Genetics of IgA nephropathy by integrative network-based association studies

基于综合网络关联研究的 IgA 肾病遗传学

• 批准号: 10660683
• 负责人: KRZYSZTOF KIRYLUK
• 金额: $ 68.52万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-17 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660683
• 关键词: Acceleration; Affect; Antibodies; Antigen-Antibody Complex; B-Cell Antigen Receptor; Biological; Biological Markers; Blood; Blood Vessels; CRISPR/Cas technology; Callback; Candidate Disease Gene; Cell Nucleus; Cell secretion; Cells; Characteristics; Childhood; Chromosome Mapping; Circulation; Clinical; Clinical Research; Complement; Complex; Defect; Deposition; Development; Disease; Disease Progression; Disease susceptibility; Drug Targeting; Epigenetic Process; Exhibits; Family; Funding; Galactose; Gene Targeting; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genomics; Glomerulonephritis; Goals; Grant; Health; Henoch-Schoenlein Purpura; Heritability; Heterozygote; Histopathology; Human; IGA Glomerulonephritis; IgA receptor; IgA1; Immune; Immune system; Immunoglobulin A; Immunoglobulins; Immunologics; Immunophenotyping; In Vitro; Individual; Injury to Kidney; Intestinal Mucosa; Joints; Kidney; Kidney Diseases; Kidney Failure; Knock-out; Ligands; Maps; Mediating; Mendelian randomization; Meta-Analysis; Modeling; Mucous Membrane; Multicenter Studies; Myeloid Cells; Nephritis; Network-based; Outcome; Pakistan; Pathogenesis; Pathogenicity; Patients; Pharmaceutical Preparations; Phenotype; Prospective cohort; Proteome; Regulatory Element; Resolution; Risk; Role; Serum; Severities; Signal Transduction; Skin; Small Interfering RNA; Study of serum; Susceptibility Gene; System; Therapeutic Intervention; Time; Validation; Variant; Vasculitis; biobank; candidate validation; causal variant; clinical translation; cohort; consanguineous family; cytokine; disorder risk; endophenotype; experimental study; gain of function; gastrointestinal; genetic analysis; genetic architecture; genetic signature; genetic variant; genome resource; genome wide association study; genome-wide; genomic locus; glycosylation; high risk; insight; interest; loss of function; multiple omics; new therapeutic target; novel; phenome; population based; prospective; receptor; response; risk variant; trait; vascular inflammation; vascular injury

Abstract: IgA Nephropathy is the most common form of primary glomerulonephritis and an important cause of kidney failure worldwide. The affected individuals develop characteristic IgA1-containing antibody complexes that deposit in the kidney, producing progressive renal injury. The disease is associated with a specific pathogenic defect in the O-glycosylation of IgA1 that promotes formation of immune complexes. Similar to other immune- mediated disorders, IgA nephropathy has a complex genetic architecture. In the prior funding period, we completed a GWAS for IgA nephropathy (10,146 cases and 28,751 controls) and we identified 30 genome- wide significant risk loci, explaining 11% of disease risk. We observed clear convergence of biological candidate genes on a common set of cytokine ligand-receptor pairs involved in mucosal IgA responses, including on targets of existing drugs. In a GWAS of 2,170 cases and 5,928 controls, we also defined novel genome-wide significant loci for IgA vasculitis, a related childhood condition with kidney complications. We further enhanced these efforts by studies of serum IgA (GWAS in 41,263 individuals) and galactose-deficient- IgA1 levels (GWAS in 10,193 individuals). Mendelian randomization provided strong genetic support for the causal role of these endophenotypes. The overall goal of this proposal is to leverage these findings to identify causal genes underlying shared genetic susceptibility between these traits. In Aim 1, we plan to conduct multi- phenotype mapping across all four traits to better define shared and trait-specific loci. Multiome single nuclei sequencing will be used to generate high resolution regulatory maps of IgA+ cells for fine-mapping and prioritization of candidate causal genes. In Aim 2, we will study the role of the prioritized genes in health and disease by leveraging Pakistani Genomic Resource, the largest cohort of human knockouts (KOs), with homozygous KOs for >5000 genes and heterozygous KOs for >18,000 genes. We will perform call-back studies in selected consanguineous families to identify carriers of loss-of-function and gain-of-function variants in the genes of interest, followed by clinical and detailed immunophenotyping studies. These efforts will be complemented by targeted gene perturbation experiments in IgA1-producing cells. In Aim 3, we will perform phenome-wide association studies, and correlate our new genetic findings with clinical features. Based on these findings, we will formulate and validate an integrated genomic risk score for kidney disease progression in two large prospective cohorts of IgA nephropathy and IgA vasculitis with nephritis. These studies are expected to refine our proposed disease pathogenesis model, define new therapeutic targets, and accelerate clinical translation of our genetic findings.

