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Combination Allele-Specific Real-Time PCR for Differentiation of ß₂-Adrenergic Receptor Coding Single-Nucleotide Polymorphisms

¹ Department of Clinical Pharmacology, Section of Experimental Oncology/Molecular Pharmacology,² Department of Dermatology, Division of General Dermatology, and³ Department of Ophthalmology, University of Vienna, Vienna, Austria;⁴ Institute of Medical Physics, Vienna, Austria

^aaddress correspondence to this author at: Department of Clinical Pharmacology, University of Vienna, Vienna General Hospital, Waehringer Guertel 18-20, Vienna, Austria A-1090; fax 43-1-40400-2998, e-mail trevor.lucas@univie.ac.at

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The ß₂-adrenergic receptor (ADRB2) is a GTP-binding-protein-coupled receptor produced by a wide variety of cell types. Stimulation of ADRB2 by catecholamines or synthetic therapeutic agonists promotes physiologic processes as varied as smooth muscle relaxation and lipolysis. Stimulation of ADRB2 is characterized by rapid desensitization governed by receptor internalization, which plays a direct role in the response to catecholamines and synthetic agonists governing cellular responses (1).

ADRB2 is transcribed from an intronless gene on chromosome 5q32 that encodes a 413-residue protein with 7 transmembrane domains (2). Within the ADRB2 gene, 13 single-nucleotide polymorphisms (SNPs) have been identified (3), including 3 coding ADRB2 missense polymorphisms that alter protein function (4). A threonine-to-isoleucine (T164I) substitution in the fourth transmembrane domain alters ligand binding and decreases adenylate cyclase activation but is rare in the population (5). The extracellular domain N-terminal arginine-to-glycine (R16G) and glutamine-to-glutamic acid (Q27E) polymorphisms are common and widely distributed within the population. These polymorphisms strongly influence the degree of agonist-mediated receptor down-regulation. Whereas Q27E induces complete resistance to down-regulation in combination with R16, R16G increases agonist-mediated receptor down-regulation in both haplotypes (5).

The importance of developing rapid ADRB2 screening protocols that differentiate codon 16/27 diplotypes is emphasized by the number of studies linking these genotypes to clinical and pharmacologic responses. SNPs representing the partial haplotype at codons 16 and 27 are variously associated with altered vasodilation (6) and high blood pressure (7), play roles in the development of type II diabetes (8), and have been linked to preterm delivery (9), agonist desensitization (10), albuterol responses (11), increased IgE in asthmatic families (12), obesity (13), hypertriglyceridemia, and development of fatty liver (14. . . [Full Text of this Article]

The following articles in journals at HighWire Press have cited this article:

				M. F. Sabato, A.-M. Irani, B. L. Bukaveckas, L. B. Schwartz, D. S. Wilkinson, and A. Ferreira-Gonzalez A Simple and Rapid Genotyping Assay for Simultaneous Detection of Two ADRB2 Allelic Variants Using Fluorescence Resonance Energy Transfer Probes and Melting Curve Analysis J. Mol. Diagn., May 1, 2008; 10(3): 258 - 264. [Abstract] [Full Text] [PDF]