Obesity and Asthma Subphenotypes and Underlying Genetic and Genomic Pathways

肥胖和哮喘亚表型以及潜在的遗传和基因组途径

• 批准号: 9267052
• 负责人: Erick Forno
• 金额: $ 15.42万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267052
• 关键词: Adipocytes; Adult; Affect; Age; Asthma; Bioinformatics; Biological; Body Composition; Body mass index; Boston; Breathing; Candidate Disease Gene; Central obesity; Characteristics; Child; Childhood; Childhood Asthma; Cluster Analysis; Complex; Coronary artery; Costa Rica; DNA Methylation; Data; Databases; Discriminant Analysis; Disease; Education; Environment; Epidemiology; Epigenetic Process; Epithelial; Fatty acid glycerol esters; Fellowship; Floor; Gender; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Determinism; Genetic study; Genomics; Genotype; Glucosamine-6-phosphate isomerase; Glucose; Human Resources; Insulin; Intervention; Laboratories; Leptin; Leukocytes; Literature; Manuscripts; Mentors; Methylation; Molecular Profiling; Nasal Epithelium; Nose; Obesity; Ontology; Overweight; PRKCA gene; Pathway interactions; Patients; Pediatric Hospitals; Pediatric Research; Pediatrics; Peru; Pharmacotherapy; Phenotype; Predisposition; Prevalence; Proteomics; Proxy; Public Health; Public Health Schools; Puerto Rican; Quality of life; Quantitative Trait Loci; Recruitment Activity; Regulation; Reporting; Research; Research Personnel; Residencies; Resource Allocation; Respiratory physiology; Sample Size; Severities; Single Nucleotide Polymorphism; Societies; Syndrome; Techniques; Testing; Time; Universities; Validation; Variant; Visceral; Wages; Waist-Hip Ratio; Weight; Work; asthmatic; atopy; base; clinical care; cohort; design; epidemiology study; faculty research; genetic association; genetic epidemiology; genetic variant; genome wide association study; genome-wide; genomic data; high risk; improved; innovation; interest; medical schools; meetings; new therapeutic target; novel marker; novel strategies; obesity in children; programs; public health relevance; response; subcutaneous; symposium

 DESCRIPTION (provided by applicant): Candidate: Dr. Erick Forno is a pediatric pulmonologist with a strong background in asthma research. He graduated medical school from Cayetano Heredia University (Perú), did residency in Pediatrics at Children's Hospital of Denver (2006) and fellowship at Children's Hospital Boston / Harvard Medical School (2009). He also has a Master's in Public Health (MPH) from Harvard School of Public Health (2009). His main scientific interest is the association between childhood obesity and asthma. He is author or co-author of 31 manuscripts, 26 of which are on the epidemiology and genetic epidemiology of childhood asthma. In 2013 he was elected to the Society of Pediatric Research (SPR). Environment: Children's Hospital of Pittsburgh (CHP) of UPMC, affiliated with the University of Pittsburgh School of Medicine, is a leading pediatric center for clinical care, research, and education excellence. Dr. Forno works in the new Rangos Research Center, comprised of 10 floors of state-of-the-art laboratories, offices, and conference facilities. With a variety of scietific conferences and meetings held at CHP, the School of Medicine, and the Graduate School of Public Health, as well as world-class research faculty, the University of Pittsburgh offers exceptional opportunities to young investigators. In addition to superb mentoring by Dr. Juan Celedón, Dr. Forno's primary mentor, institutional commitment includes >80% research protected time; dedicated office space and resource allocation; shared personnel including a genetic statistician, database manager, and laboratory staff; and guaranteed salary support until July 2016. The University of Pittsburgh Genomics and Proteomics Core Laboratories (GPCL) offers full laboratory and bioinformatics support for genome-wide (GW) genotyping, DNA methylation, and gene expression analysis, on both Illumina and Affymetrix platforms. Research: SIGNIFICANCE: Childhood asthma and obesity are major public health problems. While there is ample evidence of a relationship between both and increased recognition of an "obese asthmatic" phenotype, the underlying mechanisms are still unclear. In this project we aim to better characterize sub-phenotypes of obese asthma in children, and to identify underlying genetic, epigenetic, and genomic mechanisms. This will allow us to better recognize specific groups of patients and identify novel biomarkers and treatment approaches. INNOVATION: The proposed research represents a significant departure from the status quo, which defines obese asthma solely based on high body mass index (BMI) and assumes all obese asthmatic children are similar. It is also innovative because it will integrate enhanced phenotyping with genome-wide (GW) epigenetic and genomic data in order to identify biologically plausible genetic variants. AIMS: Our hypothesis is that "obese asthma" is heterogeneous and comprised of several sub-phenotypes, each with specific genetic and genomic pathways. Our specific aims are: 1) To define obese asthmatic subphenotypes via unsupervised analysis and validate them in external cohorts; 2) To identify epigenetic and genomic pathways associated with such enhanced phenotypes, using GW DNA methylation and expression profiling in both nasal epithelium and white blood cells (WBCs); and 3) To identify expression and methylation quantitative trait loci (eQTLs and mQTLs) and perform an mQTL/eQTL-weighted study of genetic association to identify genetic variants associated with "obese asthma" phenotypes. APPROACH: In Aim 1, we will use cluster analysis, discriminant analysis, and recursive partitioning to define clusters of obese asthmatic children with similar phenotypic characteristics using data from a cohort of Puerto Rican children with and without asthma (Puerto Ricans share high burdens of both asthma and obesity). These clusters will be validated in two independent cohorts: CAMP (Childhood Asthma Management Program, n=1,041) and GARCS (Genetics of Asthma in Costa Rica Study, n=1,150). In Aim 2, we will obtain GW DNA methylation and gene expression profiling from nasal epithelium and WBCs in 500 children that are being recruited. We will analyze changes in nasal epithelial and WBC methylation and gene expression associated with the clusters identified in Aim 1. Genes significantly up- or down-regulated will be included in gene ontology analyses to identify pathways related to the sub-phenotypes. In Aim 3, we will identify eQTL and mQTL that are also associated with clusters from Aim 1. Then, we will look at genes and pathways from Aim 2 in mQTL/eQTL-weighted GWAS data to detect SNPs that underlie these "obese asthma" sub-phenotypes. FUTURE DIRECTIONS: Will include expanding sample size, multi-"omic" integration, functional validation, and recruitment of an independent cohort specifically designed to study obesity and asthma.

