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Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review
2015; Wiley; Volume: 71; Issue: 4 Linguagem: Inglês
10.1111/all.12821
ISSN1398-9995
AutoresAbderrahim Oussalah, Cristobalina Mayorga, M. Blanca, A. Barbaud, Alla Nakonechna, Josefina Cernadas, Maia Gotua, Knut Brockow, Jean‐Christoph Caubet, Andreas J. Bircher, Marija Atanasković, P. Démoly, Luciana Kase Tanno, Ingrid Terreehorst, José Julio Laguna, Antonino Romano, Jean‐Louis Guéant,
Tópico(s)Food Allergy and Anaphylaxis Research
ResumoAllergyVolume 71, Issue 4 p. 443-462 Review ArticleFree Access Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review A. Oussalah, A. Oussalah Faculty of Medicine of Nancy, NGERE – Nutrition, Genetics and Environmental Risk Exposure, INSERM U954, University of Lorraine, Vandoeuvre-lès-Nancy, France Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition and Metabolism, University Hospital of Nancy, Vandoeuvre-lès-Nancy, FranceSearch for more papers by this authorC. Mayorga, C. Mayorga Research Laboratory, IBIMA, Regional University Hospital of Malaga, UMA, Malaga, Spain Allergy Unit, IBIMA, Regional University Hospital of Malaga, UMA, Malaga, SpainSearch for more papers by this authorM. Blanca, M. Blanca Allergy Unit, IBIMA, Regional University Hospital of Malaga, UMA, Malaga, SpainSearch for more papers by this authorA. Barbaud, A. Barbaud Department of Dermatology and Allergology, University Hospital of Nancy, Vandoeuvre-lès-Nancy, FranceSearch for more papers by this authorA. Nakonechna, A. Nakonechna Allergy and Immunology, Clinic Royal Liverpool and Broadgreen University Hospital, Thomas Drive Liverpool, UKSearch for more papers by this authorJ. Cernadas, J. Cernadas Immunoallergy Department, Centro Hospitalar Sao Joao, Porto, PortugalSearch for more papers by this authorM. Gotua, M. Gotua Center for Allergy and Immunology Research, Tbilisi, GeorgiaSearch for more papers by this authorK. Brockow, K. Brockow Klinik für Dermatologie und Allergologie am Biederstein, Technische Universität München, München, GermanySearch for more papers by this authorJ.-C. Caubet, J.-C. Caubet Division of Paediatrics, University Hospital of Geneva, Geneva, SwitzerlandSearch for more papers by this authorA. Bircher, A. Bircher Dermatologie/Allergologie, Universitätsspital Basel, Basel, SwitzerlandSearch for more papers by this authorM. Atanaskovic, M. Atanaskovic Department of Allergology and Pulmonology, University Children's Hospital, Belgrade, SerbiaSearch for more papers by this authorP. Demoly, P. Demoly Department of Pulmonology, Division of Allergy, Hôpital Arnaud de Villeneuve, University Hospital of Montpellier, Montpellier, FranceSearch for more papers by this authorL. K. Tanno, L. K. Tanno Hospital Sírio-Libanês, São Paulo, BrazilSearch for more papers by this authorI. Terreehorst, I. Terreehorst Academisch Medisch Centrum, University of Amsterdam, Amsterdam, NetherlandsSearch for more papers by this authorJ. J. Laguna, J. J. Laguna Allergy Unit, Hospital de la Cruz Roja and Department of Immunology Alfonso X el Sabio University, Madrid, SpainSearch for more papers by this authorA. Romano, A. Romano Allergy Unit, Complesso Integrato Columbus, Rome and IRCCS Oasi Maria S.S., Troina, ItalySearch for more papers by this authorJ.-L. Guéant, Corresponding Author J.