Genomics of glomerular disease

肾小球疾病的基因组学

• 批准号: 10413152
• 负责人: KRZYSZTOF KIRYLUK
• 金额: $ 87.01万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-14 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413152
• 关键词: APOL1 gene; Accounting; Address; African American population; Autoimmune; Autoimmune Diseases; Biological; Biological Markers; Biopsy; Blood; Clinical; Collaborations; Communities; Coupled; Data; Data Set; Diabetes Mellitus; Diagnosis; Disease; Disease Pathway; End stage renal failure; Etiology; Focal Segmental Glomerulosclerosis; Gene Expression Profile; Gene Expression Regulation; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Translation; Genetic Variation; Genetic study; Genomic medicine; Genomics; Hypertension; IGA Glomerulonephritis; Immune; Inflammatory; Inflammatory Bowel Diseases; Institutes; International; Investments; Kidney Failure; Knowledge; Lupus; Maps; Mediating; Membranous Glomerulonephritis; Meta-Analysis; Molecular; Molecular Disease; Molecular Profiling; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Nephrotic Syndrome; Outcome; Participant; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Population; Prevention; Prospective Studies; Prospective cohort; Renal glomerular disease; Resources; Risk; Role; Sample Size; Sampling; South Asian; Specificity; Steroids; Subcategory; Susceptibility Gene; System; Therapeutic; Translating; United States; Variant; admixture mapping; case control; cell type; clinical translation; cohort; design; disorder subtype; exome; functional genomics; gene function; gene regulatory network; genetic approach; genetic architecture; genetic association; genetic resource; genetic variant; genome sequencing; genome wide association study; genomic data; genomic locus; insertion/deletion mutation; insight; kidney biopsy; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; peripheral blood; rare variant; risk variant; screening; therapeutic target; transcriptome; transcriptomics; treatment response; validation studies; whole genome

Abstract: Glomerular disorders represent the third-most common cause of end-stage renal disease after diabetes and hypertension. IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN) and minimal change disease (MCD) account for the majority of idiopathic glomerular diseases. Recent genetic studies have identified several genetic loci for these disorders and have begun to identify critical molecular pathways involved in their pathogenesis. However, well-designed and adequately powered genetic association studies are still missing for most glomerular disease types. Moreover, the field is faced with major challenges, including the need to validate the new loci across diverse patient cohorts, understand dysregulated pathways downstream of risk alleles and their consequences on clinical outcomes, define disease-specificity and interactions of risk alleles, and place their functional consequences within a coherent biological network. Such insights can then be translated into clinical benefits, including reliable biomarkers, effective strategies for screening and prevention, and rational selection of potential therapeutic targets. This proposal will address the above challenges by aiming to discover, validate, and fine-map known and novel genetic susceptibility loci by collaborative genetic studies. This will include a pioneering partnership with AstraZeneca and Columbia's Institute for Genomic Medicine to perform whole genome sequencing (WGS) of 4,000 cases of glomerular disease, including the entire CureGN study, the largest prospective cohort of patients with glomerular disorders. This will be followed by international meta-analyses and genetic validation studies in additional 26,000 cases of biopsy-confirmed primary glomerular disorders. Next, we will aim to discover precise pathogenic mechanisms underpinning each of the new genetic loci using systems genetics studies in the CureGN cohort. We will integrate the genetic data with blood transcriptomic studies and clinico-pathologic analyses to identify the key molecular disease drivers and their clinical and histopathologic consequences. Our studies will leverage the largest investment of NIDDK in glomerular diseases to refine the molecular pathogenesis and will be critical in defining targets for novel therapeutic interventions.

摘要： 肾小球疾病是终末期肾病的第三大常见原因，仅次于糖尿病和 高血压。IgA肾病(IgAN)、局灶节段性肾小球硬化(FSGS)、膜性肾病 特发性肾小球疾病以微小病变病(MCD)和微小病变病(MN)为主。近期 遗传学研究已经确定了这些疾病的几个遗传位点，并已开始确定关键的 参与其发病机制的分子途径。然而，设计良好、动力充足的基因 大多数肾小球疾病类型的相关性研究仍然缺乏。此外，该领域还面临着重大 挑战，包括需要在不同的患者队列中验证新的基因座，理解失调 风险等位基因下游的通路及其对临床结果的影响，定义了疾病特异性 以及风险等位基因的相互作用，并将它们的功能后果置于一个连贯的生物网络中。 这样的洞察力然后可以转化为临床益处，包括可靠的生物标志物、有效的治疗策略 筛查和预防，合理选择潜在治疗靶点。这项提案将解决 以上挑战，旨在通过以下方式发现、验证和精细绘制已知和新的遗传易感基因座 协作性基因研究。这将包括与阿斯利康和哥伦比亚的开创性合作 基因组医学研究所对4,000例肾小球进行全基因组测序 疾病，包括整个CureGN研究，这是肾小球疾病患者的最大预期队列。 随后将对另外26,000个病例进行国际荟萃分析和遗传验证研究 活检证实为原发性肾小球疾病。接下来，我们将致力于发现精确的致病机制 使用CureGN队列中的系统遗传学研究来支持每个新的遗传位点。我们会 将基因数据与血液转录研究和临床病理分析相结合，以确定关键 分子疾病驱动因素及其临床和组织病理学后果。我们的研究将利用 NIDDK在肾小球疾病中的最大投资，以完善分子发病机制，并将是关键 确定新的治疗干预措施的目标。

项目成果

Membranous Nephropathy: From Research Bench to Personalized Care.

• DOI: 10.3390/jcm10061205
• 发表时间: 2021-03-14
• 期刊: Journal of clinical medicine
• 影响因子: 3.9
• 作者: Moszczuk B;Kiryluk K;Pączek L;Mucha K
• 通讯作者: Mucha K

Glomerular Diseases of the Kidney Allograft: Toward a Precision Medicine Approach.

• DOI: 10.1016/j.semnephrol.2022.01.005
• 发表时间: 2022-01
• 期刊: SEMINARS IN NEPHROLOGY
• 影响因子: 3.3
• 作者: Zanoni, Francesca;Khairallah, Pascale;Kiryluk, Krzysztof;Batal, Ibrahim
• 通讯作者: Batal, Ibrahim

Global Incidence of IgA Nephropathy by Race and Ethnicity: A Systematic Review.

• DOI: 10.34067/kid.0000000000000165
• 发表时间: 2023-08-01
• 期刊: Kidney360
• 作者: Kiryluk K;Freedberg DE;Radhakrishnan J;Segall L;Jacobson JS;Mathur M;Mohan S;Neugut AI
• 通讯作者: Neugut AI