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G-Protein-Coupled Receptors and Asthma Endophenotypes

The Cysteinyl Leukotriene System in Perspective

Molecular Diagnosis & Therapy volume 10, pages 353–366 (2006)Cite this article

Abstract

Genetic variation in specific G-protein coupled receptors (GPCRs) is associated with a spectrum of respiratory disease predispositions and drug response phenotypes. Although certain GPCR gene variants can be disease-causing through the expression of inactive, overactive, or constitutively active receptor proteins, many more GPCR gene variants confer risk for potentially deleterious endophenotypes. Endophenotypes are traits, such as bronchiole hyperactivity, atopy, and aspirin intolerant asthma, which have a strong genetic component and are risk factors for a variety of more complex outcomes that may include disease states.

GPCR genes implicated in asthma endophenotypes include variants of the cysteinyl leukotriene receptors ((YSLTR1 and CYSLTR2), and prostaglandin D2 receptors (PTGDR and CRTH2), thromboxane A2 receptor (TBXA2R), β2-adrenergic receptor (ADRB2), chemokine receptor 5 (CCR5), and the G protein-coupled receptor associated with asthma (GPRA.) This review of the contribution of variability in these genes places the contribution of the cysteinyl leukotriene system to respiratory endophenotypes in perspective. The genetic variant(s) of receptors that are associated with endophenotypes are discussed in the context of the extent to which they contribute to a disease phenotype or altered drug efficacy.

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Acknowledgments

This work was supported in part by grants from the National Science and Engineering Research Council and Dairy Farmers of Canada (to David E.C. Cole), from Genome Canada/Ontario Genomics Institute (to Kathy A. Siminovitch and David E.C. Cole), and from the Canadian Institutes of Health Research (to Miles D. Thompson). The authors wish to acknowledge the assistance of the technical staff from the Analytical Genetics Technology Centre (AGTC) at the University Health Network (Toronto, ON, Canada). The authors have no conflicts of interest directly relevant to the contents of this article.

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Authors and Affiliations

  1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    Miles D. Thompson & David E. C. Cole

  2. Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan

    Jun Takasaki

  3. Laboratory of Molecular Pharmacology, Section of Eicosanoid Pharmacology, Department of Pharmacological Sciences, University of Milan, Milan, Italy

    Valérie Capra & G. Enrico Rovati

  4. Department Medical Genetics and Microbiology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

    Kathy A. Siminovitch

  5. Department of Pharmacology, University of Toronto, Toronto, Canada

    W. McIntyre Burnham

  6. McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada

    Thomas J. Hudson & Yohan Bossé

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  1. Miles D. Thompson
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Thompson, M.D., Takasaki, J., Capra, V. et al. G-Protein-Coupled Receptors and Asthma Endophenotypes. Mol Diag Ther 10, 353–366 (2006). https://doi.org/10.1007/BF03256212

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