-L. Guéant Faculty of Medicine of Nancy, NGERE – Nutrition, Genetics and Environmental Risk Exposure, INSERM U954, University of Lorraine, Vandoeuvre-lès-Nancy, France Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition and Metabolism, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France Correspondence Jean-Louis Guéant, INSERM U954, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, U954, Vandoeuvre-lès-Nancy F-54511, France. Tel.: +33 3 83 68 32 71 Fax: +33 3 83 68 32 79 E-mail: jean-louis.gueant@univ-lorraine.frSearch for more papers by this authoron behalf of the Task force ‘Genetic predictors of drug hypersensitivity’ of the European Network on Drug Allergy (ENDA) of EAACI, on behalf of the Task force ‘Genetic predictors of drug hypersensitivity’ of the European Network on Drug Allergy (ENDA) of EAACISearch for more papers by this author A. Oussalah, A. Oussalah Faculty of Medicine of Nancy, NGERE – Nutrition, Genetics and Environmental Risk Exposure, INSERM U954, University of Lorraine, Vandoeuvre-lès-Nancy, France Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition and Metabolism, University Hospital of Nancy, Vandoeuvre-lès-Nancy, FranceSearch for more papers by this authorC. Mayorga, C. Mayorga Research Laboratory, IBIMA, Regional University Hospital of Malaga, UMA, Malaga, Spain Allergy Unit, IBIMA, Regional University Hospital of Malaga, UMA, Malaga, SpainSearch for more papers by this authorM. Blanca, M. Blanca Allergy Unit, IBIMA, Regional University Hospital of Malaga, UMA, Malaga, SpainSearch for more papers by this authorA. Barbaud, A. Barbaud Department of Dermatology and Allergology, University Hospital of Nancy, Vandoeuvre-lès-Nancy, FranceSearch for more papers by this authorA. Nakonechna, A. Nakonechna Allergy and Immunology, Clinic Royal Liverpool and Broadgreen University Hospital, Thomas Drive Liverpool, UKSearch for more papers by this authorJ. Cernadas, J. Cernadas Immunoallergy Department, Centro Hospitalar Sao Joao, Porto, PortugalSearch for more papers by this authorM. Gotua, M. Gotua Center for Allergy and Immunology Research, Tbilisi, GeorgiaSearch for more papers by this authorK. Brockow, K. Brockow Klinik für Dermatologie und Allergologie am Biederstein, Technische Universität München, München, GermanySearch for more papers by this authorJ.-C. Caubet, J.-C. Caubet Division of Paediatrics, University Hospital of Geneva, Geneva, SwitzerlandSearch for more papers by this authorA. Bircher, A. Bircher Dermatologie/Allergologie, Universitätsspital Basel, Basel, SwitzerlandSearch for more papers by this authorM. Atanaskovic, M. Atanaskovic Department of Allergology and Pulmonology, University Children's Hospital, Belgrade, SerbiaSearch for more papers by this authorP. Demoly, P. Demoly Department of Pulmonology, Division of Allergy, Hôpital Arnaud de Villeneuve, University Hospital of Montpellier, Montpellier, FranceSearch for more papers by this authorL. K. Tanno, L. K. Tanno Hospital Sírio-Libanês, São Paulo, BrazilSearch for more papers by this authorI. Terreehorst, I. Terreehorst Academisch Medisch Centrum, University of Amsterdam, Amsterdam, NetherlandsSearch for more papers by this authorJ. J. Laguna, J. J. Laguna Allergy Unit, Hospital de la Cruz Roja and Department of Immunology Alfonso X el Sabio University, Madrid, SpainSearch for more papers by this authorA. Romano, A. Romano Allergy Unit, Complesso Integrato Columbus, Rome and IRCCS Oasi Maria S.S., Troina, ItalySearch for more papers by this authorJ.-L. Guéant, Corresponding Author J.