title: Association analysis of thromboxane A synthase 1 gene polymorphisms with aspirin intolerance in asthmatic patients.
abstract: OBJECTIVE
  Thromboxane A synthase (TBXAS1) converts prostaglandin H to thromboxane A, a potent constrictor of smooth respiratory muscle. Thus, functional alterations of the TBXAS1 gene may contribute to aspirin-intolerant asthma (AIA).
  
  
  METHODS
  We investigated the relationship between SNPs in the TBXAS1 gene and AIA. Asthmatics (n = 470) were categorized into AIA (20% or greater decreases in forced expiratory volume in 1 s [FEV(1)], or 15% to 19% decreases in FEV(1) with naso-ocular or cutaneous reactions) and aspirin-tolerant asthma (ATA). A total of 101 SNPs were genotyped. mRNA expression of the TBXAS1 gene by peripheral blood mononuclear cells and plasma thromboxane B2 (TXB2) concentrations were measured by reverse transcriptase (RT)-PCR and ELISA.
  
  
  RESULTS
  Logistic regression analysis showed that the rare allele frequency of rs6962291 in intron 9 was significantly lower in the AIA group (n = 115) than in the ATA group (n = 270) (p(corr) = 0.04). The linear regression analysis revealed a strong association of rs6962291 with the aspirin challenge-induced FEV(1) fall (p = 0.003). RT-PCR revealed an exon-12-deleted splice variant. We measured TBXAS1 mRNA levels in peripheral blood mononuclear cells. The mRNA levels of the full-length wild-type and splice variant were significantly higher in the TT homozygotes than in the AA homozygotes of rs6962291 (1.00 ± 0.18 vs 0.57 ± 0.03 and 1.00 ± 0.18 vs 0.21 ± 0.05, p = 0.047 and 0.001, respectively). The plasma TXB2 level was significantly lower in rs6962291 AA carriers than in rs6962291 TT (p = 0.016) carriers.
  
  
  CONCLUSIONS
  The rare allele of rs6962291 may play a protective role against aspirin hypersensitivity via a lower catalytic activity of the TBXAS1 gene, attributed to the increase of a nonfunctioning isoform of TBXAS1.
authors: Genome Research Center for Allergy & Respiratory Disease, Soonchunhyang University Bucheon Hospital, 1174 Jung-dong, Wonmi-gu, Bucheon, Gyeonggi-do, 420-767, Republic of Korea.
authors: Sun-Hee
authors: SH
authors: Oh
authors: Yong-Hoon
authors: YH
authors: Kim
authors: Se-Min
authors: SM
authors: Park
authors: Sung-Hwan
authors: SH
authors: Cho
authors: Jong-Sook
authors: JS
authors: Park
authors: An-Soo
authors: AS
authors: Jang
authors: Sung-Woo
authors: SW
authors: Park
authors: Soo-Taek
authors: ST
authors: Uh
authors: Youg-Mok
authors: YM
authors: Lee
authors: Mi-Kyeong
authors: MK
authors: Kim
authors: Inseon S
authors: IS
authors: Choi
authors: Sang Heon
authors: SH
authors: Cho
authors: Chein-Soo
authors: CS
authors: Hong
authors: Yong Won
authors: YW
authors: Lee
authors: Jae-Young
authors: JY
authors: Lee
authors: Byoung Whui
authors: BW
authors: Choi
authors: Byung Lae
authors: BL
authors: Park
authors: Hyoung Doo
authors: HD
authors: Shin
authors: Choon-Sik
authors: CS
authors: Park
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects*; D001241:Aspirin / Q000008:administration & dosage / Q000009:adverse effects*; D055963:Asthma, Aspirin-Induced / Q000235:genetics*; D005260:Female; D005541:Forced Expiratory Volume / Q000235:genetics; D005787:Gene Frequency; D030342:Genetic Diseases, Inborn / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000097:blood / Q000235:genetics*; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D013929:Thromboxane B2; D013930:Thromboxane-A Synthase; D001241:Aspirin