associated with the presence of coronary atherosclerosis in patients with RA. Replication of this finding in independent validation cohorts will be of interest.
Project description:There are co-morbidity between osteoporosis (OP) and rheumatoid arthritis (RA). Some genetic risk factors have been identified for these two phenotypes respectively in previous research; however, they accounted for only a small portion of the underlying total genetic variances. Here, we sought to identify additional common genetic loci associated with OP and/or RA. The conditional false discovery rate (cFDR) approach allows detection of additional genetic factors (those respective ones as well as common pleiotropic ones) for the two associated phenotypes. We collected and analyzed summary statistics provided by large, multi-center GWAS studies of FNK (femoral neck) BMD (a major risk factor for osteoporosis) (n = 53,236) and RA (n = 80,799). The conditional quantile-quantile (Q-Q) plots can assess the enrichment of SNPs related to FNK BMD and RA, respectively. Furthermore, we identified shared loci between FNK BMD and RA using conjunction cFDR (ccFDR). We found strong enrichment of p-values in FNK BMD when conditional Q-Q was done on RA and vice versa. We identified 30 novel OP-RA associated pleiotropic loci that have not been reported in previous OP or RA GWAS, 18 of which located in the MHC (major histocompatibility complex) region previously reported to play an important role in immune system and bone health. We identified some specific novel polygenic factors for OP and RA respectively, and identified 30 novel OP-RA associated pleiotropic loci. These discovery findings may offer novel pathobiological insights, and suggest new targets and pathways for drug development in OP and RA patients.
Project description:This study was to explore the association of low-density lipoprotein receptor related protein 5 (LRP5) gene polymorphism with bone mineral density (BMD), bone turnover markers and glycometabolism in postmenopausal women with type 2 diabetes mellitus (T2DM) and/or osteoporosis (OP) in Shanghai. 354 unrelated Han Chinese post-menopausal women were recruited from Shanghai and divided into 4 groups: OP group (n=90), T2DM group (n=96), T2DM + OP group (n=90) and control group (n=78). The LRP5 genotypes were determined by DNA sequencing. The BMD was measured by dual-energy X-ray absorptiometry. The bone transformation indicators and glycometabolism index (HbA1c and Fasting insulin) were also detected. The association of LRP5 polymorphism with BMD, bone turnover markers and glycometabolism was evaluated. Result showed that, In OP group, the BMD of L2-4 was higher in patients with rs3736228 CC genotype than those with CT/TT genotypes (P<0.05). After adjustment for age, body mass index (BMI) and years of menopause, A1330V polymorphism was still associated with BMD of L2-4 (P<0.01). In the control group, HbA1c was significantly higher in patients with A1330V CC genotype than those with CT/TT genotypes (P<0.05), but no significant difference was found after adjustment for BMI, age and years of menopause (P>0.05). Thus, LRP5 gene is an impressionable gene in postmenopausal women with OP in Shanghai. T2DM patients have a high BMD when compared with controls, which may be related to BMI and FINS. LRP5 genotype is not an impressionable gene in postmenopausal women with T2DM in Shanghai.
Project description:Osteoporosis is characterized by low bone mineral density (BMD). One of the most important factors that influence BMD is the genetic contribution. The collagen type 1 alpha 1 (COL1A1) and the JAGGED (JAG1) have been investigated in relation to BMD. The aim of this study was to investigate the possible association between two single-nucleotide polymorphisms (SNPs) of COL1A1, their haplotypes, and one SNP of JAG1 with BMD in postmenopausal Mexican-Mestizo women. Seven hundred and fifty unrelated postmenopausal women were included. Risk factors were recorded and BMD was measured in lumbar spine, total hip, and femoral neck by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Two SNPs in COL1A1 (rs1800012 and rs1107946) and one in JAG1 (rs2273061) were studied. Real-time PCR allelic discrimination was used for genotyping. The differences between the means of the BMDs according to genotype were analyzed with covariance. Deviations from Hardy-Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r (2), and haplotype analysis of COL1A1 was conducted. Under a dominant model, the rs1800012 polymorphism of the COL1A1 showed an association with BMD of the lumbar spine (P?=?0.021). In addition, analysis of the haplotype of COL1A1 showed that the G-G haplotype presented a higher BMD in lumbar spine. We did not find an association between the s1107946 and rs2273061 polymorphisms of the COL1A1 and JAG1, respectively. Our results suggest that the rs1800012 polymorphism of the COL1A1, in addition to one haplotype, were significantly associated with BMD variation in Mexican-Mestizo postmenopausal women.
