Epigenetics of Chronic Kidney Disease

慢性肾脏病的表观遗传学

• 批准号: 10545074
• 负责人: KATALIN SUSZTAK
• 金额: $ 48.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545074
• 关键词: Address; Affect; Agreement; Alternative Splicing; American; Award; Binding; Biological Assay; Candidate Disease Gene; Catalogs; Cells; Chromatin; Chromatin Structure; Chromosome Mapping; Chronic Kidney Failure; Code; DNA Sequence; Data Set; Development; Diagnostic; Disease; Distant; Epigenetic Process; Equipment and supply inventories; Ethnic Origin; Funding; Gene Dosage; Gene Expression; Gene Expression Profiling; Genes; Genotype; Heritability; Human; Inherited; Kidney; Kidney Diseases; Lead; Link; Mendelian randomization; Methods; Modeling; Mus; Organ; Pathogenesis; Pathway interactions; Phenotype; Predisposition; Quantitative Trait Loci; RNA Splicing; Regulator Genes; Renal Hypertension; Renal tubule structure; Role; Sample Size; Sampling; Scientist; Secondary to; Therapeutic; Tissue Banks; Transcript; Translating; Transposase; Untranslated RNA; Variant; Work; causal variant; cell type; diabetic; disease diagnostic; disorder risk; epigenome; follow-up; gene expression variation; genome wide association study; genome-wide analysis; improved; innovation; knockout gene; novel; novel therapeutics; risk variant; success; therapeutic development; transcription factor

The estimated heritability of kidney disease is around 50%. Common variants, that are almost always non-coding, account for much of the predisposition to prevalent, later-onset kidney diseases such as diabetic and hypertensive kidney disease (DKD, HKD). Genome wide association studies (GWAS) have provided a comprehensive inventory of these variants, each variant with modest impact on disease risk, but in aggregate they can explain most of disease heritability. Despite the remarkable success of GWAS, it has not translated into improved disease diagnostics and therapeutics as we fail to understand how non-coding variants cause kidney disease. The generally agreed model is that disease causing variants are on gene regulatory (open chromatin) region, alter transcription factor binding strength and quantitatively change the expression of a target gene in a cell type specific manner. Causal variant identification is impeded as DNA sequences that are close to each other are inherited together making it difficult to pick from the many linked variants. Due to secondary chromatin structure the nearest coding gene is not always the causal gene. The genotype effect may be cell-type specific explaining organ specific disease development. During the last award cycle, we catalogued genotype-driven gene-expression variation (eQTL; expression quantitative trait loci) in the glomerular and tubule compartments of human kidneys. Integration of the kidney GWAS and eQTL catalogues has been successful in identifying putative disease-causing genes and in a follow-up mouse gene knock-out study we showed that Dab2 is such new disease-causing gene. Kidney single cell gene expression analysis pointed to enrichment of disease associated genes in proximal tubules.

肾脏疾病的遗传力估计约为50％。常见变体，几乎总是 非编码，解释了流行的晚期肾脏疾病（例如糖尿病）的大部分倾向 和高血压肾脏疾病（DKD，HKD）。基因组广泛的关联研究（GWAS）提供了 这些变体的全面清单，每个变体都对疾病风险产生适度的影响，但总体上 他们可以解释大多数疾病的遗传力。尽管GWAS取得了巨大的成功，但尚未翻译 由于我们无法理解非编码变体，因此可以改善疾病诊断和治疗剂 引起肾脏疾病。 普遍认为的模型是导致变异的疾病是基因调节的（开放的 染色质）区域，改变转录因子结合强度并定量改变表达 特定于细胞类型的靶基因的靶基因。因果变异鉴定被阻碍作为DNA序列 彼此接近的人共同继承，使得很难从许多链接的变体中挑选。到期的 对于二级染色质结构，最近的编码基因并不总是因果基因。基因型效应 可能是细胞类型的特定解释器官特定疾病发育。 在最后一个奖励周期中，我们对基因型驱动的基因表达变异（EQTL; 在人肾的肾小球和小管室中的表达定量性状基因座。整合 肾脏GWAS和EQTL目录已经成功地识别了假定的致病基因 在一项随访小鼠基因敲除研究中，我们表明DAB2是如此新的致病基因。 肾脏单细胞基因表达分析指出，在近端富集了疾病相关基因 小管。