Differential Contribution of the CysLTR1 Gene in Patients with Aspirin Hypersensitivity Seung-Hyun Kim & Eun-Mi Yang & Han-Jung Park & Young-Min Ye & Hyun-Young Lee & Hae-Sim Park Received: 8 May 2007 / Accepted: 14 June 2007 / Published online: 20 July 2007 # Springer Science + Business Media, LLC 2007 Abstract In this study, we compared the roles of CysLT receptor type 1 (CysLTR1) and leukotriene C4 synthase (LTC4S) gene polymorphisms in two major aspirin-related allergic diseases, aspirin-intolerant asthma (AIA) and aspirin-induced chronic urticaria/angioedema (AICU). CysLTR1-634C>T and LTC4S-444A>C polymorphisms were genotyped and its functional effect on the promoter activity was compared. As in vivo functional study, changes of peripheral mRNA level of CysLTR1 were measured by real-time PCR before and after aspirin challenge. A significant association was found for the CysLTR1 promoter polymorphism and the AIA phenotype compared to AICU (P=0.015). In U937 cells, the variant genotype reporter construct showed significantly higher promoter activity than the common genotype (P <0.05). The CysLTR1 mRNA levels increased significantly after aspirin challenge in AIA patients (P=0.013). In conclusion, the CysLTR1 polymorphism may contribute to develop to the AIA phenotype and be used as a genetic marker for differentiat- ing two major aspirin hypersensitivity phenotypes. Keywords Aspirin-induced asthma . genetic polymorphism . leukotriene receptor Introduction The distinct clinical syndromes of aspirin hypersensitivity, including aspirin-intolerant asthma (AIA) and aspirin- induced urticaria/angioedema (AICU), result from the inhibitory action of aspirin or other nonsteroidal anti- inflammatory drugs (NSAIDs) on prostaglandin formation from arachidonic acids, leading to enhanced production of cysteinyl leukotrienes (CysLTs), such as LTC4, LTD4, and LTE4, which are potent inflammatory mediators [1–4]. In the Korean population, the prevalence of AIA is about 20% of adult asthmatics, based on bronchial lysine-aspirin provocation tests [5], and AICU occurs in more than 30% of chronic urticaria patients, based on oral aspirin provo- cation tests [6]. Interest in the pathologic role of CysLT in AIA has increased after the demonstration of therapeutic efficiency for CysLT receptor antagonists in the manage- ment of AIA patients [7, 8]. However, in contrast to AIA, the association of the cutaneous reaction with aspirin hypersensitivity has not been investigated. Up to 40% of patients with chronic urticaria exhibit increased wheal size and swelling after intake of aspirin [6, 9], and it has been suggested that increased levels of CysLTs resulting from alterations in arachidonate metabolism may exacerbate late- phase allergic reactions in AICU patients, as in AIA patients [9–11]. However, the pharmacologic effects of CysLT receptor antagonists on AICU patients have not been investigated. CysLTs, such as LTC4, LTD4, and LTE4, are known as slow-acting anaphylactic substances and important lipid mediators of the pathogenesis of eosinophilic airway inflammation characterized by bronchoconstriction, mucus secretion, and airway hyperresponsiveness [12]. CysLT synthesis involves three major enzymes: 5-lipoxygenase, 5- lipoxygenase-activating protein, and leukotriene C4 syn- J Clin Immunol (2007) 27:613–619 DOI 10.1007/s10875-007-9115-x S.-H. Kim : E.-M. Yang : H.-J. Park : Y.-M. Ye : H.-Y. Lee : H.-S. Park (*) Department of Allergy and Rheumatology, Ajou University School of Medicine, San-5, Woncheondong, Youngtonggu, Suwon 442-721, Republic of Korea e-mail: hspark@ajou.ac.kr