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.

抽象的镰状细胞病 (SCD) 肾病或 SCDN，定义为存在蛋白尿或肾小球肾功能低下滤过率 (GFR) 影响高达 30% 的成年 SCD 患者我们已经发现 SCD 患者的 GFR 下降。没有 SCD 的非裔美国人中可能进展为终末期肾病的患者几乎是其两倍。疾病；两者都是 SCD 早期死亡的潜在危险因素。 SCDN 与其他内皮病的相关性，尤其是肺动脉高压。目前的治疗选择仅限于用于其他肾脏疾病的治疗，例如糖尿病肾病、因此，尽早识别高危患者并开发有效的治疗方法。专门针对 SCDN 的病理生理学是至关重要的，遗传因素（最突出的是 APOL1）的影响。然而，APOL1 不足以解释所有 SCDN 风险，提示其他临床和风险。 NHLBI 的 TOPMed 计划是一个取得重大进展的绝佳机会。 SCD 个性化医疗的发现，包括我们的队列 (OMG-SCD) 以及其他队列。 TOPMed SCD队列，总共>4100个样本，具有全基因组序列结果和丰富的临床数据，包括我们的 OMG-SCD 队列存储了以前用于生成的血浆样本。代谢组学和初步蛋白质组学数据，并确定与 GFR 快速下降相关的两种代谢物以及八种蛋白质，包括半胱氨酸蛋白酶抑制剂-C 和补体因子 D，估计 GFR 低于 90 mL/min/1.73 m2. 生成额外的蛋白质组数据将有助于生物标志物的发现和基础生物学具体来说，我们建议：（1）确定 SCDN 的新临床和遗传危险因素； (2) 确定 SCDN 的蛋白质组生物标志物；以及 (3) 建立风险模型以对患有和的 SCD 患者进行分类我们将利用大量的、特征明确的 TOPMed SCD 队列来发现 SCDN 的分子基础是 SCD 最大的临床挑战之一，因为其存在巨大的风险我们的工作有望在 SCDN 风险因素（遗传位点、生物标志物），指出因果生物学机制，从而促进风险分层临床研究，以进一步针对这一患者群体的精准医疗方法的发展。

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.

全基因组荟萃分析确定了镰状细胞病肾病的新候选基因。

DOI：
发表时间：
2023-09-12
期刊：
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
通讯作者：
Ashley

Gene-metabolite annotation with shortest reactional distance enhances metabolite genome-wide association studies results.

具有最短反应距离的基因代谢物注释增强了代谢物全基因组关联研究结果。

DOI：
发表时间：
2023-03-24
期刊：
影响因子：
0
作者：
Baron, Cantin;Cherkaoui, Sarah;Therrien;Ilboudo, Yann;Poujol, Raphaël;Mehanna, Pamela;Garrett, Melanie E;Telen, Marilyn J;Ashley;Bartolucci, Pablo;Rioux, John D;Lettre, Guillaume;Des Rosiers, Christine;Ruiz
通讯作者：
Ruiz

Genetic Modifiers of Sickle Cell Disease.

镰状细胞病的遗传修饰剂。

DOI：
10.1016/j.hoc.2022.06.006
发表时间：
2022-12-01
期刊：
Hematology/oncology clinics of North America
影响因子：
0
作者：
Thomas Pincez;A. Ashley;G. Lettre;M. Telen
通讯作者：
M. Telen

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

单基因镰状细胞病多基因血液学性状的变异和影响。

DOI：
发表时间：
2023-03-01
期刊：
影响因子：
10.1
作者：
Pincez, Thomas;Lo, Ken Sin;D'Orengiani, Anne;Garrett, Melanie E;Brugnara, Carlo;Ashley;Telen, Marilyn J;Galacteros, Frederic;Joly, Philippe;Bartolucci, Pablo;Lettre, Guillaume
通讯作者：
Lettre, Guillaume

Gene-metabolite annotation with shortest reactional distance enhances metabolite genome-wide association studies results.

具有最短反应距离的基因代谢物注释增强了代谢物全基因组关联研究结果。

DOI：
发表时间：
2023-12-15
期刊：
影响因子：
5.8
作者：
Baron, Cantin;Cherkaoui, Sarah;Therrien;Ilboudo, Yann;Poujol, Raphaël;Mehanna, Pamela;Garrett, Melanie E;Telen, Marilyn J;Ashley;Bartolucci, Pablo;Rioux, John D;Lettre, Guillaume;Rosiers, Christine Des;Ruiz
通讯作者：
Ruiz