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.
Genetics Research, GlaxoSmithKline Research Triangle Park, NC, USA. Sreekumar.g.pillai@gsk.com
Sreekumar G
SG
Pillai
Diane J
DJ
Cousens
Ashley A
AA
Barnes
Peter T
PT
Buckley
Mathias N
MN
Chiano
Louise K
LK
Hosking
Lee-Ann
LA
Cameron
Mary E
ME
Fling
James J
JJ
Foley
Andrew
A
Green
Henry M
HM
Sarau
Dulcie B
DB
Schmidt
Catherine S
CS
Sprankle
Malcolm N
MN
Blumenthal
Jorgen
J
Vestbo
Karen
K
Kennedy-Wilson
William E
WE
Wixted
Michael J
MJ
Wagner
Wayne H
WH
Anderson
Diane M
DM
Ignar
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