 描述（由适用提供）：候选人：Erick Forno博士是一名儿科肺科医生，在哮喘研究方面具有很强的背景。他从卡耶塔诺·埃雷迪亚大学（Cayetano Heredia University）毕业于医学院，在丹佛儿童医院（2006年）和波士顿儿童医院 /哈佛医学院（2009年）的儿童医院居住在儿科医院（2006年）。他还拥有哈佛公共卫生学院（2009年）的公共卫生硕士学位（MPH）。他的主要科学兴趣是儿童肥胖与哮喘之间的关联。他是31个手稿的作者或合着者，其中26位是关于儿童哮喘的流行病学和遗传流行病学。 2013年，他当选为儿科研究协会（SPR）。 环境：UPMC的匹兹堡儿童医院（CHP），匹兹堡大学医学院的会员，是领先的临床护理，研究和教育卓越的儿科中心。 Forno博士在新的Rangos研究中心工作，由10层最先进的实验室，办公室和会议设施组成。匹兹堡大学在卫生卫生会议，医学院和公共卫生研究生院以及世界一流的研究学院举行了各种科学会议和会议，为年轻的调查人员提供了非凡的机会。除了胡安·塞莱登（JuanCeledón）博士精神上的精神外，Forno博士的主要精神，机构承诺还包括80％的研究受保护的时间；专用的办公空间和资源分配；共享人员，包括遗传统计学家，数据库经理和实验室人员；并保证薪水支持直到2016年7月。 匹兹堡大学的基因组学和蛋白质组学核心实验室（GPCL）在Illumina和Affymetrix平台上为全基因组（GW）基因分型，DNA甲基化和基因表达分析提供了全面的实验室和生物信息学支持。 研究： 意义：童年哮喘和肥胖是主要的公共卫生问题。虽然有很多 两者之间存在关系的证据与对“肥胖哮喘”表型的认识增加，基本机制仍然不清楚。在这个项目中，我们旨在更好地表征儿童肥胖哮喘的亚表征，并鉴定潜在的遗传，表观遗传和基因组机制。这将使我们能够更好地识别特定的患者组，并确定新颖的生物标志物和治疗方法。 创新：拟议的研究代表了与现状的重要不同，该现状仅基于高体重指数（BMI）定义肥胖哮喘，并假设所有肥胖的哮喘儿童都是相似的。它也具有创新性，因为它将将增强的表型与全基因组（GW）的表观遗传学和基因组数据整合在一起，以鉴定具有生物学上合理的遗传变异。 目的：我们的假设是“肥胖哮喘”是异质的，包括几种亚表现型，每种都有特定的遗传和基因组途径。我们的具体目的是：1）通过无监督分析来定义肥胖的哮喘亚表格，并在外部人群中验证它们； 2）使用GW DNA甲基化和鼻上皮细胞和白细胞（WBC）中的GW DNA甲基化和表达分析，以鉴定与这种增强表型相关的表观遗传和基因组途径； 3）识别表达和甲基化定量性状位置（EQTL和MQTLS），并对遗传关联进行MQTL/EQTL加权研究，以鉴定与“肥胖性哮喘”表型相关的遗传变异。 方法：在AIM 1中，我们将使用聚类分析，判别分析和递归分区来定义具有相似表型特征的肥胖哮喘儿童的簇，并使用来自有或没有哮喘的波多黎各人的数据（波多黎各人有和没有哮喘的儿童）（波多黎各人都具有哮喘和肥胖症的高燃烧）。这些集群将在两个独立的队列中进行验证：CAMP（童年哮喘管理计划，n = 1,041）和GARCS（哥斯达黎加研究中哮喘的遗传学，n = 1,150）。在AIM 2中，我们将在500名正在招募的儿童的鼻上皮和WBC中获得GW DNA甲基化和基因表达分析。我们将分析鼻皮上和WBC甲基化的变化以及与AIM 1中鉴定的簇相关的基因表达。基因显着上调或下调的基因将是 包含在基因本体分析中，以识别与亚表征相关的途径。在AIM 3中，我们将确定与AIM 1的簇相关的EQTL和MQTL。然后，我们将研究MQTL/EQTL加权GWAS数据中的AIM 2的基因和途径，以检测这些“肥胖的”子表型的SNP，以检测这些SNP。 未来的方向：将包括扩大样本量，多种“ OMIC”整合，功能验证以及专门设计旨在研究肥胖和哮喘的独立队列的招募。