Alternative titles; symbols
Other entities represented in this entry:
DO: 0111579;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q22.1 | {Asthma, aspirin-induced, susceptibility to} | 208550 | Autosomal recessive | 3 | PTGER2 | 176804 |
| 17q21.32 | {Asthma, aspirin-induced, susceptibility to} | 208550 | Autosomal recessive | 3 | TBX21 | 604895 |
| 17q21.32 | Asthma and nasal polyps | 208550 | Autosomal recessive | 3 | TBX21 | 604895 |
A number sign (#) is used with this entry because of evidence of an association between aspirin-induced asthma and polymorphisms in the TBX21 (604895), PTGER2 (176804), and LTC4S (246530) genes.
Lockey et al. (1973) observed 2 families. In 1 family, consanguinity suggested recessive inheritance. The late onset and discordance in a pair of identical twins suggested that environmental factors may be important also. Miller (1971) reported affected sisters. Von Maur et al. (1974) described a family in which autosomal dominant inheritance of aspirin asthma was suggested. In addition to mode of inheritance, differences from prior reports included an earlier age of onset, lack of nasal polyps and sinusitis, and milder asthma.
Spector et al. (1979) found that oral challenge with aspirin caused bronchoconstriction in 19% of consecutive adult asthma patients, and other studies involving challenge with nonsteroidal antiinflammatory drugs (NSAIDs) in both adults and children with asthma confirm a prevalence of 10 to 20%. Aspirin causes bronchoconstriction in aspirin-intolerant asthma (AIA) patients by triggering cysteinyl-leukotriene production, probably by removing PGE(2)-dependent inhibition. To investigate why aspirin does not cause bronchoconstriction in all individuals, Cowburn et al. (1998) immunostained enzymes of the leukotriene and prostanoid pathways in bronchial biopsies from AIA patients, aspirin-tolerant asthma (ATA) patients, and normal (N) subjects. Counts of cells expressing the terminal enzyme for cysteinyl-leukotriene synthesis, LTC4 synthase (246530), were 5-fold higher in AIA biopsies than in ATA biopsies and 18-fold higher than in N biopsies. Aspirin may remove PGE(2)-dependent suppression in all subjects, but only in AIA patients does increased bronchial expression of LTC4 synthase allow marked overproduction of cysteinyl-leukotriene leading to bronchoconstriction. Cowburn et al. (1998) speculated that a polymorphism directed to the regulation of LTC4 synthase expression could be a predisposing factor for the AIA group.
Arm and Austen (2002) stated that between 3% and 10% of asthma patients have acute, severe asthma accompanied by rhinorrhea and sometimes associated with hives, flushing, or abdominal pain after the injection of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs). The common feature of drugs that provoke asthma attacks in aspirin-intolerant persons is that they inhibit cyclooxygenase-1 (COX1; 176805); selective inhibition of cyclooxygenase-2 (COX2; 600262) appears not to provoke such a response. Cautious, incremental administration of oral doses of aspirin can lead to a state in which persons with aspirin-sensitive asthma can ingest aspirin without untoward reactions, but daily administration must be continued to maintain this state.
Patients with asthma and aspirin sensitivity have greater cysteinyl leukotriene production and greater airway hyperresponsiveness to the effects of inhaled cysteinyl leukotrienes than their aspirin-tolerant counterparts. Sousa et al. (2002) hypothesized that the latter effect reflects elevated expression of the cysteinyl leukotriene receptor CYSLT1 (300201) on inflammatory cells in the target organ and that its expression is downregulated by aspirin desensitization. They found elevated numbers of nasal inflammatory leukocytes expressing the CYSLT1 receptor in aspirin-sensitive patients with chronic rhinosinusitis as compared with their non-aspirin-sensitive counterparts and the downregulation of receptor expression after desensitization to aspirin.
Sanak et al. (1997) identified a -444A-C promoter polymorphism in the LTC4S gene that was overrepresented among patients with aspirin-intolerant asthma. Six of 11 AIA patients were homozygous for the -444C allele, compared to only 1 individual in the aspirin-tolerant asthmatic and control groups. The frequency of the -444C allele was nearly doubled in AIA (0.436) compared to aspirin-tolerant asthmatics (0.227) and nonasthmatic controls (0.226), yielding a relative risk of 3.89 for the -444C allele.
