ADRB2 polymorphism Arg16Gly modifies the natural outcome of heart failure and dictates therapeutic response to β-blockers in patients with heart failure.

Autor:	Huang J; 1Division of Cardiology, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 430030 Wuhan, China.; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, 430030 Wuhan, China., Li C; 1Division of Cardiology, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 430030 Wuhan, China.; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, 430030 Wuhan, China., Song Y; 3Institute of Molecular Medicine, Peking-Tsinghua Centre for Life Sciences, Peking University, 100871 Beijing, China., Fan X; 4Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100037 Beijing, China., You L; 5Division of Cardiology, The Second Hospital of Hebei Medical University, 050000 Shijiazhuang, China., Tan L; 1Division of Cardiology, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 430030 Wuhan, China., Xiao L; 1Division of Cardiology, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 430030 Wuhan, China., Li Q; 1Division of Cardiology, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 430030 Wuhan, China., Ruan G; 1Division of Cardiology, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 430030 Wuhan, China., Hu S; 1Division of Cardiology, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 430030 Wuhan, China., Cui W; 5Division of Cardiology, The Second Hospital of Hebei Medical University, 050000 Shijiazhuang, China., Li Z; 1Division of Cardiology, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 430030 Wuhan, China., Ni L; 1Division of Cardiology, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 430030 Wuhan, China., Chen C; 1Division of Cardiology, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 430030 Wuhan, China.; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, 430030 Wuhan, China., Woo AY; 3Institute of Molecular Medicine, Peking-Tsinghua Centre for Life Sciences, Peking University, 100871 Beijing, China.; 6Department of Pharmacology, School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, 110016 Shenyang, China., Xiao RP; 3Institute of Molecular Medicine, Peking-Tsinghua Centre for Life Sciences, Peking University, 100871 Beijing, China., Wang DW; 1Division of Cardiology, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 430030 Wuhan, China.; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, 430030 Wuhan, China.
Jazyk:	angličtina
Zdroj:	Cell discovery [Cell Discov] 2018 Oct 23; Vol. 4, pp. 57. Date of Electronic Publication: 2018 Oct 23 (Print Publication: 2018).
DOI:	10.1038/s41421-018-0058-6
Abstrakt:	We sought to investigate the association of single nucleotide polymorphisms (SNPs) of the genes involved in βAR signaling with the response of patients to βAR blockers. A total of 2403 hospitalized patients with chronic heart failure (HF) were enrolled in a multicenter observational study as the first cohort and followed up for a mean period of 20 months. Genes for β1AR, β2AR, and the major cardiac G-protein-coupled receptor kinases (GRKs) GRK2 and GRK5 were analyzed to identify SNPs, and patients were stratified according to genotypes. A second independent cohort enrolling 919 patients with chronic HF was applied to validate the observed associations. The signaling properties of the key identified SNPs were assessed in vitro. Our data showed that HF patients harboring the Gly16 allele in the gene for β2AR ( ADRB2 ) had an increased risk of the composite end point relative to patients who were homozygous for Arg16. Notably, these patients showed a beneficial response to βAR-blocker treatment in a G allele-dose-dependent manner, whereas Arg16 homozygotes had no response to βAR-blocker therapy. This Arg16Gly genotype-dependent heterogeneity in clinical outcomes of HF was successfully validated in the second independent population. Besides, the in vitro experiments revealed that G allele carriers were defective in β2AR-coupled inhibitory adenylate cyclase g (G i ) protein signaling. Competing Interests: The authors declare that they have no conflict of interest.
Databáze:	MEDLINE
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