A coding polymorphism in the CYSLT2 receptor with reduced affinity to LTD4 is associated with asthma.
BACKGROUND
Cysteinyl leukotrienes (CYSLTR) are potent biological mediators in the pathophysiology of asthma for which two receptors have been characterized, CYSLTR1 and CYSLTR2. The leukotriene modifying agents currently used to control bronchoconstriction and inflammation in asthmatic patients are CYSLTR1-specific leukotriene receptor antagonists. In this report, we investigated a possible role for therapeutic modulation of CYSLTR2 in asthma by investigating genetic association with asthma and further characterization of the pharmacology of a coding polymorphism.


METHODS
The association of CYSLTR2 polymorphisms with asthma was assessed by transmission disequilibrium test in two family-based collections (359 families from Denmark and Minnesota, USA and 384 families from the Genetics of Asthma International Network).


RESULTS
A significant association of the coding polymorphism, 601A>G, with asthma was observed (P = 0.003). We replicated these findings in a collection of 384 families from the Genetics of Asthma International Network (P = 0.04). The G allele is significantly under-transmitted to asthmatics, indicating a possible role for this receptor in resistance to asthma. The potency of cysteinyl leukotrienes at the wild-type CYSLTR2 and the coding polymorphism 601A>G were assessed using a calcium mobilization assay. The potency of LTC4 and LTE4 was similar for both forms of the receptor and LTB4 was inactive, however, LTD4 was approximately five-fold less potent on 601A>G compared to wild-type CYSLTR2.


CONCLUSIONS
Since 601A>G alters the potency of LTD4 and this variant allele may be associated with resistance to asthma, it is possible that modulation of the CYSLTR2 may be useful in asthma pharmacotherapy.
Pillai
Sreekumar G
SG
Genetics Research, GlaxoSmithKline Research Triangle Park, NC, USA. Sreekumar.g.pillai@gsk.com
Cousens
Diane J
DJ
Barnes
Ashley A
AA
Buckley
Peter T
PT
Chiano
Mathias N
MN
Hosking
Louise K
LK
Cameron
Lee-Ann
LA
Fling
Mary E
ME
Foley
James J
JJ
Green
Andrew
A
Sarau
Henry M
HM
Schmidt
Dulcie B
DB
Sprankle
Catherine S
CS
Blumenthal
Malcolm N
MN
Vestbo
Jorgen
J
Kennedy-Wilson
Karen
K
Wixted
William E
WE
Wagner
Michael J
MJ
Anderson
Wayne H
WH
Ignar
Diane M
DM
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001249:Asthma / Q000235:genetics*; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003001:Cloning, Molecular; D005192:Family Health; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D017998:Leukotriene D4 / Q000235:genetics*; D015289:Leukotrienes / Q000378:metabolism; D015810:Linkage Disequilibrium; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D018077:Receptors, Leukotriene / Q000235:genetics*
D015289:Leukotrienes; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D017998:Leukotriene D4; C412375:cysteinyl leukotriene receptor 2