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Osteoporosis- and obesity-risk interrelationships: an epigenetic analysis of GWAS-derived SNPs at the developmental gene TBX15.

骨质疏松症和肥胖-风险相互关系: 发育基因 tbx15 处 GWAS 衍生 SNPs 的表观遗传分析。

  • 影响因子:4.73
  • DOI:10.1080/15592294.2020.1716491
  • 作者列表:"Zhang X","Ehrlich KC","Yu F","Hu X","Meng XH","Deng HW","Shen H","Ehrlich M
  • 发表时间:2020-01-24
Abstract

:A major challenge in translating findings from genome-wide association studies (GWAS) to biological mechanisms is pinpointing functional variants because only a very small percentage of variants associated with a given trait actually impact the trait. We used an extensive epigenetics, transcriptomics, and genetics analysis of the TBX15/WARS2 neighbourhood to prioritize this region's best-candidate causal variants for the genetic risk of osteoporosis (estimated bone density, eBMD) and obesity (waist-hip ratio or waist circumference adjusted for body mass index). TBX15 encodes a transcription factor that is important in bone development and adipose biology. Manual curation of 692 GWAS-derived variants gave eight strong candidates for causal SNPs that modulate TBX15 transcription in subcutaneous adipose tissue (SAT) or osteoblasts, which highly and specifically express this gene. None of these SNPs were prioritized by Bayesian fine-mapping. The eight regulatory causal SNPs were in enhancer or promoter chromatin seen preferentially in SAT or osteoblasts at TBX15 intron-1 or upstream. They overlap strongly predicted, allele-specific transcription factor binding sites. Our analysis suggests that these SNPs act independently of two missense SNPs in TBX15. Remarkably, five of the regulatory SNPs were associated with eBMD and obesity and had the same trait-increasing allele for both. We found that WARS2 obesity-related SNPs can be ascribed to high linkage disequilibrium with TBX15 intron-1 SNPs. Our findings from GWAS index, proxy, and imputed SNPs suggest that a few SNPs, including three in a 0.7-kb cluster, act as causal regulatory variants to fine-tune TBX15 expression and, thereby, affect both obesity and osteoporosis risk.

摘要

: 翻译全基因组关联研究 (GWAS) 发现的主要挑战 to 生物学机制是精确定位功能性变异,因为只有极少数与给定性状相关的变异实际上影响性状。我们使用了 TBX15/WARS2 邻域的广泛表观遗传学、转录组学和遗传学分析来优先考虑该区域骨质疏松症遗传风险的最佳候选因果变异 (估计骨密度,eBMD) 和肥胖 (腰臀比或腰围调整体重指数)。TBX15 编码一种在骨骼发育和脂肪生物学中很重要的转录因子。手工处理 692 个 GWAS 衍生的变异,给出了 8 个强候选的因果 SNPs,这些 SNPs 在皮下脂肪组织 (SAT) 或成骨细胞中调节 TBX15 转录,高度和特异性表达该基因。这些 SNPs 都没有通过贝叶斯精细图谱确定优先级。8 个调控因果 SNPs 在增强子或启动子染色质中,优先见于 SAT 或成骨细胞 TBX15 intron-1 或上游。它们重叠了强烈预测的等位基因特异性转录因子结合位点。我们的分析表明,这些 SNPs 独立于 tbx15 中的两个错义 SNPs 起作用。值得注意的是,其中 5 个调控 SNPs 与 eBMD 和肥胖相关,并且两者具有相同的性状增加等位基因。我们发现 WARS2 肥胖相关 SNPs 可归因于与 TBX15 intron-1 SNPs 的高连锁不平衡。我们从 GWAS 索引、代理和插补 SNPs 的研究结果表明,一些 SNPs,包括 0.7 kb 集群中的三个,作为因果调控变体来微调 TBX15 表达和, 从而,影响肥胖和骨质疏松症的风险。

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相关文献
影响因子:4.73
发表时间:2020-01-24
来源期刊:Epigenetics
DOI:10.1080/15592294.2020.1716491
作者列表:["Zhang X","Ehrlich KC","Yu F","Hu X","Meng XH","Deng HW","Shen H","Ehrlich M"]

