BACKGROUND: Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed eQTL analysis and bioinformatics network analysis. METHODS: We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction onlumbar spine (LS-) and femoral neck (FN-) BMD, in 25,353 individuals from eight cohorts. In a second stage, we followed up the 12 top SNPs (P(1X10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. RESULTS:We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect=0.02 & p-valueŽ=3.0X10(-5) ; female effect=-0.007 & p-value=3.3X10(-2) ) and eleven suggestive loci associated with either FN-or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (P(5X10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. CONCLUSION: Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found influencing BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP.
COBISS.SI-ID: 3286641
Genetic factors influencing the pathogenesis of osteoporosis are still largelyunknown. We employed genome-wide gene expression approach in order to discover novel genes involved in the pathogenesis of osteoporosis. To this end, primary cultures of osteoblasts isolated from osteoporotic and non-osteoporotic human bone tissue samples were prepared. One thousand six hundred six genes were found to be differentially expressed, indicating increased demand for protein synthesis and decreased cell proliferation rate in osteoblasts from osteoporotic tissue as compared to osteoblasts from non-osteoporotic tissue. At first, top four genes, based on the microarray data and potential role in bone metabolism, were further studied in bone tissue samples of 55 patients. PTN and COL15A1 were both downregulated in osteoporotic bone tissue (6.2- and 3.4-fold, respectively, both p ( 0.05), while IBSP and CXCL2 were both upregulated (5.7-fold, p ( 0.05, and 2.1-fold, p ) 0.05). Further biostatistical analysis of the microarray data by gene set enrichment analysis suggested oxidative stress may have an important part in the pathogenesis of osteoporosis. Thus, secondly, we tested it by an in vitro assay on human osteosarcoma cell line cells treated with hydrogen peroxide. After 72 h of treatment with 500 ?M hydrogen peroxide, the upregulation of thesame genes involved in the response to oxidative stress as on the microarrays was observed: MT1G (metallothionein 1G, 22.1-fold, p ( 0.05), TXNRD1 (thioredoxin reductase 1, 3.7-fold, p ( 0.05), AOX1 (aldehyde oxidase 1, 24.5-fold, p ( 0.05) and GSR (glutathione reductase, 4.7-fold, p ( 0.05). Our results present a novel list of genes and metabolic pathways that may be associated with the pathogenesis of osteoporosis. PTN, CXCL2, COL15A1, IBSP, AOX1, MT1G, GSR and TXNRD1 are candidate genes for further studies in the assessment of the genetic susceptibility to osteoporosis. In addition, differences in protein synthesis, cell proliferation rate and response to oxidative stress may also be involved in the pathogenesis of osteoporosis.
COBISS.SI-ID: 2678385
Bone mineral density (BMD) is the most widely used predictor of fracture risk.We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 1 17 genome-wide association studies and 32,961 1 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 1 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P ( 5 Ž 1 10Ž8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P ( 5 Ž 1 10Ž4, Bonferroni corrected), of which six reached P ( 5 Ž 1 10Ž8, including at 1 18p1111.21 (FAM210A), 7q21.3 (SLC25A13), 11 11 11q13.2 (LRP5), 4q22.1 1 (MEPE), 2p16.2 (SPTBN1) and 1 10q21.1 1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
COBISS.SI-ID: 3233137
BACKGROUND: Pro-inflammatory cytokines possess osteoclastogenic or anti-osteoclastogenic activities. They influence osteoclasts directly or via the receptor activator of nuclear factor kappaB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) system. Recent evidence suggests that inflammation may play a role in osteoporosis (OP) and osteoarthritis (OA). We aimed therefore to determine whether there is a difference between both groups: first, in the expression of the osteoclastogenic and anti-osteoclastogenic cytokines, second, in correlation of these cytokines with bone mineral density(BMD) and levels of bone turnover markers (BTM) and third, in correlation between the expression of these cytokines and osteoclast specific genes and RANK/RANKL/OPG genes. METHODS: Human bone samples from 54 age and sex matched patients with OP or OA were collected during hip arthroplasty surgery. The expression of 25 genes encoding pro-inflammatory cytokines, their receptors, osteoclast specific genes and RANK/RANKL/OPG genes was measured using quantitative real-time PCR. Total hip, femoral neck and lumbar spine BMD and BTM in blood samples were measured. The comparison between OP and OA was assessed using Student's t-test or Mann-Whitney U test and correlations between gene expression, BMD and BTM were determined using nonparametric correlation. RESULTS: The results demonstrated a higher expression of interleukin (IL)-6 and IL-1alpha in OP, and interferon (IFN)-gamma in OA (p ( 0.0005). Negative correlations of total hip BMD with tumor necrosis factor-alpha (TNF-alpha) in OA and with RANKL/RANK in OP were found (p ( 0.05). Significant correlations with BTM were shown for IL-1alpha and IFN-gamma in OP (rho = 0.608 and 0.634) and for TNF-alpha, IL-6 and transforming growth factor-beta1 (TGF-beta1) in OA (rho = 0.591, -0.521 and 0.636). Results showed OP specific negative correlations (IFN-gamma with ITGB3, IFN-beta1 with CTSK, tartrate resistant acid phosphatase (TRAP), CALCR,RANK, RANKL, IL-1alpha with CTSK, OPG, IL-17A with CALCR) and positive (TGF-beta1 with CTSK, TRAP, RANK), and OA specific negative (IL-1alpha with osteoclast associated immunoglobulin-like receptor (OSCAR), TNF-alpha with RANK, RANKL, OPG) and positive (IL-6 with RANK, RANKL, OPG) correlations. CONCLUSIONS: Our results demonstrate that the relationship between osteoclastogenic and anti-osteoclastogenic pro-inflammatory cytokines differs in human OP and OA bone and could present an important factor for characteristics of OP and OA bone phenotypes.
COBISS.SI-ID: 3207537
Objective: Oxidative stress participates in decreasing bone formation and stimulating bone resorption. Furthermore, antioxidant enzymes have been observed to have low protective activity in women with osteoporosis. The aim of the present study was to examine any association of selected gene polymorphisms of the glutathione S-reductase (GSR), superoxide dismutase (SOD1and SOD2), and catalase (CAT) genes, alone or in combination, with the bone mineral density (BMD) values of femoral neck (fn), lumbar spine (ls), andtotal hip (th) in Slovenian postmenopausal women. Methods: The gene polymorphisms of CAT, GSR, SOD1, and SOD2 genes in 468 postmenopausal women were analyzed using restriction fragment length polymorphism and a fluorescent5'-exonuclease genotyping method. BMD_fn, BMD_ls, and BMD_th were measured using dual-energy x-ray absorptiometry. Moreover, univariate statistic analysis and two-way analysis of variance for interaction testing were performed. Results: A significant association of BMD_th values (P = 0.027) was found in genotype subgroups of 423-287G)A GSR polymorphism located in the third intron among postmenopausal women. Furthermore, women with at least one G allele showed significantly higher levels of BMD_fn (P = 0.044), BMD_th (P = 0.009), and BMD_ls (P = 0.043) than those that are AA homozygotes.Interestingly, the 423-287G)A_GSR*1154-393T)A_GSR combination was significantly associated with BMD_fn (P = 0.013) and BMD_th (P = 0.002) in postmenopausal women. Conclusions: The results of our study demonstrate for the first time that antioxidant enzyme GSR gene polymorphisms are significantly associated with BMD, suggesting that the A allele of 423-287G)A GSR polymorphism could contribute to decreased BMD values in postmenopausal women.
COBISS.SI-ID: 3156593