Project description:The receptor activator of nuclear factor-?B (RANK) and the osteoprotegerin (OPG) cascade system have been reported to be essential in osteoclastogenesis. In recent years, several studies have investigated the association between polymorphisms of RANK, its ligand RANKL and OPG genes and the risk of rheumatoid arthritis (RA) in different populations. However, the results arising from these studies were conflicting. To determine the association between RANK, RANKL and OPG gene polymorphisms and the risk of RA. We conducted a hospital-based case-controlled study in Changzhou with 574 RA cases and 804 controls. The genotyping of RANK gene rs1805034 polymorphism was conducted by single base extension combined with matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). We also undertook a meta-analysis of the literature referring to polymorphisms of RANK, RANKL and OPG genes and RA risk. This case-controlled study found that the polymorphism in the RANK gene rs1805034 was not related to RA risk. Stratification analyses by sex and age suggested that RANK gene rs1805034 polymorphism was not associated with the risk of RA among groups of male, female, age ? 55 and age > 55. Our meta-analysis found that the rs2277438 polymorphism in RANKL gene increased the risk of RA, whereas RANK gene rs1805034, OPG gene rs3102735, OPG gene rs2073618, OPG gene rs3134069 polymorphisms were not related to RA susceptibility. In conclusion, this case-controlled study and meta-analysis indicated that the RANKL gene rs2277438 polymorphism increased the RA risk, and that RANK gene rs1805034, OPG gene rs3102735, OPG gene rs2073618, OPG gene rs3134069 polymorphisms were not related to RA risk.
Project description:BACKGROUND:Multiligand receptor for advanced glycation end products (RAGE), osteoprotegerin, and Golgb1 genes may be implicated in atherosclerosis and vascular diseases. Single nucleotide polymorphisms (SNPs) rs1035798 in RAGE gene, rs2073617 and rs2073618 in TNFRSF11B, and rs3732410 in Golgb1 will be investigated on whether there is an association with hemorrhagic stroke (HS) in Chinese population. METHODS:A total of 600 subjects including 199 HS patients and 401 controls were assayed. These samples were divided into two groups: the ?50 year and >50 year groups. Genotyping of SNPs was determined using the SEQUENOM MassARRAY matrix-assisted laser desorption ionization-time-of-flight-mass spectrometry. The association between genotype and HS risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) with multivariate unconditional logistic regression analyses. RESULTS:Our data showed that in the ?50 year group, the rs1035798 major allele homozygote C/C in RAGE gene was associated with an increased risk of HS, while Golgb1 rs3732410 minor allele homozygote G/G was associated with a decreased risk of HS. In the >50 year group, the major allele homozygote G/G of rs2073618 was found to be associated with an increased risk of HS. CONCLUSIONS:The polymorphisms rs1035798 of RAGE gene, rs2073618 of TNFRSF11B, and rs3732410 of Golgb1 might be involved in the risk of HS at different stage of ages.
