Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome ...that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6x10(-8)), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6x10(-13); SOX6, p = 6.4x10(-10)) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Bone quality is an important determinant of osteoporosis, and proper osteoblast differentiation plays an important role in the control and maintenance of bone quality. We investigated the impact of ...activin signaling on human osteoblast differentiation, extracellular matrix formation, and mineralization. Activins belong to the transforming growth factor-β superfamily and activin A treatment strongly inhibited mineralization in osteoblast cultures, whereas the activin antagonist follistatin increased mineralization. Osteoblasts produced activin A and follistatin in a differentiation-dependent manner, leading to autocrine regulation of extracellular matrix formation and mineralization. In addition, mineralization in a vascular smooth muscle cell-based model for pathological calcification was inhibited. Comparative activin A and follistatin gene expression profiling showed that activin signaling changes the expression of a specific range of extracellular matrix proteins prior to the onset of mineralization, leading to a matrix composition with reduced or no mineralizing capacity. These findings demonstrate the regulation of osteoblast differentiation and matrix mineralization by the activin A-follistatin system, providing the possibility to control bone quality as well as pathological calcifications such as atherosclerosis by using activin A, follistatin, or analogs thereof.--Eijken, M., Swagemakers, S., Koedam, M., Steenbergen, C., Derkx, P., Uitterlinden, A. G., van der Spek, P. J., Visser, J. A., de Jong, F. H., Pols, H. A. P., van Leeuwen, J. P. T. M. The activin A-follistatin system: potent regulator of human extracellular matrix mineralization.
The relationship between use of corticosteroids and fracture risk was estimated in a meta‐analysis of data from seven cohort studies of ∼42,000 men and women. Current and past use of corticosteroids ...was an important predictor of fracture risk that was independent of prior fracture and BMD.
Introduction: The aims of this study were to validate that corticosteroid use is a significant risk factor for fracture in an international setting and to explore the effects of age and sex on this risk.
Materials and Methods: We studied 42,500 men and women from seven prospectively studied cohorts followed for 176,000 patient‐years. The cohorts comprised the EPOS/EVOS study, CaMos, the Rotterdam Study, Dubbo Osteoporosis Epidemiology Study (DOES), and prospective cohorts at Sheffield, Rochester, and Gothenburg. The effect of ever use of corticosteroids, BMD, age, and sex on all fracture, osteoporotic fracture, and hip fracture risk alone was examined using Poisson regression in each cohort and for each sex. The results of the different studies were merged from the weighted β coefficients.
Results: Previous corticosteroid use was associated with a significantly increased risk of any fracture, osteoporotic fracture, and hip fracture when adjusted for BMD. Relative risk of any fracture ranged from 1.98 at the age of 50 years to 1.66 at the age of 85 years. For osteoporotic fracture, the range of relative risk was 2.63‐1.71, and for hip fracture 4.42‐2.48. The estimate of relative risk was higher at younger ages, but not significantly so. No significant difference in risk was seen between men and women. The risk was marginally and not significantly upwardly adjusted when BMD was excluded from the model. The risk was independent of prior fracture. In the three cohorts that documented current corticosteroid use, BMD was significantly reduced at the femoral neck, but fracture risk was still only partly explained by BMD.
Conclusion: We conclude that prior and current exposure to corticosteroids confers an increased risk of fracture that is of substantial importance beyond that explained by the measurement of BMD. Its identification on an international basis validates the use of this risk factor in case‐finding strategies.
It remains unclear if inflammation itself may induce cancer, if inflammation is a result of tumor growth, or a combination of both exists. The aim of this study was to examine whether C-reactive ...protein (CRP) levels and CRP gene variations were associated with an altered risk of colorectal, lung, breast, or prostate cancer.
A total of 7,017 participants age > or = 55 years from the Rotterdam Study were eligible for analyses. Mean follow-up time was 10.2 years. High-sensitivity CRP measurements were performed to identify additional values of 0.2 to 1.0 mg/L compared with standard procedures. Genotypes of the CRP gene were determined with an allelic discrimination assay.
High levels (> 3 mg/L) of CRP were associated with an increased risk of incident cancer (hazard ratio, 1.4; 95% CI, 1.1 to 1.7) compared with persons with low levels (< 1 mg/L), even after a potential latent period of 5 years was introduced. Although CRP seems to affect several cancer sites, the association was strongest for lung cancer (hazard ratio, 2.8; 95% CI, 1.6 to 4.9). A CRP single nucleotide polymorphism associated with decreased CRP levels was associated with an increased lung cancer risk of 2.6 (95% CI, 1.6 to 4.4) in homozygous carriers.
Baseline CRP levels seem to be a biomarker of chronic inflammation preceding lung cancer, even after subtracting a 5-year latent period. Furthermore, CRP gene variation associated with low CRP blood levels was relatively common in patients with lung cancer. Both chronic inflammation and impaired defense mechanisms resulting in chronic inflammation might explain these results.