-L. Guéant Faculty of Medicine of Nancy, NGERE – Nutrition, Genetics and Environmental Risk Exposure, INSERM U954, University of Lorraine, Vandoeuvre-lès-Nancy, France Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition and Metabolism, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France Correspondence Jean-Louis Guéant, INSERM U954, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, U954, Vandoeuvre-lès-Nancy F-54511, France. Tel.: +33 3 83 68 32 71 Fax: +33 3 83 68 32 79 E-mail: jean-louis.gueant@univ-lorraine.frSearch for more papers by this authoron behalf of the Task force ‘Genetic predictors of drug hypersensitivity’ of the European Network on Drug Allergy (ENDA) of EAACI, on behalf of the Task force ‘Genetic predictors of drug hypersensitivity’ of the European Network on Drug Allergy (ENDA) of EAACISearch for more papers by this author First published: 17 December 2015 https://doi.org/10.1111/all.12821Citations: 34 Edited by: Stephan Weidinger AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Drug hypersensitivity includes allergic (AR) and nonallergic reactions (NARs) influenced by genetic predisposition. We performed a systematic review of genetic predictors of IgE-mediated AR and NAR with MEDLINE and PubMed search engine between January 1966 and December 2014. Among 3110 citations, the search selected 53 studies, 42 of which remained eligible. These eligible studies have evaluated genetic determinants of immediate reactions (IR) to beta-lactams (n = 19), NAR against aspirin (n = 12) and other nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 8), and IR to biologics (n = 3). We reported two genomewide association studies and four case–control studies on candidate genes validated by replication. Genes involved in IR to beta-lactams belonged to HLA type 2 antigen processing, IgE production, atopy, and inflammation, including 4 genes validated by replications, HLA-DRA, ILR4, NOD2, and LGALS3. Genes involved in NAR to aspirin belonged to arachidonic acid pathway, membrane-spanning 4A gene family, histamine production pathway, and pro-inflammatory cytokines, while those involved in NAR to all NSAIDs belonged to arachidonic acid pathway and HLA antigen processing pathway. ALOX5 was a common predictor of studies on NAR to both aspirin and NSAIDs. Although these first conclusions could be drawn, this review highlights also the lack of reliable data and the need for replicating studies in contrasted populations, taking into account worldwide allele frequencies, gene–gene interactions, and contrasted situations of environmental exposure. Adverse drug reactions are defined by the World Health Organization as noxious and unintended responses to drugs at normal doses 1. The classical pharmacological classification of adverse drug reactions by Rawlins and Thompson distinguishes two types: type A reactions, which are dose-dependent and predictable, and type B, which are not dose-dependent and are unpredictable 2. Type B reactions include hypersensitivity reactions produced by the release of cellular mediators through both immune and nonimmune mechanisms 3, 4. Allergy reactions (AR) refer to hypersensitivity reactions for which typically either an IgE or non-IgE mechanism – like T-cell-mediated mechanism – is demonstrated either with positive skin tests or in vitro tests (e.g., specific IgE or cellular tests) while nonallergic reactions (NARs) refer to those for which no specific immunological mechanism can be demonstrated 5-7. According to the International Consensus on drug allergy, hypersensitivity reactions are commonly classified as immediate or nonimmediate, depending on the time interval between the last drug administration and the manifestations of the reaction 8, 9. Immediate reactions occur within the first hour after the last drug administration and are manifested as urticaria, angioedema, rhinitis, bronchospasm, or anaphylaxis. Nonimmediate reactions may occur at any time from 1 h after