# Integrative Genomics of the Asthma-COPD Overlap

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $399,266

## Abstract

ABSTRACT
Asthmatics with persistent symptoms are at great risk of developing fixed airways obstruction (AO). The
overarching hypothesis of this proposal is that it is this subset of asthmatics that is at greatest risk of developing
COPD and that this susceptibility is caused by specific genetic and epigenetic variants that influence the
expression of key asthma- and COPD-susceptibility genes expressed in the bronchial epithelium (BE), including
HHIP and FAM13A, TSLP and ORMDL3. We argue that characterization of these targets (and defining
additional candidates) will facilitate the development of more directed therapies to counter the adverse effects of
airway remodeling. To test these hypotheses, we propose three Specific Aims. In Aim 1, we will characterize the
mRNA and miRNA transcriptomic profiles in BE of the susceptible asthmatic in subjects from two well-
characterized cohorts: (i) asthmatics from CAMP who exhibit normal lung growth vs. those with abnormal
growth or early decline; (ii) asthmatics in COPDGene with normal lung function (GOLD 0) vs. abnormal lung
function (GOLD II-III). RNA-seq expression profiles (n=175) will be generated using the Illumina Hi-Seq 2000.
We hypothesize that asthmatics with reduced lung function decline, compared to those with preserved lung
function, demonstrate a specific pattern of BE gene expression, including increased ORMDL3 and TSLP
expression, and reduced HHIP and FAM13A expression. We will characterize the co-expression network
influenced by these genes to define additional candidates that contribute to lung function decline. In Aim 2, we
will use an integrative genomics approach to map the genetic variants that influence the expression of key
genes at the core of the asthma-COPD co-expression networks. These studies will be performed in the BE
samples collected in Aim 1, and complemented by Asthma BRIDGE (n=1548) and ECLIPSE (n=200) cohorts,
with available genomic data (genotype, expression, methylation). Identified regulatory variants will be tested for
association as COPD-susceptibility loci in COPDGene (n=10,300), and as determinants of fixed AO in CAMP
(n=968). In Aim 3, we will characterize the functional consequences of dysregulation of the candidate genes in
an air-liquid interface model. We will compare cellular responses to cigarette smoke among resistant and
susceptible subjects (n=6 per group, 24 samples total) in air liquid interface using BE derived from subjects from
the CAMP and COPDGene cohorts. We will compare these responses following shRNA-mediated knockdown
of candidate genes (ORMDL3, TSLP, HHIP and FAM13A) and formally test whether these responses are
similar in asthma and COPD. We speculate that in both the CAMP and COPDGene derived samples, we will
see similar cellular responses in the susceptible subjects that are distinct from those in asthmatics with normal
lung function, providing key insights in to the mechanisms by which these genes impact lung function.

## Key facts

- **NIH application ID:** 9982414
- **Project number:** 5P01HL132825-05
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Benjamin Alexander Raby
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $399,266
- **Award type:** 5
- **Project period:** 2016-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982414

## Citation

> US National Institutes of Health, RePORTER application 9982414, Integrative Genomics of the Asthma-COPD Overlap (5P01HL132825-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9982414. Licensed CC0.

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