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Association of thromboxane A1 synthase (TBXAS1) gene polymorphism with acute urticaria induced by nonsteroidal anti-inflammatory drugs

2013; Elsevier BV; Volume: 132; Issue: 4 Linguagem: Inglês

10.1016/j.jaci.2013.04.045

1097-6825

Carmen Vidal, Liliana Porras-Hurtado, Raquel Cruz, J. Quiralte, Victòria Cardona, C. Colás, Luisa-Fernanda Castillo-León, Carmen Marcos, Teresa Soto, Raquel Lopez-Abad, Dolores Hernández Fernández de Rojas, M. Audícana, Margarita Armisén, Virginia Rodríguez, Celsa Perez‐Carral, Esther Moreno, Rosario Cabañes, Mercè Corominas, Antonio Fernández Parra, T Lobera, Dolores Quiñones, Pedro Ojeda, Ildefonso Luna, María Torres, Ángel Carracedo,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs all over the world and represent the second most frequent cause of drug-induced hypersensitivity reactions (0.5% to 1.9% of the general population).1Kowalski M.L. Makowska J.S. Blanca M. Bavbek S. Bochenek G. Bousquet J. et al.Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs)—classification, diagnosis and management: review of the EAACI/ENDA and GA2LEN/HANNA.Allergy. 2011; 66: 818-829Crossref PubMed Scopus (376) Google Scholar In some circumstances an underlying disease, such as chronic urticaria or bronchial asthma, accompanies the clinical expression of this hypersensitivity.1Kowalski M.L. Makowska J.S. Blanca M. Bavbek S. Bochenek G. Bousquet J. et al.Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs)—classification, diagnosis and management: review of the EAACI/ENDA and GA2LEN/HANNA.Allergy. 2011; 66: 818-829Crossref PubMed Scopus (376) Google Scholar, 2Stevenson D.D. Sanchez-Borges M. Szczeklik A. Classification of allergic and pseudoallergic reactions to drugs that inhibit cyclooxygenase enzymes.Ann Allergy Asthma Immunol. 2001; 87: 177-180Abstract Full Text PDF PubMed Scopus (222) Google Scholar According to the pattern of reactivity among different NSAIDs, these reactions can be classified into cross-reactive or multiple hypersensitivity (MR), with cross-reactivity among different nonstructurally related NSAIDs, and selective (SR), in which a unique specific NSAID is the culprit drug.1Kowalski M.L. Makowska J.S. Blanca M. Bavbek S. Bochenek G. Bousquet J. et al.Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs)—classification, diagnosis and management: review of the EAACI/ENDA and GA2LEN/HANNA.Allergy. 2011; 66: 818-829Crossref PubMed Scopus (376) Google Scholar, 2Stevenson D.D. Sanchez-Borges M. Szczeklik A. Classification of allergic and pseudoallergic reactions to drugs that inhibit cyclooxygenase enzymes.Ann Allergy Asthma Immunol. 2001; 87: 177-180Abstract Full Text PDF PubMed Scopus (222) Google Scholar, 3Chaudhry T. Hissaria P. Wiese M. Heddle R. Kette F. Smith W.B. Oral drug challenges in non-steroidal anti-inflammatory drug-induced urticaria, angioedema and anaphylaxis.Intern Med J. 2012; 42: 665-671Crossref PubMed Scopus (33) Google Scholar Either MR or SR could be related to some genetic background. Thus knowledge of possible genetic variations in patients with NSAID hypersensitivity might provide information about individual susceptibility to these side effects (both detrimental and beneficial). In this setting the present study was aimed at investigating the search for 1 or more polymorphisms associated with isolated acute cutaneous NSAID hypersensitivity, both the MR and SR types, in a Spanish population with no underlying chronic or recurrent urticaria or respiratory disease. Nineteen allergy departments throughout Spain participated in the study. A total of 563 adult patients (mean age, 43.6 years; range, 18-86 years; 58.8% male) given a diagnosis of acute urticaria, angioedema, or both because of NSAID hypersensitivity and 551 healthy control subjects (mean age, 38.2 years; range, 18-77 years; 68.6% male) without a history of NSAID hypersensitivity were enrolled from December 2009 to August 2011. Cutaneous NSAID hypersensitivity was classified into MR (n = 314, 57.8%) and SR (n = 249, 45.8%) types, depending on oral challenge test results, skin test (when necessary), and the pattern of reactivity. A total of 217 single nucleotide polymorphisms (SNPs) in 48 genes were studied. Detailed information on the methods used can be found in this article's Online Repository at www.jacionline.org. From the initial dataset of 1114 subjects, 41 samples were discarded because of a low genotyping rate (<80%). Sample quality was 96.4% and 96.1% for cases and control subjects, respectively. Finally, 303 patients in the MR group, 240 patients in the SR group, and 530 healthy control subjects were enrolled for genotype-phenotype