骨质疏松症易感基因BDNF的遗传学关联分析及功能研究

发布时间：2018-03-09 23:09

本文选题：关联分析　切入点：单核苷酸多态性　出处：《遗传》2017年08期 　论文类型：期刊论文

【摘要】：为探索脑源性神经营养因子BDNF基因与中国汉族人群骨密度(bone mineral density,BMD)的关系,解析该基因调节骨质疏松症的功能机制,进而为中国汉族人群的骨质疏松症的防治提供依据。本研究从我国陕西地区征集了1300例汉族样本,并测量髋部/脊椎骨密度。选取BDNF基因上的14个标签SNPs进行基因分型,与1300例样本BMD进行关联分析,发现8个SNPs与髋部/脊椎BMD显著关联(P0.05)。其中,SNP rs16917237同时与髋部和脊椎骨密度关联,经Bonferroni校正后仍表现出显著性(0.05/14=0.0036)。整合连锁不平衡和单体型分析、表观功能注释、表达数量基因座分析、代谢通路分析进一步探索BDNF基因调节骨质疏松症的机制。构建小鼠前成骨细胞系(MC3T3-E1)人骨形态形成蛋白(rh BMP-2)诱导分化模型,利用小干扰RNA(si RNA)敲除BDNF。结果显示:14个SNPs位于同一单体型内;rs16917237在成骨细胞中表现出较强的激活型组蛋白H3K4me1、H3K4me3、H3K27ac修饰信号以及P300结合信号,表明其在成骨细胞中可能具有调控活性;rs16917237在11个组织中均能显著影响BDNF基因表达;BDNF基因位于与成骨细胞增殖分化相关的MAPK通路中;BDNF敲低能够显著降低MAPK通路中与成骨分化相关的CREB基因m RNA和蛋白表达水平,提示其可能通过调控CREB表达进而影响成骨分化。生物信息学分析和功能实验结果一致,表明BDNF基因可能是影响骨质疏松症的重要功能基因。
[Abstract]:To explore the relationship between brain-derived neurotrophic factor (BDNF) gene and bone mineral density (BMD) in Chinese Han population, the functional mechanism of brain-derived neurotrophic factor (BDNF) regulating osteoporosis was analyzed. In this study, 1 300 Han nationality samples were collected from Shaanxi area of China, and hip / vertebra density was measured. 14 SNPs tags on BDNF gene were selected for genotyping. Correlation analysis with 1 300 samples of BMD showed that 8 SNPs were significantly associated with hip / spinal BMD (P0.05A). Among them, SNPs were associated with both hip and vertebral density, and were still significantly correlated with the density of hip and vertebrae after Bonferroni correction. Integrated linkage disequilibrium and haplotype analysis were also observed. The mechanism of BDNF gene regulating osteoporosis was further explored by apparent functional annotation, quantitative locus analysis and metabolic pathway analysis. A mouse preosteoblast cell line (MC3T3-E1) was established to induce differentiation of human bone morphogenetic protein (rh BMP-2). Small interfering RNA(si RNAs were used to knockout BDNF. The results showed that 14 SNPs were located in the same haplotype, rs16917237 showed strong activated histone H3K4me1H3K4me3H3K27ac modification signal and P300 binding signal in osteoblasts. These results suggest that rs16917237 may have regulatory activity in osteoblasts. In 11 tissues, the expression of BDNF gene was significantly affected by the presence of BDNF knockout in the MAPK pathway associated with proliferation and differentiation of osteoblasts. The expression level of CREB gene m RNA and protein related to osteogenic differentiation, The results of bioinformatics analysis were consistent with the results of functional experiments, suggesting that BDNF gene may be an important functional gene affecting osteoporosis.
【作者单位】：西安交通大学生命科学与技术学院生物医学信息工程教育部重点实验室;
【基金】：国家自然科学基金项目(编号:31471188,81573241) 中国博士后科学基金项目(编号:2016M602797) 陕西省自然科学基础研究项目(编号:2016JQ3026)资助~~
【分类号】：R580

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