Clinical and molecular implications of RGS2 promoter genetic variation in severe asthma.

Autor: Cardet JC; Division of Allergy and Immunology, Internal Medicine Department, Morsani College of Medicine, University of South Florida, Tampa, Fla. Electronic address: jcardet@usf.edu., Kim D; Departments of Medicine, Molecular Pharmacology and Physiology, and Medical Engineering, Morsani College of Medicine, University of South Florida, Tampa, Fla., Bleecker ER; Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Ariz., Casale TB; Division of Allergy and Immunology, Internal Medicine Department, Morsani College of Medicine, University of South Florida, Tampa, Fla., Israel E; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass., Mauger D; Division of Statistics and Bioinformatics, Department of Public Health Sciences, Pennsylvania State University, Hershey, Pa., Meyers DA; Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Ariz., Ampleford E; Department of Internal Medicine, Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC., Hawkins GA; Department of Internal Medicine, Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC., Tu Y; Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, Neb., Liggett SB; Departments of Medicine, Molecular Pharmacology and Physiology, and Medical Engineering, Morsani College of Medicine, University of South Florida, Tampa, Fla., Ortega VE; Department of Internal Medicine, Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
Jazyk: angličtina
Zdroj: The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2022 Sep; Vol. 150 (3), pp. 721-726.e1. Date of Electronic Publication: 2022 Apr 08.
DOI: 10.1016/j.jaci.2022.03.024
Abstrakt: Background: Regulator of G protein signaling (RGS) 2 terminates bronchoconstrictive Gαq signaling; murine RGS2 knockout demonstrate airway hyperresponsiveness. While RGS2 promoter variants rs2746071 and rs2746072 associate with a clinical mild asthma phenotype, their impact on human airway smooth muscle (HASM) contractility and asthma severity outcomes is unknown.
Objective: We sought to determine whether reductions in RGS2 expression seen with these 2 RGS2 promoter variants augment HASM contractility and associate with an asthma severity phenotype.
Methods: We transfected HASM with a range of RGS2-specific small interfering RNA (siRNA) concentrations and determined RGS2 protein expression by Western blot analysis and intracellular calcium flux induced by histamine (a Gαq-coupled H1 receptor bronchoconstrictive agonist). We conducted regression-based genotype association analyses of RGS2 variants from 611 patients from the National Heart, Lung, and Blood Institute Severe Asthma Research Program 3.
Results: RGS2-specific siRNA caused dose-dependent increases in histamine-stimulated bronchoconstrictive intracellular calcium signaling (2-way ANOVA, P < .0001) with a concomitant decrease in RGS2 protein expression. RGS2-specific siRNA did not affect Gαq-independent ionomycin-induced intracellular calcium signaling (P = .42). The minor allele frequency of rs2746071 and rs2746072 was 0.46 and 0.28 among African American/non-Hispanic Black patients and was 0.28 and 0.27 among non-Hispanic White patients, among whom these single nucleotide polymorphisms were in stronger linkage disequilibrium (r 2  = 0.97). Among non-Hispanic White patients, risk allele homozygotes for rs2746072 and rs2746071 each had nearly 2-fold greater asthma exacerbation rates relative to alternative genotypes with wild-type alleles (P additive  = 2.86 × 10 -5 /P recessive  = 5.22 × 10 -6 and P additive  = 3.46 × 10 -6 /P recessive  = 6.74 × 10 -7 , respectively) at baseline, which was confirmed by prospective longitudinal exacerbation data.
Conclusion: RGS2 promoter variation associates with a molecular and clinical phenotype characterized by enhanced bronchoconstrictive stimulation in vitro and higher asthma exacerbations rates in non-Hispanic White patients.
(Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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