摘要： 伊加肾病是原发性肾小球肾炎中最常见的一种，也是肾损害的重要原因。 全世界的失败受影响的个体产生特征性的含有IgA 1的抗体复合物， 存款在肾脏，产生进行性肾损伤。这种疾病与一种特定的致病性 促进免疫复合物形成的IgA 1 O-糖基化缺陷。与其他免疫系统类似- 伊加肾病是一种由多种免疫调节因子介导的疾病，具有复杂的遗传结构。在上一个融资周期，我们 完成了一项伊加肾病的GWAS（10，146例病例和28，751例对照），我们确定了30个基因组， 广泛的显著风险位点，解释了11%的疾病风险。我们观察到明显的生物学收敛 参与粘膜伊加应答的一组常见细胞因子配体-受体对上的候选基因， 包括现有药物的靶点。在2,170例病例和5,928例对照的GWAS中，我们还定义了新的 伊加血管炎的全基因组显著位点，IgA血管炎是一种与肾脏并发症相关的儿童疾病。我们 进一步加强了这些努力的研究血清伊加（GWAS在41,263人）和半乳糖缺乏， IgA 1水平（10，193人中的GWAS）。孟德尔随机化提供了强有力的遗传支持， 这些内在表型的因果作用。本提案的总体目标是利用这些调查结果， 这些性状之间存在共同的遗传易感性的因果基因。在目标1中，我们计划进行多项 表型作图在所有四个性状，以更好地定义共享和性状特异性基因座。多体单核 测序将用于产生伊加+细胞的高分辨率调控图谱，用于精细定位， 候选致病基因的优先排序。在目标2中，我们将研究优先基因在健康中的作用， 巴基斯坦基因组资源是最大的人类基因敲除（科斯）队列， >5000个基因的纯合科斯和> 18，000个基因的杂合科斯。我们将执行回调 在选定的近亲家庭中进行研究，以确定功能丧失和功能获得变异的携带者 在感兴趣的基因，其次是临床和详细的免疫表型研究。这些努力将 通过在产生IgA 1的细胞中进行靶向基因扰动实验来补充。在目标3中，我们将 全表型关联研究，并将我们的新遗传发现与临床特征相关联。基于 根据这些发现，我们将制定并验证肾脏疾病进展的综合基因组风险评分 在伊加肾病和伊加血管炎伴肾炎的两个大型前瞻性队列中。这些研究 预计将完善我们提出的疾病发病机制模型，定义新的治疗靶点，并加速 我们基因发现的临床转化。

项目成果

Clinical Predictors and Prognosis of Recurrent IgA Nephropathy in the Kidney Allograft.

• DOI: 10.1159/000519834
• 发表时间: 2022-01
• 期刊: Glomerular diseases
• 作者: Kavanagh, Catherine R;Zanoni, Francesca;Leal, Rita;Jain, Namrata G;Stack, Megan Nicole;Vasilescu, Elena-Rodica;Serban, Geo;Shaut, Carley;Kamal, Jeanne;Kudose, Satoru;Martinho, Antonio;Alves, Rui;Santoriello, Dominick;Canetta, Pietro A;Cohen, David;Radhakrishnan, Jai;Appel, Gerald B;Stokes, Michael B;Markowitz, Glen S;D'Agati, Vivette D;Kiryluk, Krzysztof;Andeen, Nicole K;Batal, Ibrahim
• 通讯作者: Batal, Ibrahim

Leukemia Inhibitory Factor Signaling Enhances Production of Galactose-Deficient IgA1 in IgA Nephropathy

• DOI: 10.1159/000505748
• 发表时间: 2020-05-01
• 期刊: KIDNEY DISEASES
• 影响因子: 3.7
• 作者: Yamada, Koshi;Huang, Zhi Qiang;Novak, Jan
• 通讯作者: Novak, Jan