G-protein-coupled receptors and asthma endophenotypes: the cysteinyl leukotriene system in perspective.
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 (CYSLTR1 and CYSLTR2), and prostaglandin D2 receptors (PTGDR and CRTH2), thromboxane A2 receptor (TBXA2R), beta2-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.
Thompson
Miles D
MD
Department of Laboratory Medicine and Pathobiology, University of Toronto, and Department of Medical Genetics and Microbiology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. miles.thompson@utoronto.ca
Takasaki
Jun
J
Capra
Valérie
V
Rovati
G Enrico
GE
Siminovitch
Kathy A
KA
Burnham
W McIntyre
WM
Hudson
Thomas J
TJ
Bossé
Yohan
Y
Cole
David E C
DE
D001241:Aspirin / Q000378:metabolism; D001249:Asthma / Q000235:genetics* / Q000378:metabolism; D004342:Drug Hypersensitivity / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D015289:Leukotrienes / Q000235:genetics*; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D018077:Receptors, Leukotriene / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D015289:Leukotrienes; D043562:Receptors, G-Protein-Coupled; D018077:Receptors, Leukotriene; D001241:Aspirin