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Genome-wide association study in NSAID-induced acute urticaria/angioedema in Spanish and Han Chinese populations Aim: Acute urticaria/angioedema (AUA) induced by cross-intolerance to NSAIDs is the most frequent clinical entity in hypersensitivity reactions to drugs. In this work, we conducted a genome-wide association study in Spanish and Han Chinese patients suffering from NSAID-induced AUA. Materials & methods: A whole-genome scan was performed on a total of 232 cases (112 Spanish and 120 Han Chinese) with NSAIDinduced AUA and 225 unrelated controls (124 Spanish and 101 Han Chinese). Results: Although no polymorphism reached genome-wide significance, we obtained suggestive associations for three clusters in the Spanish group (RIMS1, BICC1 and RAD51L1) and one region in the Han Chinese population (ABI3BP). Five regions showed suggestive associations after meta-analysis: HLF, RAD51L1, COL24A1, GalNAc-T13 and FBXL7. A majority of these genes are related to Ca2+, cAMP and/or P53 signaling pathways. Conclusion: The associations described were different from those related to the metabolism of arachidonic acid and could provide new mechanisms underlying NSAID-induced AUA. Original submitted 7 June 2013; Revision submitted 19 August 2013 KEYWORDS: acute urticaria/angioedema n drug hypersensitivity n genome-wide association study n mast cells n NSAIDs
NSAIDs are the most frequently prescribed medicines in the world, and many can be obtained over the counter [1,2]. However, they are not free from side effects. In fact, they are responsible for 21–25% of reported adverse drug events, including hypersensitivity reactions (HRs) [3,4]. Recent studies carried out by our group show that NSAIDs are the drugs most frequently involved in HRs to drugs [5,6]. HRs to drugs are produced by the release of vasoactive mediators, and include both specific and nonspecific immunological mechanisms [5,6]. In the first group, in which affected patients are termed to be selective responders, the reaction is mediated by specific IgE antibodies or T cells, whereas, in the second group, with the so-called cross-intolerance (CI), the reaction is produced by chemically unrelated NSAIDs without the intervention of specific immunological mechanisms [7,8]. The latter is the most frequent cause of HRs to drugs [5,6]. Clinical manifestations of CI can involve both the skin (urticaria) and the respiratory system (asthma and/or rhinitis and nasal polyposis), with acute urticaria/angioedema (AUA) being the most common entity in patients with CI [5]. Aspirin-induced asthma (AIA) has been the most studied model, with the inhibition of cyclooxygenase-1 (COX-1) being the proposed mechanism [9]. This leads to a reduction in the
production of prostaglandin (PG)E2, resulting in a shift in arachidonic acid (AA) metabolism towards 5-lypooxygenase (5-LO) pathway products, mainly cysteinyl-leukotrienes (LTs; LTC4, LTD4 and LTE4), responsible for the bronchoconstriction and other effects. Supporting the COX-1 hypothesis are increased basal levels of urinary LTE4 [10,11], with further increases after aspirin challenge in urine, nasal washes, bronchoalveolar lavage and exhaled breath condensates [11–16]. Since similar patterns have been found in patients with chronic urticaria (CU), this mechanism has also been suggested in patients with skin involvement [17,18]. However, urinary levels of PGE2, the main product of COX-1, did not show differentiation between AIA and aspirin-tolerant asthmatic (ATA) patients and healthy controls [19]. Furthermore, no significant differences have been found in exhaled breath condensate between AIA and ATA patients, whereas LT levels were lower in the AIA group [20]. Moreover, an overproduction of PGD2 during aspirin-intolerant bronchoconstriction has also been reported [21], and no differences in the levels of 5-LO products have been found in blood from patients with AIA and ATA [22]. In recent years, different studies have been published concerning genetic susceptibility to CI to NSAIDs, mainly in Asian populations.
10.2217/PGS.13.166 © 2013 Future Medicine Ltd
Pharmacogenomics (2013) 14(15), 1857–1869
José Antonio CornejoGarcía‡, Lieh-Bang Liou‡, Natalia Blanca-López, Inmaculada Doña, ChienHsiun Chen, Yi-Chun Chou, Hui-Ping Chuang, Jer-Yuarn Wu, YuanTsong Chen, María del Carmen Plaza-Serón, Cristobalina Mayorga, Rosa María GuéantRodríguez, Shih-Chang Lin, María José Torres, Paloma Campo, Carmen Rondón, José Julio Laguna, Javier Fernández, Jean-Louis Guéant, Gabriela Canto, Miguel Blanca & Ming Ta Michael Lee* *Author for correspondence: Laboratory for International Alliance on Genomic Research, RIKEN Center for Integrative Medical Sciences, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan Tel.: +81 45 503 9589 Fax: +81 45 503 9566 [email protected] ‡ Authors contributed equally For a full list of affiliations, please see page 1869
part of
ISSN 1462-2416
1857
Research Article
Cornejo-García, Liou, Blanca-López et al.