the initial drug administration and are often induced by T cells and other mechanisms. We have performed a systematic review on genetic variants associated with drugs-induced immediate hypersensitivity reactions, using a highly sensitive search strategy, which was applied to retrieve all articles from electronic bibliographic databases. Materials and methods Selection criteria and data extraction The literature search was conducted using MEDLINE-indexed literature using the PubMed search engine from the National Center for Biotechnology Information (www.pubmed.gov) (January 1966 to October 2014), using the following medical subject heading (MeSH) terms: [(Receptors, IgE) OR (Immunoglobulin E) OR (E, Immunoglobulin) OR IgE OR (Hypersensitivity, Immediate) OR allergy OR anaphylactic OR anaphylaxis] vs AND (Therapeutics OR Drugs OR (Drug Hypersensitivity) OR (Drug Hypersensitivity Syndrome) OR Penicillins OR beta-Lactams OR betalactams OR (Anti-Inflammatory Agents, Non-Steroidal) OR aspirin) AND (Genes OR (Polymorphism, Genetic) OR (Polymorphism, Single Nucleotide) OR (High-Throughput Nucleotide Sequencing) OR (Genome-Wide Association Study) OR genetic variant OR immunochip) (See supplementary methods for the exhaustive MeSH term-based search strategy). Additional articles were retrieved from primary search references. A study was considered eligible for the systematic review if it has assessed the potential association between at least one genetic variant and a drugs-induced immediate hypersensitivity reaction phenotype. Both candidate gene and genomewide association study approaches were eligible for the systematic review. No language restrictions were applied. The following data were extracted, when available, based on a predefined protocol using Microsoft Excel®: author; year; geographical region; study design (case–control, cohort, family-based); study approach (candidate gene, genomewide association study), number of cases, clinical phenotype of cases, number of controls, clinical phenotype of controls, discovery/initial cohort, validation/replication cohort, genetic variants with their corresponding genes or loci, and effect sizes (odds ratios or hazard ratios); nominal P-values and multiple-correction P-values when applicable; functional validation; and proportion of positive drug-specific IgE among patients with immediate-type hypersensitivity to beta-lactams. Two investigators (AO, J-LG) independently reviewed the titles and abstracts of all citations identified by the literature search. Eligible articles were reviewed in duplicate in an independent manner by the two investigators. Disagreement in data extraction was resolved by consensus. All eligible studies were assessed for their quality using the validated STREGA reporting recommendations framework (STrengthening the REporting of Genetic Association Studies) 10. A quantitative ‘STREGA score’ was calculated for each study and was based on a list of 25 items. Concomitantly, selected articles were rated in three categories according the level of evidence as follows: high (A), studies with adequate study power and replication/validation, for which further research is very unlikely to change our confidence in the risk association of the gene predictor; good (B), studies with adequate study power but no reported replication/validation, for which further research may have an impact on the estimates of the risk association; and moderate (C), studies with inadequate study power and no reported replication, for which further research is very likely to have an impact on the estimates of risk association. Adequate population