analysis. Patients in the SR group were older (mean age, 48.3 ± 15.9 years) than those in the MR group (mean, 40.0 ± 14.4 years; P < .0001). Patients in the SR group were more frequently women (67.1%) than those in the MR group (52.2%, P = .0004). The prevalence of atopy (skin prick test [SPT] response positivity) was significantly higher in the MR group than in the SR group (66.2% vs 37.8%, respectively; P < .0001). The prevalence of atopy (as assessed by means of Phadiatop positivity) in the control group was 36.7%. The quality control procedure discarded 10 SNPs, and statistical analyses were finally performed on 207 SNPs. Table I shows the top associated SNPs (P < .005) after adjusting for age and sex for the MR group. The most significant association was found for rs6962291 (thromboxane A synthase 1 [TBXAS1]) under the log-additive genetic model (P = 1.6 × 10−5), which remained significant after correction for multiple comparisons (false discovery rate–adjusted P value [Q value] = .0158). The minor allele (AA) seems to have a protective effect. Other SNPs from TBXAS1 and 1 SNP from 5-lipoxygenase (ALOX5) also show suggestive probabilities (Q < .2).Table IResults of the top associated SNPs (P < .005) after adjusting for age and sex for the MR hypersensitivity groupSNPGeneModelGenotypeControl subjectsCasesOR95% CIP valueQ valueNo. (%)No. (%)rs4948672ALOX5RecGG/CG434 (85.1)231 (77.3)1−−CC76 (14.9)68 (22.7)1.821.25-2.65.00664.1199rs2938392PPARGRecCC/CT399 (77.3)256 (84.8)1−−TT117 (22.7)46 (15.2)0.580.39-0.85.00452.3310rs11147439ALOX5APLog-add∗The log-additive model assumes that on a log scale, each additional copy of the minor allele increases the effect (risk or protective) by the same amount. Genotypes are coded as 0, 1, and 2, and the calculated ORs summarize the effect of the minor allele.CC116 (23.5)98 (32.7)AT260 (52.6)151 (50.3)0.730.59-0.91.00466.3310AA118 (23.9)51 (17.0)rs10487667TBXAS1DomTT231 (44.5)172 (57.9)1−−GT/GG288 (55.5)125 (42.1)0.580.44-0.79.00034.1177rs6962291TBXAS1Log-add∗The log-additive model assumes that on a log scale, each additional copy of the minor allele increases the effect (risk or protective) by the same amount. Genotypes are coded as 0, 1, and 2, and the calculated ORs summarize the effect of the minor allele.TT171 (33.3)139 (46.5)AT254 (49.4)136 (45.5)0.620.49-0.771.6 × 10−5.0158AA89 (17.4)24 (8.0)Dom, Dominant; Log-add, log-additive; OR, odds ratio; Rec, recessive.∗ The log-additive model assumes that on a log scale, each additional copy of the minor allele increases the effect (risk or protective) by the same amount. Genotypes are coded as 0, 1, and 2, and the calculated ORs summarize the effect of the minor allele. Open table in a new tab Dom, Dominant; Log-add, log-additive; OR, odds ratio; Rec, recessive. As can be seen in Table II, no SNPs achieved a significant association in the SR group. However, 3 independent SNPs belonging to ALOX5 appear to be associated with this kind of hypersensitivity (nominal P < .005 and Q < .2), and the other 2 (rs2291427 and rs901681) also showed suggestive nominal probabilities (P = .008 and P = .006, respectively; see Table E1 in this article's Online Repository at www.jacionline.org). The linkage disequilibrium coefficients (D′) among the SNPs of the ALOX5 gene were calculated for all the study subjects. As can be seen in Fig E1 in this article's Online Repository at www.jacionline.org, associated SNPs belong to different blocks of linkage, pointing to a possible role of this gene in the risk of this selective allergy.Table IIResults for SR hypersensitivity after adjusting for age and sexSNPGeneModelGenotypeControl subjectsCasesOR95% CIP valueQ valueNo. (%)No. (%)rs1565096ALOX5DomAA326 (63.2)122 (51.5)1−−AG/GG190 (36.8)115 (48.5)1.831.28-2.62.00086.1423rs4948672ALOX5RecGG/CG434 (85.1)181 (76.7)1−−CC76 (14.9)55 (23.3)2.221.41-3.49.00061.1199rs7894352ALOX5DomGG326 (62.6)129 (55.4)1−−AG/AA195 (37.4)104 (44.6)1.781.24-2.57.00170.1813Dom, Dominant; OR, odds ratio; Rec, recessive. Open table in a new tab Dom, Dominant; OR, odds ratio; Rec, recessive. In this study we have showed, for the first time, a significant role of the minor allele rs6962291 of TBXAS1 in patients with MR NSAID acute cutaneous hypersensitivity. Up to 46 different SNPs of the same gene have been analyzed (see Fig E2 in this article's Online Repository at www.jacionline.org), and rs10487667 also showed a suggestive probability, pointing out that the TBXAS1 gene could be related to this condition. For both SNPs, the allele frequency was higher within control subjects than patients, suggesting a protective role of this minor allele. TBXAS1 catalyzes the conversion of prostaglandin H2 to thromboxane A2, and thromboxane A2 induces platelet aggregation and smooth muscle contraction.4Chase M.B. Baek S.J. Purtell D.C. Schwartz S. Shen R.F. Mapping of the human thromboxane synthase gene (TBXAS1) to chromosome 7q34-q35 by two-color fluorescence in situ hybridization.Genomics. 