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

基本信息

批准号：
9494637
负责人：
Erick Forno
金额：
$ 15.8万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/9494637
关键词：
Adipocytes Adult Affect Age Asthma Bioinformatics Biological Body Composition Body mass index Boston 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 Expression Profiling 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 Inhalation Insulin Intervention Laboratories Leptin Leukocytes Literature Manuscripts Mentors Methylation Nasal Epithelium Nose Obesity Ontology Overweight PRKCA gene Pathway interactions Patients Pediatric Hospitals Pediatric Research Pediatrics Peru Phenotype Predisposition Prevalence Proteomics Proxy Public Health Public Health Schools Puerto Rican Quality of life Quantitative Trait Loci 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 multiple omics new therapeutic target novel marker novel strategies obesity in children programs public health relevance recruit response subcutaneous symposium targeted treatment

项目摘要

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（由申请人提供）：候选人：Erick Forno 博士是一位儿科肺科医生，具有深厚的哮喘研究背景。他毕业于卡耶塔诺埃雷迪亚大学（秘鲁）医学院，并在丹佛儿童医院做过儿科住院医师（2006 年）。波士顿儿童医院/哈佛医学院研究员（2009 年）。他还拥有哈佛公共卫生学院公共卫生硕士学位 (MPH)。 (2009). 他的主要科学兴趣是儿童肥胖与哮喘之间的关联。他是 31 篇论文的作者或合著者，其中 26 篇论文涉及儿童哮喘的流行病学和遗传流行病学。儿科研究（SPR）。环境：匹兹堡大学医学中心 (UPMC) 匹兹堡儿童医院 (CHP) 隶属于匹兹堡大学医学院，是一家领先的儿科临床护理、研究和卓越教育中心。 Forno 博士在新的 Rangos 研究中心工作，该中心由以下机构组成。 10 层楼设有最先进的实验室、办公室和会议设施，在 CHP、医学院和公共卫生研究生院举办各种科学会议和会议，并进行世界一流的研究。除了 Forno 博士的主要导师 Juan Celedón 博士的出色指导外，匹兹堡大学还为年轻研究人员提供了绝佳的机会，机构承诺包括超过 80% 的研究保护时间；遗传统计学家、数据库管理员和实验室工作人员；并保证工资支持至 2016 年 7 月。匹兹堡大学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全面的实验室和生物信息学支持。研究：意义：儿童哮喘和肥胖是主要的公共卫生问题。尽管有证据表明两者之间存在关系，但其潜在机制仍不清楚，在本项目中，我们的目标是更好地描述儿童肥胖哮喘的亚表型，并确定潜在的遗传、表观遗传和遗传因素。这将使我们能够更好地识别特定的患者群体并确定新的生物标志物和治疗方法。创新：拟议的研究与现状有很大不同，现状仅根据高体重指数（BMI）来定义肥胖哮喘，并假设所有肥胖哮喘儿童都是相似的。它也是创新的，因为它将增强的表型与基因组相结合。广泛（GW）表观遗传和基因组数据，以确定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，由几种亚表型组成，每种亚表型都有特定的遗传和基因组途径。我们的具体目标是：1）通过无监督分析定义肥胖哮喘亚表型并在外部队列中验证它们； 2) 使用鼻上皮和白细胞 (WBC) 中的 GW DNA 甲基化和表达谱来鉴定与此类增强表型相关的表观遗传和基因组途径；3) 鉴定表达；和甲基化数量性状位点（eQTL 和 mQTL），并进行 mQTL/eQTL 加权遗传关联研究，以确定与“肥胖哮喘”表型相关的遗传变异。方法：在目标 1 中，我们将使用来自患有和不患有哮喘的波多黎各儿童队列的数据，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聚类（波多黎各人都患有哮喘和哮喘）这些集群将在两个独立队列中进行验证：CAMP（儿童哮喘管理计划，n=1,041）和 GARCS （哥斯达黎加哮喘遗传学研究，n=1,150）在目标 2 中，我们将从正在招募的 500 名儿童的鼻上皮和白细胞中获得 GW DNA 甲基化和基因表达谱。我们将分析鼻上皮和白细胞的变化。与目标 1 中确定的簇相关的甲基化和基因表达。显着上调或下调的基因将被包括在基因本体分析中，以识别与亚表型相关的通路。在目标 3 中，我们将识别也与目标 1 中的簇相关的 eQTL 和 mQTL。然后，我们将在 mQTL/ 中查看来自目标 2 的基因和通路。 eQTL 加权 GWAS 数据可检测构成这些“肥胖哮喘”亚表型的 SNP。未来方向：将包括扩大样本量、多“组学”整合、功能验证以及招募专门用于研究肥胖和哮喘的独立队列。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glycemic control and FEV1 recovery during pulmonary exacerbations in pediatric cystic fibrosis-related diabetes.

DOI：
10.1016/j.jcf.2019.12.016
发表时间：
2020-01
期刊：
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
影响因子：
0
作者：
W. Okoniewski;K. Hughan;G. Weiner;D. Weiner;E. Forno
通讯作者：
W. Okoniewski;K. Hughan;G. Weiner;D. Weiner;E. Forno

Childhood obesity and asthma: To BMI or not to BMI?