size was defined with a study power 1-β = 0.9 and α = 0.05, a genotype relative risk at 2.0, and a disease prevalence at 0.01, assuming both allelic and additive models, according to the algorithm of Skol et al. 11. Table S1 reports the study power calculation according to disease-related allele frequency assuming both allelic and additive genetic models. Results Literature search results The search strategy generated 3110 citations of which 53 appeared to be relevant to the systematic review. Only publications dealing with evaluation of genetic predictors of immediate-type immune and nonimmune reactions to drugs were selected. Of these 53 studies, eleven were excluded for the following reasons: drug association with asthma, in eight cases, letter to the editor without reporting original in two cases and genotype data not clearly reported in one case (see Table S2 for detailed exclusion grounds for articles excluded from the systematic review), leaving 42 studies eligible to the systematic review (Fig. 1). Among the 42 selected studies that reported genetic predictors in association with immediate-type hypersensitivity, 19 were related to BLs 12-30 (Table 1), 12 to aspirin 31-42 (Table 2), and eight to other NSAIDs 43-50 (Table 3). Three studies reported genetic predictors in association with biologicals, including hypersensitivity to asparaginase 51, EGF receptor inhibitors 52, and infliximab 53 (Table 4). Tables S3 to 6 report quality assessment of the 42 eligible studies according to the STREGA recommendations 10. The studies on IR to BLs found an association with genes that were previously identified as predictors of atopy, increased IgE production and inflammation, at least in Europe, China, and US. In contrast, the genetic predictors of hypersensitivity reactions to aspirin and other NSAIDs are mainly due to mechanisms related to their influence on the synthesis and release of newly formed mediators. Figure 1Open in figure viewerPowerPoint PRISMA flow diagram of the systematic review. Table 1. Studies that reported genetic predictors in association with immediate-type hypersensitivity to beta-lactam antibiotics (19 studies) First author, year, journal STREGA score Rate Geographical region Study design and approach Cases, (n) Cases, phenotype Controls, (n) Controls, phenotype Replication cohort Potentially causal variants Effect size Functional validation Positive drug-specific IgE References (Spengler & de Weck, 1977, Monogr Allergy) 6/25 C Switzerland Cases only (candidate gene) 46 BL allergy 0 – No None NR Lymphocyte culture with penicillin NR 12 (Qiao et al., 2004, Allergy) 9/25 B Korea Case–control (candidate gene) 448 BL allergy 101 Healthy controls No FcεR1β E237G (FcεR1β = MS4A2)* NR Specific IgE antibodies 261/448 (58.3%) 13 (Qiao et al., 2005, Allergy) 10/25 B China Case–control (candidate gene) 245 BL allergy 101 Healthy controls No IL-4Ralpha*Q576 (IL-4Ralpha = IL4R)* NR Specific IgE to penicillins (eight types); Serum levels of IL−4, IL-13 and IFN-gamma 141/245 (57.6%) 14 (Yang et al., 2005, Eur J Clin Pharmacol) 10/25 C China Case–control (candidate gene) 158 BL allergy 89 Healthy controls No IL4 IL13 NR Serum levels of IL-4 and IL-13 NR 15 (Gueant-Rodriguez et al., 2006, Pharmacogenet Genomics) 16/25 B Italy Case–control (candidate gene) 210 BL allergy 265 Healthy controls No IL13 R130Q IL4RA I50V (IL4Ralpha = IL4R)* IL4RA S478P IL4RA Q551R 130 (RQ+QQ); OR = 1.44 (0.95–2.18); P = 0.0881 50II; OR = 1.65 (1.06–2.57); P = 0.0272 478 SS; OR = 1.82 (1.07–3.12); P = 0.0271 551QQ; OR = 1.67 (1.02–2.74); P = 0.0426 Serum IgE levels NR 16 [Yang et al., 