1993; 16: 771-773Crossref PubMed Scopus (20) Google Scholar, 5Miyata A. Yokoyama C. Ihara H. Bandoh S. Takeda O. Takahashi E. et al.Characterization of the human gene (TBXAS1) encoding thromboxane synthase.Eur J Biochem. 1994; 224: 273-279Crossref PubMed Scopus (59) Google Scholar This SNP has been recently described as having a protective role in relation to aspirin intolerance in asthmatic patients. Expression analyses have demonstrated that this polymorphism encodes for a nonfunctional isoform of TBXAS1 because of the synthesis of a truncated TBXAS1 mRNA, which affects the heme-binding domain, reducing its catalytic activity.6Oh S.H. Kim Y.H. Park S.M. Cho S.H. Park J.S. Jang A.S. et al.Association analysis of thromboxane A synthase 1 gene polymorphisms with aspirin intolerance in asthmatic patients.Pharmacogenomics. 2011; 12: 351-363Crossref PubMed Scopus (37) Google Scholar The same authors showed a significant contribution of TBXA2R in the pathogenesis of MR NSAID acute urticaria but did not study the possible role of TBXAS1 in this clinical form of the disease.7Palikhe N.S. Kim S.H. Lee H.Y. Kim J.H. Ye Y.M. Park H.S. Association of thromboxane A2 receptor (TBXA2R) gene polymorphism in patients with aspirin-intolerant acute urticaria.Clin Exp Allergy. 2011; 41: 179-185Crossref PubMed Scopus (30) Google Scholar We have analyzed rs3786989 and rs4523, 2 different TBXA2R polymorphisms, but we were not able to show any relationship with MR or SR. Despite no SNPs achieving a significant association in patients with SR NSAID hypersensitivity, a certain relationship could be suggested for ALOX5. A complementary analysis stratified according to the specific drug involved showed that our results might be mainly due to pyrazolones, but further studies are needed to truly prove this association (data not shown). The high prevalence of atopy detected in patients in the MR group (66.2%) is remarkable and in accordance with previous data from other investigators.8Doña I. Blanca-López N. Cornejo-García J.A. Torres M.J. Laguna J.J. Fernández J. et al.Characteristics of subjects experiencing hypersensitivity to non-steroidal anti-inflammatory drugs: patterns of response.Clin Exp Allergy. 2011; 41: 86-95Crossref PubMed Scopus (194) Google Scholar One limitation of the study is that we used a serum assay for IgE to common allergens instead of SPTs to characterize the atopic status in control subjects (overall accuracy of 85%, with the SPT as the gold standard),9Vidal C. Gude F. Boquete O. Fernández-Merino M.C. Meijide L.M. Rey J. et al.Evaluation of the Phadiatop test in the diagnosis of allergic sensitization in a general adult population.J Investig Allergol Clin Immunol. 2005; 15: 124-130PubMed Google Scholar but the associations between specific SNPs and NSAID hypersensitivity remain similar with or without atopy as a covariate. As far as the power of the study is concerned, considering our actual sample size, the number of cases and control subjects, and a P value threshold of less than 5 × 10−5, we had 80% power to detect an odds ratio of 0.32/2.2 to 0.46/2.03 for SNPs showing a frequency of the risk genotype in control subjects and 0.2 to 0.4 for the MR group. In the SR group we had some power limitations because of the smaller population size. In fact, we had a power of 61% to detect as significant the odds ratio we found for rs4948672 (ALOX5). We would have needed to study at least 312 cases and 690 control subjects to be able to identify this effect as statistically significant with a power of 80%. In conclusion, our findings suggest a role of the TBXAS1 and ALOX5 genes in MR and SR NSAID hypersensitivity, respectively, when no underlying disease is present. We thank Ana Fiandor and Santiago Quirce (Hospital La Paz Institute for Health Research [IdiPAZ], Madrid), Rosa de la Fuente (Hospital Universitario Río Hortega, Valladolid), Ramón Lleonart (Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat), Maria José Barasona (Hospital Universitario Reina Sofía, Córdoba), Ignacio Dávila (Complejo Asistencial Universitario de Salamanca), and Beatriz Núñez and Ramón Núñez (Complejo Hospitalario Universitario de Santiago) for their contribution in collecting patients. Download .doc (.04 MB) Help with doc files Supplementary DataFig E2View Large Image Figure ViewerDownload Hi-res image Download (PPT) Download .docx (.05 MB) Help with docx files Table E1