METHODS::A major challenge in translating findings from genome-wide association studies (GWAS) to biological mechanisms is pinpointing functional variants because only a very small percentage of variants associated with a given trait actually impact the trait. We used an extensive epigenetics, transcriptomics, and genetics analysis of the TBX15/WARS2 neighbourhood to prioritize this region's best-candidate causal variants for the genetic risk of osteoporosis (estimated bone density, eBMD) and obesity (waist-hip ratio or waist circumference adjusted for body mass index). TBX15 encodes a transcription factor that is important in bone development and adipose biology. Manual curation of 692 GWAS-derived variants gave eight strong candidates for causal SNPs that modulate TBX15 transcription in subcutaneous adipose tissue (SAT) or osteoblasts, which highly and specifically express this gene. None of these SNPs were prioritized by Bayesian fine-mapping. The eight regulatory causal SNPs were in enhancer or promoter chromatin seen preferentially in SAT or osteoblasts at TBX15 intron-1 or upstream. They overlap strongly predicted, allele-specific transcription factor binding sites. Our analysis suggests that these SNPs act independently of two missense SNPs in TBX15. Remarkably, five of the regulatory SNPs were associated with eBMD and obesity and had the same trait-increasing allele for both. We found that WARS2 obesity-related SNPs can be ascribed to high linkage disequilibrium with TBX15 intron-1 SNPs. Our findings from GWAS index, proxy, and imputed SNPs suggest that a few SNPs, including three in a 0.7-kb cluster, act as causal regulatory variants to fine-tune TBX15 expression and, thereby, affect both obesity and osteoporosis risk.

影响因子:3.23
发表时间:2020-01-24
DOI:10.1007/s00432-019-03119-3
作者列表:["Riffel P","Schwaab J","Lutz C","Naumann N","Metzgeroth G","Fabarius A","Schoenberg SO","Hofmann WK","Valent P","Reiter A","Jawhar M"]

METHODS:PURPOSE:Systemic mastocytosis (SM) is characterized by the expansion of clonal mast cells that infiltrate various organ systems. The extent of organ infiltration and subsequent organ damage distinguishes between indolent SM (ISM) defined by a nearly normal life expectancy and advanced SM (AdvSM) defined by poor prognosis. In ISM, measurement of the bone mineral density (BMD) frequently reveals osteoporosis. In contrast, the clinical implication of an increased BMD and osteosclerosis remains unclear. METHODS:BMD was evaluated in 61 patients with mastocytosis (ISM, n = 29, 48%; AdvSM, n = 32, 52%). We correlated the prevalence of osteoporosis, increased BMD and osteosclerosis with clinical parameters, disease variant and prognosis. RESULTS:Osteoporosis was detected in 11/29 (38%) patients with ISM but only in 2/32 (6%) patients with AdvSM (p = 0.004). An increased BMD was detected in 1/29 (3%) patients with ISM and 24/32 (75%) patients with AdvSM (p < 0.001) while osteosclerosis was only detected in AdvSM patients (16/32, 50%). AdvSM patients with increased BMD had higher levels of bone marrow mast cell infiltration, higher serum tryptase and alkaline phosphatase levels compared to ISM as well as higher number of high-molecular risk mutations (p < 0.05). In addition, we found that the prognosis of AdvSM patients with increased BMD is inferior compared to those without increased BMD (median overall survival 3.6 years versus not reached, p = 0.031). CONCLUSIONS:Osteoporosis is a common feature in ISM but not in AdvSM. An increased BMD is frequently present in AdvSM but not in ISM and is associated with more advanced disease and inferior outcome.

影响因子:5.94
发表时间:2020-01-24
DOI:10.1016/j.nano.2020.102153
作者列表:["Kotak DJ","Devarajan PV"]

METHODS::We present salmon calcitonin (SCT) loaded Hydroxyapatite nanoparticles (HAP-NPs) for sublingual osteoporosis therapy. Surface stabilized HAP-NPs were prepared by aqueous precipitation. SCT was loaded by ionic complexation, as confirmed by FTIR. SCT-HAP-NPs exhibited high loading efficiency (~85%), average size (~100nm), and zeta potential (~-25 mv). Stability of SCT was established by circular dichroism spectroscopy and HPLC analysis. Confocal laser scanning microscopy confirmed deep penetration of SCT-HAP-NPs into the mucosa with >4-fold enhancement in permeability relative to SCT solution. Sublingual SCT-HAP-NPs revealed relative bioavailability of ~15% compared to the subcutaneous injection in rabbits (200iu). Significant and comparable improvement in serum biomarkers with increase in bone mass and mechanical strength and decreased bone erosion compared to subcutaneous SCT was confirmed in ovariectomized (OVX) osteoporosis rat model. Such comparable pharmacodynamic effect at the same dose suggested targeted bone delivery and promise of sublingual SCT-HAP-NPs as a non-invasive alternative to the injection.

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