A functional G300S variant of the cysteinyl leukotriene 1 receptor is associated with atopy in a Tristan da Cunha isolate.
Atopy is a well-defined immune phenotype that is reported to be a risk factor for asthma. Among the many loci that contribute to a genetic predisposition to asthma, the cysteinyl leukotriene receptor genes and their variants have been important subjects of study because they are functionally and pharmacologically implicated in the atopy phenotype affecting many asthma subjects. Moreover, the product of cysteinyl-leukotriene 1 receptor gene (CysLT1), located at Xq13.2, is targeted by LT receptor antagonists. In our earlier association study, the M201V variant of the cysteinyl-leukotriene 2 receptor gene (CysLT2), located at 13q14, was implicated in atopic asthma. Here we report the screening of the coding region of the CysLT1, gene in the highly asthmatic Tristan da Cunha population. In this population, we discovered a CysLT1 G300S variant that is carried with a significantly higher frequency in atopics and asthmatics from the Tristan da Cunha population. Furthermore, we report the asthma independent association of the CysLT1 G300S variant with atopy. Subsequently, we compared the changes conferred by each SNP on CysLT function. The CysLT1 300S receptor interacts with LTD4 with significantly greater potency. For the 300S variant, a statistically significant decrease in the effector concentration for half-maximum response (EC50) for intracellular Ca flux and total InsP generation is observed. Other aspects of the receptor function and activity, such as desensitization, pharmacologic profile in response to montelukast, and cellular localization, are unchanged. These in vitro analyses provide evidence that the 300S CysLT1 variant, found more commonly in atopics in the Tristan da Cunha population, encodes a functionally more sensitive variant.
Thompson
Miles D
MD
Laboratory Medicine, Banting Institute, Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada. miles.thompson@utoronto.ca
Capra
Valérie
V
Takasaki
Jun
J
Maresca
Giovanna
G
Rovati
G Enrico
GE
Slutsky
Aurther S
AS
Lilly
Craig
C
Zamel
Noe
N
McIntyre Burnham
W
W
Cole
David E
DE
Siminovitch
Katherine A
KA
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001266:Atlantic Islands; D001483:Base Sequence; D019556:COS Cells; D020013:Calcium Signaling; D002522:Chlorocebus aethiops; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018077:Receptors, Leukotriene / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D017931:DNA Primers; D007295:Inositol Phosphates; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D011994:Recombinant Proteins; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor