# Effects of Rare Variants and Ancestry on Beta Agonist Response in Asthma and COPD

> **NIH NIH R01** · MAYO CLINIC ARIZONA · 2023 · $674,066

## Abstract

SUMMARY
Surveillance trials suggest that the risk for life-threatening asthma exacerbations and asthma-related deaths
are increased with long-acting β2-adrenergic receptor (β2AR) agonist (LABA) therapy, although prospective
randomized trials, including FDA-mandated safety studies, have not confirmed these observations when LABA
is combined with an inhaled corticosteroid (ICS). Despite this, the risk for adverse outcomes and treatment
failure during LABA therapy is higher in African Americans compared to Whites. We have shown that rare
genetic variants in the β2-adrenergic receptor gene (ADRB2) are associated with exacerbations in asthma
subjects taking LABAs. We have also shown that African ancestry is strongly associated with lower lung
function in African Americans with severe asthma and COPD. These data provide a strong rationale for using
conventional and functional genetic approaches to elucidate role of ancestry-specific genetic variation,
including novel variants and variation in important components of the β2AR signaling pathway, that determine
beta agonist response and lung function. We hypothesize that ethnic-specific genetic variants, particularly
rare variants and β2AR pathway variation, have important effects on beta agonist response and
baseline lung function. We propose the following Specific Aims: Aim 1: To identify novel genetic
variants associated with beta agonist response and measures of lung function in multi-ethnic asthma
and COPD cohorts using a combination of rare variant-based, admixture-based whole-genome
analyses, and GWAS. We will leverage existing comprehensive genotyping with imputation and Next-
Generation Sequencing (NGS) datasets from 1,919 asthma subjects from SARP1-3, 839 subjects from Asthma
Clinical Research Network trials, 2,807 (1,122 African/African American and 554 Hispanic) asthma subjects
from three LABA-ICS clinical trials, and 2,507 SPIROMICS subjects for the discovery of novel gene pathways
associated with beta agonist response and lung function. Aim 2: To validate the effects of variants in the
β2-adrenergic receptor (β2AR) pathway and novel gene pathways on beta agonist response and lung
function in multi-ethnic beta agonist-treated clinical trial cohorts. We will perform de novo NGS on 40
β2AR pathway genes and utilize existing whole-genome sequencing data for β2AR pathway analyses to
identify novel gene-gene interactions constituting predictive genetic profiles for beta agonist response and lung
function across ethnic groups .Aim 3: To validate the biologic effects of rare variants within the β2AR
signaling pathway in order to refine and support genetic predictive profiles of beta agonist therapeutic
responsiveness. β2AR pathway rare variation will be evaluated with molecular phenotyping to refine
predictive genetic profiles. The proposed studies have the potential to define an at-risk subgroup of
asthma susceptible to adverse effects of LABA therapy while identifying novel loci for beta agonist
r...

## Key facts

- **NIH application ID:** 10620284
- **Project number:** 5R01HL142992-05
- **Recipient organization:** MAYO CLINIC ARIZONA
- **Principal Investigator:** Victor E. Ortega
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $674,066
- **Award type:** 5
- **Project period:** 2021-12-02 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620284

## Citation

> US National Institutes of Health, RePORTER application 10620284, Effects of Rare Variants and Ancestry on Beta Agonist Response in Asthma and COPD (5R01HL142992-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10620284. Licensed CC0.

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