Identifying novel clinical, genetic and proteomic risk factors for sickle cell nephropathy.

识别镰状细胞肾病的新临床、遗传和蛋白质组学危险因素。

基本信息

批准号：
10382268
负责人：
ALLISON E ASHLEY-KOCH
金额：
$ 16.1万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382268
关键词：
APOL1 gene Adult Affect African American population Algorithms Alleles Biological Biological Markers Biology Body mass index Ceruloplasmin Characteristics Childhood Chromosome 13 Chronic Kidney Failure Clinical Clinical Data Clinical Research Complement Factor D Creatinine Data Data Analyses Data Set Development Diabetic Nephropathy Disease Progression End stage renal failure Etiology Exhibits Functional disorder Gene Frequency Generations Genetic Glomerular Filtration Rate Hemoglobinuria Kidney Kidney Diseases Knowledge Link Medical Genetics Mendelian randomization Meta-Analysis Metabolic Microalbuminuria Minor Modeling Molecular Morbidity - disease rate National Heart, Lung, and Blood Institute Orosomucoid Outcome Pathway interactions Patients Phenotype Plasma Platelet Count measurement Population Predisposition Proteins Proteinuria Proteomics Publishing Pulmonary Hypertension Renal function Reticulocyte count Risk Risk Factors Sample Size Sampling Serum Severities Sickle Cell Sickle Cell Anemia Stroke Testing Therapeutic Trans-Omics for Precision Medicine Walking Work biomarker discovery body system clinical risk cohort genetic association genetic risk factor genetic variant genome wide association study genome-wide genomic locus improved metabolomics mortality nephrin novel novel therapeutics patient population patient stratification personalized medicine post gamma-globulins precision medicine predictive modeling programs risk stratification therapeutic target therapeutically effective urinary whole genome

项目摘要

ABSTRACT Sickle cell disease (SCD) nephropathy or SCDN, as defined by the presence of proteinuria or low glomerular filtration rate (GFR), affects up to 30% of adult SCD patients. We have shown that GFR decline among SCD patients is nearly double that among African Americans without SCD. SCDN can progress to end-stage renal disease; both are potent risk factors for early mortality in SCD. This association may be partly attributable to the correlation of SCDN with other endotheliopathic conditions, especially pulmonary hypertension. SCDN therapeutic options are currently limited to those used for other renal diseases, such as diabetic nephropathy, and are not particularly efficacious. Thus, identifying at-risk patients early and developing effective therapeutics targeted specifically to the pathophysiology of SCDN is critical. Genetic factors, most notably APOL1, influence susceptibility to SCDN. However, APOL1 is insufficient to explain all SCDN risk, suggesting other clinical and genetic risk factors exist. NHLBI’s TOPMed program is an extraordinary opportunity to make significant discoveries in personalized medicine for SCD, including SCDN. Our cohort (OMG-SCD), together with other TOPMed SCD cohorts, total >4100 samples with whole genome sequence results and rich clinical data, including kidney-related phenotypes. Our OMG-SCD cohort has stored plasma samples, used previously to generate metabolomics and preliminary proteomics data and identify two metabolites associated with rapid GFR decline and eight proteins, including cystatin-C and complement factor D, with estimated GFR below 90 mL/min/1.73 m2. Generation of additional proteomic data would facilitate biomarker discovery and underlying biologic mechanisms of SCDN. Specifically, we propose to: (1) Identify novel clinical and genetic risk factors for SCDN; (2) Identify proteomic biomarkers for SCDN; and (3) Establish risk models to classify SCD patients with and without nephropathy. We will harness the large, well-characterized TOPMed SCD cohorts to uncover the molecular underpinnings of SCDN, one of the greatest clinical challenges in SCD, due to the profound risk for morbidity and mortality. Our work is poised to yield significant discoveries of SCDN risk factors (genetic loci, biomarkers), point toward causal biologic mechanisms, and thus facilitate risk-stratified clinical studies to further the development of precision medicine approaches in this patient population.

抽象的镰状细胞疾病（SCD）肾病或SCDN，由蛋白尿或低肾小球的存在定义过滤率（GFR）影响多达30％的成年SCD患者。我们已经证明SCD中的GFR下降了在没有SCD的非裔美国人中，患者的两倍。 SCDN可以发展到终端肾脏疾病;两者都是SCD早期死亡率的潜在危险因素。该关联可能部分归因于 SCDN与其他内皮性疾病的相关性，尤其是肺动脉高压。 SCDN 目前，治疗选择仅限于其他用于其他肾脏疾病的方法，例如糖尿病性肾病，并且不是特别高效。那就早日识别高危患者并开发有效的治疗专门针对SCDN的病理生理学是至关重要的。遗传因素，最著名的是APOL1，影响对SCDN的敏感性。但是，Apol1不足以解释所有SCDN风险，提示其他临床和存在遗传危险因素。 NHLBI的最佳计划是一个巨大的机会 SCD的个性化医学发现，包括SCDN。我们的队列（OMG-SCD）以及其他顶级SCD队列，总计> 4100个具有全基因组序列结果和丰富临床数据的样本，包括与肾脏有关的表型。我们的OMG-SCD队列已经存储了血浆样品，以前用于生成代谢组学和初步蛋白质组学数据，并识别两个与GFR快速下降相关的代谢物八种蛋白质，包括胱抑素-C和补体因子D，估计的GFR低于90 mL/min/1.73 M2。生成其他蛋白质组学数据将有助于生物标志物发现和潜在的生物学 SCDN的机制。具体而言，我们建议：（1）确定SCDN的新型临床和遗传危险因素；（2）确定SCDN的蛋白质组学生物标志物；（3）建立风险模型，将SCD患者分类为没有肾病。我们将利用大型，良好的顶级SCD队列来揭示 SCDN的分子基础是SCD中最大的临床挑战之一，这是由于巨大的风险发病率和死亡率。我们的工作被毒死，以产生SCDN危险因素的重大发现（遗传基因座，，生物标志物），指向因果生物学机制，从而促进风险分层的临床研究以进一步该患者人群的精确医学方法的发展。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genome-wide meta-analysis identifies new candidate genes for sickle cell disease nephropathy.

DOI：
10.1182/bloodadvances.2022007451
发表时间：
2023-09-12
期刊：
BLOOD ADVANCES
影响因子：
7.5
作者：
Garrett, Melanie E.;Soldano, Karen L.;Erwin, Kyle N.;Zhang, Yingze;Gordeuk, Victor R.;Gladwin, Mark T.;Telen, Marilyn J.;Ashley-Koch, Allison E.
通讯作者：
Ashley-Koch, Allison E.

Variation and impact of polygenic hematologic traits in monogenic sickle cell disease.

DOI：
10.3324/haematol.2022.281180
发表时间：
2023-03-01
期刊：
HAEMATOLOGICA
影响因子：
10.1
作者：
Pincez, Thomas;Lo, Ken Sin;Garrett, Melanie E.;Brugnara, Carlo;Ashley-Koch, Allison E.;Telen, Marilyn J.;Joly, Philippe;Bartolucci, Pablo;Lettre, Guillaume
通讯作者：
Lettre, Guillaume

Genetic Modifiers of Sickle Cell Disease.