A functional genomics pipeline for genetic discovery in diabetic kidney disease

用于糖尿病肾病遗传发现的功能基因组学管道

• 批准号: 10673703
• 负责人: JOSE CARLOS FLOREZ
• 金额: $ 63.15万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673703
• 关键词: Address; Affect; Amputation; Animals; Award; Biological; Biological Assay; Biological Markers; Biological Models; Biological Process; Biology; Blindness; Blood; Cell model; Chronic Kidney Failure; Code; Collaborations; Collagen Type IV; Complement; Complex; Complication; Complications of Diabetes Mellitus; DNA Sequence; Data; Data Set; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathy; End stage renal failure; Epigenetic Process; Etiology; Experimental Models; Frequencies; Funding Mechanisms; Gene Expression Profiling; Genes; Genetic; Genetic Determinism; Genetic Markers; Genomics; Grant; Heart Diseases; Heritability; Heterogeneity; Human; Hyperglycemia; Individual; Infrastructure; Inherited; Insulin-Dependent Diabetes Mellitus; Interdisciplinary Study; International; Ireland; Kidney; Kidney Diseases; Knowledge; Longitudinal cohort; Mediating; Mendelian randomization; Meta-Analysis; Metabolic Diseases; Methylation; Michigan; Microvascular Dysfunction; Missense Mutation; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Northern Ireland; Organ; Organoids; Participant; Pathogenesis; Pathway interactions; Patients; Pennsylvania; Phenotype; Prevention; Prevention strategy; Preventive measure; Proteins; Public Health; Regulatory Element; Research; Resources; Risk; Risk Factors; Sample Size; Sampling; Severities; Signal Transduction; Stroke; Transcript; Universities; Untranslated RNA; Validation; Variant; Work; Zebrafish; clinical predictors; cohort; computerized tools; data integration; diabetic; epigenomics; exome sequencing; functional genomics; genetic analysis; genetic association; genetic risk factor; genome sequencing; genome wide association study; genome-wide; glomerular basement membrane; glycemic control; human data; human stem cells; improved; in vivo Model; insight; kidney biopsy; kidney cell; model organism; molecular targeted therapies; novel; peripheral blood; potential biomarker; predictive tools; protein structure; rare variant; statistics; success; synergism; type I and type II diabetes; whole genome

ABSTRACT Diabetic kidney disease (DKD) is a devastating microvascular complication of both type 1 (T1D) and type 2 diabetes (T2D). It has been shown to have a heritable component, but prior searches for the genetic determinants of this condition have had limited success. In the Genetics of Nephropathy – an International Effort (GENIE) Consortium, a collaboration between Queen’s University Belfast, University of Dublin, University of Helsinki, University of Michigan, University of Pennsylvania and the Broad Institute, we have leveraged an ongoing co-funding mechanism between Ireland, Northern Ireland and the US. This international genomics consortium enucleated a larger Diabetic Nephropathy Collaborative Research Initiative, which coalesced to assemble nearly 20,000 samples from participants with T1D, with and without kidney disease. We performed a genome-wide association study (GWAS) and discovered 16 new signals at genome-wide significance. The strongest signal centered on a protective missense coding variant at COL4A3, which encodes an integral component of the glomerular basement membrane, implicating this aspect of kidney biology in DKD. In this award, we propose to build on this established infrastructure to undertake the following Specific Aims: (1) to significantly expand our sample size by including ~150,000 samples with DKD in the context of T2D, thereby substantially increasing our power to discover shared and distinct risk factors for DKD in T1D and T2D, and to use computational tools to derive biological insights into DKD pathogenesis; (2) to generate a genome-wide epigenomic dataset in both peripheral blood and human kidney to inform the relevance of genetic findings, enable the construction of predictive tools, and infer causality via Mendelian randomization; and (3) to create an experimental pipeline centered on animal, cellular and organoid models of DKD to pursue functional validation of promising genetic findings. This ongoing close collaboration of multidisciplinary and synergistic research groups should advance our knowledge of the molecular determinants of DKD, identify potential molecular targets for therapeutics, and facilitate clinical prediction.

摘要 糖尿病肾病(DKD)是一种毁灭性的1型(T1D)微血管并发症 和2型糖尿病(T2D)。它已被证明具有可遗传的成分，但之前的研究 因为这种疾病的遗传决定因素取得的成功有限。在《遗传学》中 肾病-一个国际努力(精灵)联盟，女王的合作 贝尔法斯特大学、都柏林大学、赫尔辛基大学、密歇根大学、 在宾夕法尼亚州和布罗德学院，我们利用了一个持续的联合资助机制 在爱尔兰、北爱尔兰和美国之间。这个国际基因组学联盟 摘除了一个更大的糖尿病肾病合作研究倡议，该倡议联合到 收集了近20,000名患有和不患有肾脏疾病的T1D患者的样本。 我们进行了全基因组关联研究，发现了16个新的信号 全基因组的意义。以保护性错义编码为中心的最强信号 Col4A3变异体，编码肾小球基底膜的一个整体成分 膜，暗示DKD中肾脏生物学的这一方面。在这个奖项中，我们建议建立 关于这一既定的基础设施承担以下具体目标：(1)显著 扩大我们的样本规模，在T2D环境中包括约150,000个具有DKD的样本，从而 大大增强了我们在T1D中发现DKD共同和独特风险因素的能力 和T2D，并使用计算工具得出DKD发病机制的生物学见解；(2) 在外周血和人类肾脏中生成全基因组表观基因组数据集 告知遗传发现的相关性，使预测工具的构建成为可能，并推断 通过孟德尔随机化的因果关系；以及(3)创建以以下内容为中心的实验管道 DKD的动物、细胞和器官模型寻求有希望的基因的功能验证 调查结果。多学科和协作性研究小组正在进行的密切合作 应该提高我们对DKD分子决定因素的知识，识别潜在的 治疗的分子靶点，并促进临床预测。

项目成果

Longitudinal Epigenome-Wide Analysis of Kidney Transplant Recipients Pretransplant and Posttransplant.

• DOI: 10.1016/j.ekir.2022.11.001
• 发表时间: 2023-02
• 期刊: KIDNEY INTERNATIONAL REPORTS
• 影响因子: 6
• 作者: Smyth, Laura J.;Kerr, Katie R.;Kilner, Jill;McGill, Aine E.;Maxwell, Alexander P.;McKnight, Amy Jayne
• 通讯作者: McKnight, Amy Jayne