2006, Chin Med J (Engl)] NA C China Case–control (candidate gene) 113 (248) BL allergy 87 (101) Healthy controls No HLA-DR9 HLA-DR14.1 HLA-DR17 HLA-DR4 NA Specific IgE antibodies NA 17 (Guglielmi et al., 2006, Allergy) 12/25 C France Case–control (candidate gene) 44 BL allergy 44 Healthy controls No IL4RA Ile75Val (IL-4Ralpha = IL4R)* IL10 -819C>T IL10 -592 C>A OR = 5.4 (1.16–27.7); P = 0.012 OR = 17.5 (1.26–533.07); P = 0.023 None NR 18 (Qiao et al., 2007, Eur J Clin Pharmacol) 12/25 C China Case–control (candidate gene) 102 BL llergy 86 Healthy controls No IL10 -1082 G/A IL10 –819 C/T NR Specific IgE and IgG (eight types); Serum IL-10 level NR 19 (Apter et al., 2008, J Allergy Clin Immunol) 16/25 C USA Case–control (candidate gene) 23 BL allergy 39 Healthy controls No IL4 IL4R LACTB rs2070874; OR = 3.33 (1.09–10.21); P = 0.035 rs10062446; OR = 3.61 (1.21–10.71); P = 0.021 rs11740584; OR = 4.08 (1.35–12.30); P = 0.012 rs1805010; OR = 1.35 (0.40–4.62); P = 0.63 rs2729835; OR = 2.99 (0.96– 9.28); P = 0.058 Penicillin metabolism (LACTB) NR 20 (Gueant-Rodriguez et al., 2008, Pharmacogenomics J) 12/25 B Italy Case–control (candidate gene) 167 BL allergy 260 Healthy controls No TNFA -308G>A (TNFA = TNF) Minor allele; OR = 4.29 (1.11–16.5); P = 0.0343 Specific IgE antibodies 110/169 (65.1%) 21 (Gao et al., 2008, Eur J Clin Pharmacol) 11/25 C China Case–control (candidate gene) 144 BL allergy 88 Healthy controls No IFNR1 (IFNR1 = IFNGR1)* NR Specific IgE and IgG (eight types) 88/144 (61.1%) 22 (Huang et al., 2009, Eur J Clin Pharmacol) 12/25 B China Case–control (candidate gene) 242 BL allergy 240 Healthy controls No IL-4RA Q576R (IL4RA = IL4R)* IL-4RA I75V Minor allele; OR = 1.67 (1.17–2.38); P = 0.003 Minor allele; OR = 1.21 (0.93–1.57); P = 0.19 Specific IgE (eight types) 146/242 (60.3%) 23 (Ming et al., 2011, J Int Med Res) 12/25 B China Case–control (candidate gene) 606 BL allergy 614 Healthy controls No IL18 -607A>C IL18 −137G>C Minor allele; OR = 1.51 (1.28–1.78); P < 0.001 Minor allele; OR = 1.79 (1.40–2.28); P < 0.001 None NR 24 (Huang et al., 2012, Int J Clin Pharmacol Ther) NA B China Case–control (candidate gene) 242 BL allergy 220 Healthy controls No STAT6 in2SNP3 NA Specific IgE (eight types) NA 25 (Nam et al., 2012, J Korean Med Sci) 14/25 C Korea Case–control (candidate gene) 153 HCWs who had been exposed to antibiotics 86 HCWs unexposed healthy controls No FcεR1β -109T > C (FcεR1 = MS4A2)a TT genotype; OR = 3.55 (1.32–9.53); P = 0.036 Specific IgE and IgG; In vitro functional assay 31/153 (20.3%) 26 (Cornejo-Garcia et al., 2012, Allergy) 15/25 A Spain Case–control Replication of Gueant-Rodriguez et al., 2006 (candidate gene) 340 Atopy with BL allergy 340 Healthy controls Yes IL4RA I50V IL4RA Q551R (IL4Ralpha = IL4R)a NR Specific IgE against prevalent allergens; Prevalence of atopy NR 27 (Bursztejn et al., 2013, Allergy) 13/25 A Italy Spain Case–control (candidate gene) Italy: 210 Spain: 387 BL allergy Italy: 368 Spain: 326 Healthy controls Yes NOD2 rs2066845 NOD2 rs5743293 CT/TT, rs2066845; OR = 0.28 (0.10–0.70); P = 0.003 (Italy) WT/insC genotype, rs5743293; OR = 6.08 (1.37–55.40); P = 0.007 (Spain) Specific IgE NR 28 (Gueant et al., 2014, J Allergy Clin Immunol) 22/25 A Spain Italy Case–control GWAS (Immunochip) Initial: 387 Replication: 299 BL allergy Initial: 1124 Replication: 362 Healthy controls Yes Initial study ZNF300 rs4958427 C5 rs17612 HLA-DRA | HLA-DRB5 rs7754768 HLA-DRA|HLA-DRB5 rs9268832 HLA-DRA rs7192 Replication study HLA-DRA rs7192 HLA-DRA rs8084 rs4958427; OR = 1.85; P = 1.8×10-8† rs17612; OR = 0.27; P = 4.4×10-7 rs7754768; OR = 0.63; P = 