Bone mineral density (BMD) is a heritable complex trait used in the clinical diagnosis of osteoporosis and the assessment of fracture risk. We performed meta-analysis of five genome-wide association ...studies of femoral neck and lumbar spine BMD in 19,195 subjects of Northern European descent. We identified 20 BMD loci that reached genome-wide significance (GWS; P < 5 x 10(-8)), of which 13 map to regions not previously associated with this trait: 1p31.3 (GPR177), 2p21 (SPTBN1), 3p22 (CTNNB1), 4q21.1 (MEPE), 5q14 (MEF2C), 7p14 (STARD3NL), 7q21.3 (FLJ42280), 11p11.2 (LRP4, ARHGAP1, F2), 11p14.1 (DCDC5), 11p15 (SOX6), 16q24 (FOXL1), 17q21 (HDAC5) and 17q12 (CRHR1). The meta-analysis also confirmed at GWS level seven known BMD loci on 1p36 (ZBTB40), 6q25 (ESR1), 8q24 (TNFRSF11B), 11q13.4 (LRP5), 12q13 (SP7), 13q14 (TNFSF11) and 18q21 (TNFRSF11A). The many SNPs associated with BMD map to genes in signaling pathways with relevance to bone metabolism and highlight the complex genetic architecture that underlies osteoporosis and variation in BMD.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Context: Persistence with osteoporosis treatment is poor but is important for maximum benefit.
Objective: The objective of the study was to assess the impact of physician reinforcement using bone ...turnover markers (BTMs) on persistence with risedronate treatment.
Design and Setting: This was a 1-yr multinational prospective, open-label, blinded study in 171 osteoporosis centers in 21 countries.
Patients: A total of 2382 postmenopausal women (65–80 yr old) with spine/hip T-score −2.5 or less or T-score −1.0 or less with a low-trauma fracture.
Intervention: Intervention included calcium 500 mg/d, vitamin D 400 IU/d, and risedronate 5 mg/d for 1 yr. Centers were randomized to reinforcement (RE+) or no reinforcement (RE−). At 13 and 25 wk, reinforcement based on urinary N-telopeptide of type I collagen change from baseline was provided to the RE+ patients using the following response categories: good (>30% decrease), stable (−30% to +30% change), or poor (>30% increase).
Main Outcome Measures: Persistence assessed with electronic drug monitors was measured.
Results: In the overall efficacy population (n = 2302), persistence was unexpectedly high and was similar for both groups (RE−, 77%; RE+, 80%; P = 0.160). A significant relationship between the type of message and persistence was observed (P = 0.017). Compared with RE−, intervention based on a good BTM response was associated with a significant improvement in persistence hazard ratio (HR) 0.71; 95% confidence interval (CI) 0.53–0.95. Persistence was unchanged (HR 1.02; 95% CI 0.74–1.40) or lower (HR 2.22; 95% CI 1.27–3.89) when reinforcement was based on a stable or poor BTM response, respectively. Reinforcement was associated with a lower incidence of new radiologically determined vertebral fractures (odds ratio 0.4; 95% CI, 0.2–1.0).
Conclusions: Reinforcement using BTMs influences persistence with treatment in postmenopausal women with osteoporosis, depending on the BTM response observed.
BACKGROUND Anti-Müllerian hormone (AMH) inhibits primordial follicle recruitment in the mouse ovary. We hypothesize that in women AMH signaling also regulates the usage of the primordial follicle ...pool and hence influences the onset of menopause. Since age at menopause has a strong genetic component, we investigated the role of AMH signaling using a candidate gene approach. METHODS In two large population-based cohorts of Dutch post-menopausal women (n = 2381 and n = 248), we examined the association between two polymorphisms, one in the AMH gene and one in the AMH type II receptor (AMHR2) gene, and natural age at menopause. RESULTS The AMH Ile49Ser polymorphism (rs10407022) was not associated with age at menopause in either cohort. In the Rotterdam cohort, the AMHR2 −482 A > G polymorphism (rs2002555) was associated with age at menopause in interaction with the number of offspring (P = 0.001). Nulliparous women homozygous for the G-allele entered menopause 2.6 years earlier compared with nulliparous women homozygous for the A-allele (P = 0.005). In the LASA cohort, women with the G/G genotype tended to enter menopause 2.8 years earlier compared with the A/A genotype (P = 0.063). CONCLUSIONS The observed association of the AMHR2 −482 A > G polymorphism with natural age at menopause suggests a role for AMH signaling in the usage of the primordial follicle pool in women.
Polymorphisms of the vitamin D receptor gene (VDR) have been shown to be associated with several complex diseases, including osteoporosis, but the mechanisms are unknown and study results have been ...inconsistent. We therefore determined sequence variation across the major relevant parts of VDR, including construction of linkage disequilibrium blocks and identification of haplotype alleles. We analyzed 15 haplotype-tagging SNPs in relation to 937 clinical fractures recorded in 6,148 elderly whites over a follow-up period of 7.4 years. Haplotype alleles of the 5′ 1a/1e, 1b promoter region and of the 3′ untranslated region (UTR) were strongly associated with increased fracture risk. For the 16% of subjects who had risk genotypes at both regions, their risk increased 48% for clinical fractures (P = .0002), independent of age, sex, height, weight, and bone mineral density. The population-attributable risk varied between 1% and 12% for each block and was 4% for the combined VDR risk genotypes. Functional analysis of the variants demonstrated 53% lower expression of a reporter construct with the 1e/1a promoter risk haplotype (P = 5 × 10−7) in two cell lines and 15% lower mRNA level of VDR expression constructs carrying 3′-UTR risk haplotype 1 in five cell lines (P = 2 × 10−6). In a further analysis, we showed 30% increased mRNA decay in an osteoblast cell line for the construct carrying the 3′-UTR risk haplotype (P = .02). This comprehensive candidate-gene analysis demonstrates that the risk allele of multiple VDR polymorphisms results in lower VDR mRNA levels. This could impact the vitamin D signaling efficiency and might contribute to the increased fracture risk we observed for these risk haplotype alleles.
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