By genotyping 198 Japanese patients with AIA and 274 Japanese controls, Jinnai et al. (2004) found significant association of the phenotype (permutation p = 0.001) with a G/A SNP (uS5) in the 5-prime promoter region of the PTGER2 gene (176804.0001). Analysis of haplotypes constructed according to the linkage disequilibrium pattern showed a significant association with AIA (permutation P = 0.001). The uS5 SNP is located in the regulatory region of the PTGER2 gene in a STAT-binding consensus sequence. Although STAT1 (600555) binding was not observed in gel mobility shift assay with HeLa nuclear extract, an unidentified protein was specifically bound to the allelic sequence. In vitro reporter assay of the site containing the uS5 allele showed reduced transcription activity. Jinnai et al. (2004) hypothesized that the uS5 allele may serve as a target for a transcription repressor protein or that a functional effect of the uS5 allele may decrease transcription, resulting in reduction of the PGE2 braking mechanism of inflammation and contributing to the molecular mechanism underlying AIA.
Akahoshi et al. (2005) found a significant association between a promoter SNP of the TBX21 gene (-1993T-C; 604895.0001) and aspirin-induced asthma in a Japanese cohort (p = 0.004), with increased risk associated with a C allele (OR, 1.93; 95% CI, 1.22-3.06). The association was confirmed in additional independent samples from patients with asthma and nasal polyposis (p = 0.008), regardless of aspirin hypersensitivity.
Associations Pending Confirmation
For discussion of a possible association between polymorphism in the ALOX15 gene and protection against nasal polyps and chronic rhinosinusitis, see 152392.0001.
Akahoshi, M., Obara, K., Hirota, T., Matsuda, A., Hasegawa, K., Takahashi, N., Shimizu, M., Nakashima, K., Cheng, L., Doi, S., Fujiwara, H., Miyatake, A., and 10 others. Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma. Hum. Genet. 117: 16-26, 2005. [PubMed: 15806396] [Full Text: https://doi.org/10.1007/s00439-005-1285-0]
Arm, J. P., Austen, K. F. Leukotriene receptors and aspirin sensitivity. (Editorial) New Eng. J. Med. 347: 1524-1526, 2002. [PubMed: 12421897] [Full Text: https://doi.org/10.1056/NEJMe020116]
Cowburn, A. S., Sladek, K., Soja, J., Adamek, L., Nizankowska, E., Szczeklik, A., Lam, B. K., Penrose, J. F., Austen, K. F., Holgate, S. T., Sampson, A. P. Overexpression of leukotriene C(4) synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J. Clin. Invest. 101: 834-846, 1998. [PubMed: 9466979] [Full Text: https://doi.org/10.1172/JCI620]
Jinnai, N., Sakagami, T., Sekigawa, T., Kakihara, M., Nakajima, T., Yoshida, K., Goto, S., Hasegawa, T., Koshino, T., Hasegawa, Y., Inoue, H., Suzuki, N., Sano, Y., Inoue, I. Polymorphisms in the prostaglandin E2 receptor subtype 2 gene confer susceptibility to aspirin-intolerant asthma: a candidate gene approach. Hum. Molec. Genet. 13: 3203-3217, 2004. [PubMed: 15496426] [Full Text: https://doi.org/10.1093/hmg/ddh332]
Lockey, R. F., Rucknagel, D. L., Vanselow, N. A. Familial occurrence of asthma, nasal polyps and aspirin intolerance. Ann. Intern. Med. 78: 57-63, 1973. [PubMed: 4682309] [Full Text: https://doi.org/10.7326/0003-4819-78-1-57]
Miller, F. F. Aspirin-induced bronchial asthma in sisters. Ann. Allergy 29: 263-265, 1971. [PubMed: 5155528]
Sanak, M., Simon, H.-U., Szczeklik, A. Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet 350: 1599-1600, 1997. [PubMed: 9393345] [Full Text: https://doi.org/10.1016/s0140-6736(05)64015-9]
Sousa, A. R., Parikh, A., Scadding, G., Corrigan, C. J., Lee, T. H. Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis. New Eng. J. Med. 347: 1493-1499, 2002. [PubMed: 12421891] [Full Text: https://doi.org/10.1056/NEJMoa013508]
Spector, S. L., Wangaard, C. H., Farr, R. S. Aspirin and concomitant idiosyncrasies in adult asthmatic patients. J. Allergy Clin. Immun. 64: 500-506, 1979. [PubMed: 512268] [Full Text: https://doi.org/10.1016/0091-6749(79)90059-9]
Von Maur, K., Adkinson, N. F., Jr., Van Metre, T. E., Jr., Marsh, D. G., Norman, P. Aspirin intolerance in a family. J. Allergy Clin. Immun. 54: 380-395, 1974.