Project description:Bone disease in rheumatoid arthritis (RA) is a complex phenomenon where genetic risk factors have been partially evaluated. The system formed by receptor activator for nuclear factor-κB (RANK), receptor activator for nuclear factor-κB ligand (RANKL), and osteoprotegerin (OPG): RANK/RANKL/OPG is a crucial molecular pathway for coupling between osteoblasts and osteoclasts, since OPG is able to inhibit osteoclast differentiation and activation. We aim to evaluate the association between SNPs C950T (rs2073617), C209T (rs3134069), T245G (rs3134070) in the TNFRSF11B (OPG) gene, and osteoporosis in RA. We included 81 women with RA and 52 healthy subjects in a cross-sectional study, genotyped them, and measured bone mineral density (BMD) at the lumbar spine and the femoral neck. Mean age in RA was 50 ± 12 with disease duration of 12 ± 8 years. According to BMD results, 23 (33.3%) were normal and 46 (66.7%) had osteopenia/osteoporosis. We found a higher prevalence of C allele for C950T SNP in RA. Polymorphisms C209T and T245G did not reach statistical significance in allele distribution. Further studies including patients from other regions of Latin America with a multicenter design to increase the sample size are required to confirm our findings and elucidate if C950T SNP could be associated with osteoporosis in RA.
Project description:Although many common variants have been identified for bone mineral density (BMD) and osteoporosis fractures, all the identified risk variants could only explain a small portion of heritability of BMD and osteoporosis fractures. OPG belongs to the tumor necrosis factor receptor superfamily, which plays a crucial role in bone remodeling and is thus a promising candidate gene of osteoporosis. Several studies have explored the association of OPG variants with BMD or osteoporosis fractures, however, the results remain inconsistent among different populations. In the study, we first assessed the relationship between OPG variants and BMD or osteoporosis fractures in our sample size (227 subjects with postmenopausal osteoporosis and 189 controls), and then performed a systematic meta-analysis. Among the nine SNPs genotyped, rs6469804 and rs2073618 showed significant associations with both BMD and osteoporotic fractures, while rs3102735 was only associated with BMD in our samples (P?<?0.05). For meta-analyses, data for a total of 12 SNPs were pooled (4725 patients and 37804 controls), and five SNPs, including rs6993813, rs6469804, rs3134070, rs2073618 and rs3102734, showed association with osteoporosis fractures (P?<?0.05). On light of the above analysis, we believe that OPG is one promising susceptibility gene of BMD or osteoporotic fractures.
Project description:BACKGROUND Adrenergic receptor ?2A (?2A-AR) is up-regulated in osteoporotic bone osteoblasts. Previous research demonstrated an association between polymorphism of a2A-AR gene and bone mineral density (BMD) as well as bone turnover markers (BTMs) in the Slovenian population. The present study aimed to investigate the association of rs1800544 polymorphism of ?2A-AR gene with BMD and BTMs in the Chinese elderly population with osteoporosis (OP) or with osteoporotic fractures. MATERIAL AND METHODS A total of 346 unrelated elderly individuals were recruited in the study. Rs1800544 polymorphism was determined by Snapshot technology. BTMs were determined by electrochemiluminescence. BMDs at lumbar spine (LS) and proximal femur were measured with dual-energy X-ray absorptiometry (DEXA). Hardy-Weinberg equilibrium and distribution of genotype frequencies were verified using the chi-squared test. Analysis of co-variance (ANCOVA) adjusted for confounding factors was performed to explore the relationship of rs1800544 polymorphism with BMD and BTMs in all participants and in subgroups. RESULTS The genotype distributions in all subjects and in subgroups conformed to Hardy-Weinberg equilibrium (P>0.1). Distribution of genotype frequencies of subgroups showed no significant differences (P>0.05). Patients with GG genotype in the fracture group had significantly higher serum BTMs level compared with those carrying other genotypes (P<0.05). No significant association between rs1800544 and BTMs was detected in the elderly population with OP. Comparison of BMD at each site in all participants did not show any significant difference in subgroups with CC, CG, and GG genotypes (P>0.05). CONCLUSIONS Rs1800544 polymorphism is associated with BTMs level in Chinese elderly individuals with osteoporotic fractures, indicating the involvement of genetic variation of a2A-AR gene in bone metabolism.