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

Award Number: R01HL142992
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/02/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Effects of Rare Variants and Ancestry on Beta Agonist Response in Asthma and COPD - 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 response or disease severity and elucidating novel mechanisms for inter-ethnic differences.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$97,632 )
2026	2023	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Lung Diseases Research	000	5	5/21/2026	NON-COMPETING CONTINUATION	-$97,632
														Subtotal = -$97,632

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Lung Diseases Research	000	5	2/20/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $674,066 )
2023	2023	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Lung Diseases Research	002	5	3/3/2023	NON-COMPETING CONTINUATION	$67,407
2023	2023	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Lung Diseases Research	001	5	12/23/2022	NON-COMPETING CONTINUATION	$606,659
2023	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Lung Diseases Research	000	3	11/23/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $674,066

Issue Date FY: 2022 ( Subtotal = $737,952 )
2022	2022	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Lung Diseases Research	003	4	8/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$417,775
2022	2022	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Lung Diseases Research	001	4	5/10/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$737,952
2022	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Lung Diseases Research	002	3	8/16/2022	NON-COMPETING CONTINUATION	-$417,775
2022	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Lung Diseases Research	000	3	5/9/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $737,952

Issue Date FY: 2021 ( Subtotal = $751,239 )
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Lung Diseases Research	001	3	5/19/2021	NON-COMPETING CONTINUATION	$75,124
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Lung Diseases Research	000	3	1/14/2021	NON-COMPETING CONTINUATION	$676,115
														Subtotal = $751,239

Issue Date FY: 2020 ( Subtotal = $759,465 )
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Lung Diseases Research	000	2	1/1/2020	NON-COMPETING CONTINUATION	$721,491
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Lung Diseases Research	001	2	1/31/2020	NON-COMPETING CONTINUATION	$37,974
														Subtotal = $759,465

Issue Date FY: 2019 ( Subtotal = $799,516 )
2019	2019	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Lung Diseases Research	000	1	1/22/2019	NEW	$799,516
														Subtotal = $799,516

Grand Total All Awards = $3,624,607

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

Award Number: R01HL142992

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/02/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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