Association analysis of cysteinyl-leukotriene receptor 2 (CYSLTR2) polymorphisms with aspirin intolerance in asthmatics.
OBJECTIVE
The cysteinyl leukotriene receptor 2 (CYSLTR2) gene on chromosome 13q14.12-q21.1 encodes a receptor for CYSLTs, potent biological mediators in the pathogenesis of asthma, particularly that associated with aspirin intolerance (AIA). In an effort to discover additional polymorphism(s), the variant(s) of which have been implicated in asthma and aspirin intolerance, we scrutinized genetic polymorphisms of the CYSLTR2 gene, and evaluated this locus as a potential candidate for asthma.


RESULTS
DNA sequencing in 24 Koreans of the 5-kb region of the CYSLTR2 gene, including the approximately 1500-bp promoter region, revealed four sequence variants: one in the 5'-flanking region (c.-819T>G), two in the 3'-flanking region (c.2078C>T and c.2534A>G), and one downstream of the gene (c.2545+297A>G). The SNP frequencies were 0.499 (c.-819T>G), 0.351 (c.2078C>T), 0.429 (c.2534A>G), and 0.088 (c.2545+297A>G), and five haplotypes were constructed. The SNPs and haplotypes were not associated with risk of asthma development, but were significantly associated with aspirin intolerance. The frequencies of rare alleles on c.-819T>G, c.2078C>T, and c.2534A>G were higher in subjects with AIA than in subjects with aspirin-tolerant asthma (P=0.013-0.031). Asthmatics who had rare alleles for c.-819T>G, c.2078C>T or c.2534A>G exhibited a more pronounced fall in FEV1 after aspirin provocation than did those who carried the common allele (P=0.03-0.009). Asthmatics carrying ht2 (TTGA) also showed a more pronounced decrease in FEV1% after aspirin provocation than those carrying ht1 (GCGA) (P=0.006). These associations were even stronger when combined with LTC4S polymorphisms (-444A>C [c.-444A>C]) gene.


CONCLUSIONS
CYSLTR2 polymorphisms are associated with aspirin intolerance in asthmatics.
Park
Jong Sook
JS
Asthma Genome Research Group, Soonchunhyang University Hospital, Seoul, Korea.
Chang
Hun Soo
HS
Park
Choon-Sik
CS
Lee
June-Hyuk
JH
Lee
Yong Mok
YM
Choi
Jung Hee
JH
Park
Hae-Sim
HS
Kim
Lyoung Hyo
LH
Park
Byung Lae
BL
Choi
Yoo Hyun
YH
Shin
Hyoung Doo
HD
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D001241:Aspirin / Q000009:adverse effects*; D001249:Asthma / Q000209:etiology* / Q000503:physiopathology; D016022:Case-Control Studies; D004361:Drug Tolerance; D005787:Gene Frequency; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007723:Korea; D015289:Leukotrienes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018077:Receptors, Leukotriene / Q000235:genetics*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015289:Leukotrienes; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; C412375:cysteinyl leukotriene receptor 2; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; D001241:Aspirin