Candidate: Dr. Erick Forno is a pediatric pulmonologist with a strong background in asthma research. He graduated medical school from Cayetano Heredia University (Per), 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 Celedn, 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.

Public Health Relevance

Childhood asthma and obesity are serious public health problems. The current project aims to identify and validate distinct sub-phenotypes of obese asthma, and to integrate these enhanced sub-phenotypes with genome-wide epigenetic and genomic data to detect their underlying genetic determinants. This will allow us to better recognize specific groups of patients, and identify novel biomarkers and treatment approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL125666-02
Application #
9132836
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Tigno, Xenia
Project Start
2015-09-01
Project End
2019-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Mendy, Angelico; Forno, Erick; Niyonsenga, Theophile et al. (2018) Blood biomarkers as predictors of long-term mortality in COPD. Clin Respir J 12:1891-1899
Forno, Erick; Han, Yueh-Ying; Mullen, James et al. (2018) Overweight, Obesity, and Lung Function in Children and Adults-A Meta-analysis. J Allergy Clin Immunol Pract 6:570-581.e10
Forno, Erick; Wang, Ting; Qi, Cancan et al. (2018) DNA methylation in nasal epithelium, atopy, and atopic asthma in children: a genome-wide study. Lancet Respir Med :
Forno, Erick (2018) Breast feeding in infancy and recurrent cough in adulthood: the longer the better? Thorax 73:801-802
Han, Yueh-Ying; Forno, Erick; Canino, Glorisa et al. (2018) Psychosocial risk factors and asthma among adults in Puerto Rico. J Asthma :1-9
Rosser, Franziska; Han, Yueh-Ying; Forno, Erick et al. (2018) Urinary polycyclic aromatic hydrocarbons and allergic sensitization in a nationwide study of children and adults in the United States. J Allergy Clin Immunol 142:1641-1643.e6
Han, Yueh-Ying; Forno, Erick; Shivappa, Nitin et al. (2018) The Dietary Inflammatory Index and Current Wheeze Among Children and Adults in the United States. J Allergy Clin Immunol Pract 6:834-841.e2
Forno, Erick; Han, Yueh-Ying; Libman, Ingrid M et al. (2018) Adiposity and Asthma in a Nationwide Study of Children and Adults in the United States. Ann Am Thorac Soc 15:322-330
Szentpetery, Sylvia E; Han, Yueh-Ying; Brehm, John M et al. (2018) Vitamin D insufficiency, plasma cytokines, and severe asthma exacerbations in school-aged children. J Allergy Clin Immunol Pract 6:289-291.e2
Han, Yueh-Ying; Forno, Erick; Boutaoui, Nadia et al. (2018) Vitamin D insufficiency, TH2 cytokines, and allergy markers in Puerto Rican children with asthma. Ann Allergy Asthma Immunol 121:497-498.e1

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