1.4×10-6† rs9268832; OR = 0.64; P = 4.1×10-6† rs7192; OR = 0.65; P = 8.1×10-6† Skin test NR 29 (Cornejo-García et al., 2015, Pharmacogenomics J) 15/25 A Spain Italy Case–control (candidate gene) Initial: 395 Replication: 198 BL allergy Initial: 310 Replication: 339 Healthy controls Yes LGALS3 rs11125 rs11125; OR = 3.98 (2.70–6.00); P < 0.0001† (Initial: Spain) rs11125; OR = 5.1 (3.58–7.31); P < 0.0001† (Replication: Italy) Serum level of total IgE NR 30 STREGA, STrengthening the REporting of Genetic Association Studies); BL, beta-lactam; HCW, healthcare worker; IgE, immunoglobulin E; IgG, immunoglobulin G; GWAS, genomewide association study; NR, not reported; NA, not available; OR, odds ratio. a Updated genes nomenclature according to the Human Gene Nomenclature Committee, Human Genome Organization (HUGO). b Significant after Bonferroni's multiple testing correction. Table 2. Studies that reported genetic predictors in association with immediate-type hypersensitivity to aspirin (12 studies) First author, year, journal STREGA score Rate Geographical region Study design and approach Cases 1, (n) Cases 1, phenotype Cases 1 phenotype according to EACCI classification* Cases 2, (n) Cases 2, phenotype Controls, (n) Controls, phenotype Replication cohort Potentially causal variants Effect size Functional validation References (Kim et al., 2005, J Korean Med Sci) 16/25 C Korea Case–control (candidate gene) 101 Aspirin-intolerant urticaria NIUA 95 Asirin-intolerant asthma (NERD) 123 Healthy controls No ALOX5 −1708 G>A NR None 31 (Choi et al., 2005, J Korean Med Sci) 16/25 C Korea Case–control (candidate gene) 110 Aspirin-induced urticaria/angioedema NIUA 53 53 patients without aspirin hypersensitivity who had various drug allergies presenting as exanthematous skin symptoms 99 Healthy controls No None – None 32 (Mastalerz et al., 2006, Br J Dermatol) 13/25 C Poland Family study (candidate gene) – Aspirin-induced urticaria NIUA – – – – No LTC4S GSTM1 NR None 33 (Bae et al., 2007, J Allergy Clin Immunol) 14/25 B Korea Case–control (candidate gene) 105 Aspirin-intolerant chronic urticaria NECD 154 Aspirin-tolerant chronic urticaria 222 Healthy controls No FcεR1α −344C>T (FcεR1α = FCER1A)† NR Luciferase reporter assay; electrophoretic mobility shift assay; Total IgE concentrations; Rate of atopy; anti-IgE-mediated histamine release 34 (Palikhe et al., 2008, Allergy Asthma Proc) NA B Korea Case–control (candidate gene) 119 Aspirin-intolerant chronic urticaria NECD 154 Aspirin-tolerant chronic urticaria 224 Healthy controls No FcεR1β E237G FcεR1γ −237A>G (FcεR1β = MS4A2)† (FcεR1γ = FCER1G)† NR Release of histamine 35 (Park et al., 2008, J Clin Pharm Ther) 14/25 B Korea Case–control (candidate gene) 112 Aspirin-intolerant chronic urticaria NECD 153 Aspirin-tolerant chronic urticaria 457 Healthy controls No TGFβ1 −509C>T (TGFβ1 = TGFB1)† NR Serum TGFbeta1 levels 36 (Choi et al., 2009, J Clin Pharm Ther) 16/25 B Korea Case–control (candidate gene) 239 AIU (120 patients with aspirin-intolerant chronic urticaria and 119 with aspirin-intolerant acute urticaria) NECD/NIUA – – 524 Healthy controls No TNF −1031T>C TNF −863C>A NR None 37 (Kim et al., 2009, Allergy) 16/25 B Korea Case–control (candidate gene) 111 Aspirin-intolerant chronic urticaria NECD 154 Aspirin-tolerant chronic urticaria 152 Healthy controls No HNMT 939A>G NR Histamine release from the basophils 38 (Sanchez-Borges et al., 2009, J Investig Allergol Clin Immunol) 13/25 B Venezuela Case–control (candidate gene) 110 Aspirin-induced urticaria NIUA – – 165 Healthy controls No LTC4S −444C AC+CC vs AA; OR = 1.95 (1.26–3.03); P = 0.002 Total