# Genetic and Functional Dissection of a Cluster of COPD GWAS Signals on Chromosome 4q

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $886,191

## Abstract

Project Summary
More than 20 genomic regions related to chronic obstructive pulmonary disease (COPD) susceptibility have
been discovered using genome-wide association studies (GWAS); however, the functional variants and the
genes that they influence within those COPD GWAS loci have been found in a small minority of genomic regions.
GWAS in COPD have identified several regional clusters of genetic association signals, most notably on
chromosome 4q, where genome-wide significant loci near HHIP, FAM13A, GSTCD, TET2, and BTC have been
discovered. These clustered GWAS regions could represent: 1) Independent genetic determinants influencing
separate genes; 2) Multiple GWAS loci regulating the same gene; or 3) A regional network of coordinately
regulated genes. If multiple COPD GWAS loci regulate the same gene, the biological impact of that gene in
COPD pathogenesis would be increased. The primary goals of this project are to identify the functional genetic
variants within the cluster of COPD GWAS loci on chromosome 4q; to identify the key genes influenced by these
functional variants; and to assess the impact of these key genes and functional genetic variants on COPD
pathogenesis. We hypothesize that a regional network of genes on chromosome 4q is regulated by functional
genetic variants within COPD GWAS loci that will influence COPD-related cellular phenotypes including cell
death, cellular senescence, and/or inflammation. To address this hypothesis, we will start by identifying
functional variants on chromosome 4q using massively parallel reporter assays in lung epithelial and
monocyte/macrophage cell lines along with bioinformatic approaches with public and recently generated Omics
and genetics data. We will then determine which gene or genes are influenced by these functional variants by
performing circularized chromatin conformation capture (4C-Seq) and demonstrating effects of functional
variants on gene expression of regional genes using CRISPR-Cas9 approaches. Finally, we will use cellular
models to determine the effects of inactivating the functional variants and their regulated genes on COPD-related
read-outs of cell death, cellular senescence, and inflammation. To accomplish these goals, a unique and highly
integrated approach combining molecular studies of regulatory elements and functional cell-based assays has
been developed that will likely provide important insights into COPD pathogenesis.

## Key facts

- **NIH application ID:** 9919627
- **Project number:** 5R01HL147148-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** MICHAEL H. CHO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $886,191
- **Award type:** 5
- **Project period:** 2019-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9919627

## Citation

> US National Institutes of Health, RePORTER application 9919627, Genetic and Functional Dissection of a Cluster of COPD GWAS Signals on Chromosome 4q (5R01HL147148-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9919627. Licensed CC0.

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