Table 1. Demographic and clinical data of patients and controls. Variable
Spanish population
Han Chinese population
Patients (n = 112)
Controls (n = 124)
p-value
Patients (n = 120)
Controls (n = 101)
p-value
Age, years (mean ± SD)
41.1 ± 15.5
39.4 ± 14.5
0.35
40.6 ± 15.2
48.89 ± 13.50
Genome-wide association study in NSAID-induced acute urticaria/angioedema in Spanish and Han Chinese populations Aim: Acute urticaria/angioedema (AUA) induced by cross-intolerance to NSAIDs is the most frequent clinical entity in hypersensitivity reactions to drugs. In this work, we conducted a genome-wide association study in Spanish and Han Chinese patients suffering from NSAID-induced AUA. Materials & methods: A whole-genome scan was performed on a total of 232 cases (112 Spanish and 120 Han Chinese) with NSAIDinduced AUA and 225 unrelated controls (124 Spanish and 101 Han Chinese). Results: Although no polymorphism reached genome-wide significance, we obtained suggestive associations for three clusters in the Spanish group (RIMS1, BICC1 and RAD51L1) and one region in the Han Chinese population (ABI3BP). Five regions showed suggestive associations after meta-analysis: HLF, RAD51L1, COL24A1, GalNAc-T13 and FBXL7. A majority of these genes are related to Ca2+, cAMP and/or P53 signaling pathways. Conclusion: The associations described were different from those related to the metabolism of arachidonic acid and could provide new mechanisms underlying NSAID-induced AUA. Original submitted 7 June 2013; Revision submitted 19 August 2013 KEYWORDS: acute urticaria/angioedema n drug hypersensitivity n genome-wide association study n mast cells n NSAIDs
NSAIDs are the most frequently prescribed medicines in the world, and many can be obtained over the counter [1,2]. However, they are not free from side effects. In fact, they are responsible for 21–25% of reported adverse drug events, including hypersensitivity reactions (HRs) [3,4]. Recent studies carried out by our group show that NSAIDs are the drugs most frequently involved in HRs to drugs [5,6]. HRs to drugs are produced by the release of vasoactive mediators, and include both specific and nonspecific immunological mechanisms [5,6]. In the first group, in which affected patients are termed to be selective responders, the reaction is mediated by specific IgE antibodies or T cells, whereas, in the second group, with the so-called cross-intolerance (CI), the reaction is produced by chemically unrelated NSAIDs without the intervention of specific immunological mechanisms [7,8]. The latter is the most frequent cause of HRs to drugs [5,6]. Clinical manifestations of CI can involve both the skin (urticaria) and the respiratory system (asthma and/or rhinitis and nasal polyposis), with acute urticaria/angioedema (AUA) being the most common entity in patients with CI [5]. Aspirin-induced asthma (AIA) has been the most studied model, with the inhibition of cyclooxygenase-1 (COX-1) being the proposed mechanism [9]. This leads to a reduction in the
production of prostaglandin (PG)E2, resulting in a shift in arachidonic acid (AA) metabolism towards 5-lypooxygenase (5-LO) pathway products, mainly cysteinyl-leukotrienes (LTs; LTC4, LTD4 and LTE4), responsible for the bronchoconstriction and other effects. Supporting the COX-1 hypothesis are increased basal levels of urinary LTE4 [10,11], with further increases after aspirin challenge in urine, nasal washes, bronchoalveolar lavage and exhaled breath condensates [11–16]. Since similar patterns have been found in patients with chronic urticaria (CU), this mechanism has also been suggested in patients with skin involvement [17,18]. However, urinary levels of PGE2, the main product of COX-1, did not show differentiation between AIA and aspirin-tolerant asthmatic (ATA) patients and healthy controls [19]. Furthermore, no significant differences have been found in exhaled breath condensate between AIA and ATA patients, whereas LT levels were lower in the AIA group [20]. Moreover, an overproduction of PGD2 during aspirin-intolerant bronchoconstriction has also been reported [21], and no differences in the levels of 5-LO products have been found in blood from patients with AIA and ATA [22]. In recent years, different studies have been published concerning genetic susceptibility to CI to NSAIDs, mainly in Asian populations.
10.2217/PGS.13.166 © 2013 Future Medicine Ltd
Pharmacogenomics (2013) 14(15), 1857–1869
José Antonio CornejoGarcía‡, Lieh-Bang Liou‡, Natalia Blanca-López, Inmaculada Doña, ChienHsiun Chen, Yi-Chun Chou, Hui-Ping Chuang, Jer-Yuarn Wu, YuanTsong Chen, María del Carmen Plaza-Serón, Cristobalina Mayorga, Rosa María GuéantRodríguez, Shih-Chang Lin, María José Torres, Paloma Campo, Carmen Rondón, José Julio Laguna, Javier Fernández, Jean-Louis Guéant, Gabriela Canto, Miguel Blanca & Ming Ta Michael Lee* *Author for correspondence: Laboratory for International Alliance on Genomic Research, RIKEN Center for Integrative Medical Sciences, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan Tel.: +81 45 503 9589 Fax: +81 45 503 9566 [email protected] ‡ Authors contributed equally For a full list of affiliations, please see page 1869
part of
ISSN 1462-2416
1857
Research Article
Cornejo-García, Liou, Blanca-López et al.
Table 1. Demographic and clinical data of patients and controls. Variable
Spanish population
Han Chinese population
Patients (n = 112)
Controls (n = 124)
p-value
Patients (n = 120)
Controls (n = 101)
p-value
Age, years (mean ± SD)
41.1 ± 15.5
39.4 ± 14.5
0.35
40.6 ± 15.2
48.89 ± 13.50