and mite-specific IgE 39 (Kim et al., 2011, Br J Dermatol) 14/25 C Korea Case–control (candidate gene) 275 Aspirin-induced urticaria NIUA – – 196 Healthy controls No IL18 −607A/C C-607/G−137 haplotype; OR = 1.46 (1.06–2.00); P = 0.02 Luciferase reporter assay; Electrophoretic mobility shift assays; Neutrophil chemotaxis assays 40 (Palikhe et al., 2011, Clin Exp Allergy) 16/25 B Korea Case–control (candidate gene) 167 Aspirin-intolerant acute urticaria NIUA 149 Aspirin-intolerant chronic urticaria (NECD) 265 Healthy controls No TBXA2R −4684T NR Electrophoretic mobility shift assay 41 (Palikhe et al., 2012, J Hum Genet) 13/25 B Korea Case–control (candidate gene) 141 Aspirin-intolerant chronic urticaria NECD 153 Aspirin-tolerant chronic urticaria 174 Healthy controls No PTGER4 −1254 G>A NR Dual-luciferase system; electrophoretic mobility shift assay; PTGER4 mRNA expression 42 STREGA, STrengthening the REporting of Genetic Association Studies); NR, not reported; OR, odds ratio; NIUA, NSAIDs-induced urticaria/angioedema; NERD, NSAIDs-exacerbated respiratory disease; NECD, NSAIDs-exacerbated cutaneous disease. a Nomenclature according to the European Academy of Allergy and Clinical Immunology (EAACI) classification of hypersensitivity to nonsteroidal anti-inflammatory drugs 54. b Updated genes nomenclature according to the Human Gene Nomenclature Committee, Human Genome Organization (HUGO). Table 3. Studies that reported genetic predictors in association with immediate-type hypersensitivity to NSAIDs (eight studies) First author, year, journal STREGA score Rate Geographical region Study design and approach Cases 1 (n) Cases 1 phenotype Cases 1 phenotype according to EACCI classification* Cases 2 (n) Cases 2 phenotype Controls (n) Controls phenotype Replication cohort Potentially causal variants Effect size Intermediate phenotype and functional validation References (Quiralte et al., 1999, J Allergy Clin Immunol) 14/25 C Spain Case–control (candidate gene) 21 Urticaria and/or angioedema plus hypotension and/or laryngeal edema after NSAID administration NIUA 47 Patients who had exclusively cutaneous reactions during single-blind, placebo-controlled oral challenges with NSAIDs (SNIRD) 167 Tolerant control subjects (29 of whom had also had an IgE-mediated anaphylaxis to different agents) No HLA-DRB1 * 11 OR = 7.3 (2.8–19.0); P = 0.02 None 43 (Pacor et al., 2006, Mediators Inflamm) 12/25 C Italy Case–control (candidate gene) 69 Chronic idiopathic urticaria associated with aspirin and/or NSAIDs hypersensitivity NECD – – 200 Healthy controls No None – None 44 (Agundez et al., 2012, PLoS One) 18/25 B Spain Case–control (candidate gene) 442 Urticaria + angioedema Anaphylaxis Respiratory symptoms Mixed symptoms NIUA – – 441 Healthy controls No DAO rs10156191 Minor allele OR = 1.59 (1.27–2.00); P = 6.0 × 10−5 None 45 (Cornejo-Garcia et al., 2012, Clin Exp Allergy) 17/25 A Spain Case–control (candidate gene) Initial: 486 Replication: 195 NSAIDs-induced acute urticaria NIUA – – Initial: 536 Replication: 212 Healthy controls Yes ALOX15 (rs7220870) PTGDR (rs8004654) CYSLTR1 (rs320995) Minor allele, OR = 0.77 (0.61–0.99); P = 0.041 (Malaga); OR = 0.72 (0.53–0.97); P = 0.028 (Madrid) Minor allele OR = 1.32 (1.04–1.64); P = 0.019 (Malaga) OR = 1.41 (1.08–1.89); P = 0.013 (Madrid) Minor allele OR = 1.79 (1.30–2.46); P = 0.0003 (Malaga) OR = 1.59 (1.16–1.66); P = 0.001 (Madrid) None 46 (Ayuso et al., 2013, Pharmacogenomics) 17/25 B Spain Case–control (candidate gene) 442 Hypersensitivity to NSAIDs NIUA – – 414 Healthy controls No None – None 47
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