Allergy

REVIEW ARTICLE

Genetic variants associated with drugs-induced immediate

hypersensitivity reactions: a PRISMA-compliant
systematic review
A. Oussalah1,2, C. Mayorga3, 4, M. Blanca4, A. Barbaud5, A. Nakonechna6, J. Cernadas7, M. Gotua8,
K. Brockow9, J.-C. Caubet10, A. Bircher11, M. Atanaskovic12, P. Demoly13, L. K. Tanno14, I. Terree-
horst15, J. J. Laguna16, A. Romano17 & J.-L. Gue
ant1,2 on behalf of the Task force ‘Genetic predic-
tors of drug hypersensitivity’ of the European Network on Drug Allergy (ENDA) of EAACI
1
Faculty of Medicine of Nancy, NGERE – Nutrition, Genetics and Environmental Risk Exposure, INSERM U954, University of Lorraine;
2
Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition and
Metabolism, University Hospital of Nancy, Vandoeuvre-le s-Nancy, France; 3Research Laboratory, IBIMA, Regional University Hospital of
Malaga, UMA; Allergy Unit, IBIMA, Regional University Hospital of Malaga, UMA, Malaga, Spain; 5Department of Dermatology and
4

Allergology, University Hospital of Nancy, Vandoeuvre-le s-Nancy, France; 6Allergy and Immunology, Clinic Royal Liverpool and Broadgreen
University Hospital, Thomas Drive Liverpool, UK; 7Immunoallergy Department, Centro Hospitalar Sao Joao, Porto, Portugal; 8Center for
Allergy and Immunology Research, Tbilisi, Georgia; 9Klinik fu €r Dermatologie und Allergologie am Biederstein, Technische Universit€ at
Mu €nchen, Mu €nchen, Germany; 10Division of Paediatrics, University Hospital of Geneva, Geneva; 11Dermatologie/Allergologie,
Universit€
atsspital Basel, Basel, Switzerland; 12Department of Allergology and Pulmonology, University Children’s Hospital, Belgrade, Serbia;
13
Department of Pulmonology,Division of Allergy, Ho ^pital Arnaud de Villeneuve, University Hospital of Montpellier, Montpellier, France;
14
^s, S~ao Paulo, Brazil; 15Academisch Medisch Centrum, University of Amsterdam, Amsterdam, Netherlands; 16Allergy
Hospital S
ırio-Libane
Unit, Hospital de la Cruz Roja and Department of Immunology Alfonso X el Sabio University, Madrid, Spain; 17Allergy Unit, Complesso
Integrato Columbus, Rome and IRCCS Oasi Maria S.S., Troina, Italy

To cite this article: Oussalah A, Mayorga C, Blanca M, Barbaud A, Nakonechna A, Cernadas J, Gotua M, Brockow K, Caubet J-C, Bircher A, Atanaskovic M,
Demoly P, Kase-Tanno L, Terreehorst I, Laguna JJ, Romano A, Gu

eant J-L on behalf of the Task force ‘Genetic predictors of drug hypersensitivity’ of the
European Network on Drug Allergy (ENDA) of EAACI. Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant
systematic review. Allergy 2016; 71: 443–462.

Keywords
aspirin; beta-lactam antibiotics; genetic
predictors; IgE-mediated drug allergy;
nonsteroidal anti-inflammatory drugs.
Correspondence
Jean-Louis Gue
ant, INSERM U954,
NGERE – Nutrition, Genetics, and Environ-
mental Risk Exposure, U954, Vandoeuvre-
s-Nancy F-54511, France.
le
Tel.: +33 3 83 68 32 71
Fax: +33 3 83 68 32 79
E-mail: jean-louis.gueant@univ-lorraine.fr
Accepted for publication 9 December 2015
DOI:10.1111/all.12821
Edited by: Stephan Weidinger
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 genome-
wide association studies and four case–control studies on candidate genes vali-
dated 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 pre-
dictor of studies on NAR to both aspirin and NSAIDs. Although these first con-
clusions 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.

Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 443
Genetics of IgE-mediated AR and NAR to drugs
Adverse drug reactions are defined by the World Health
Organization as noxious and unintended responses to drugs
at normal doses (1). The classical pharmacological classifica-
tion 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 hypersen-
sitivity reactions for which typically either an IgE or non-IgE
mechanism – like T-cell-mediated mechanism – is demon-
strated 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 immedi-
ate 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 anaphy-
laxis. 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 (Polymor-
phism, Genetic) OR (Polymorphism, Single Nucleotide) OR
(High-Throughput Nucleotide Sequencing) OR (Genome-
Wide Association Study) OR genetic variant OR immuno-
chip) (See supplementary methods for the exhaustive MeSH
term-based search strategy). Additional articles were retrieved
from primary search references. A study was considered eligi-
ble 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
444 Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Oussalah et al.
approaches were eligible for the systematic review. No lan-
guage restrictions were applied.
The following data were extracted, when available, based
on a predefined protocol using Microsoft ExcelÒ: 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, dis-
covery/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 vali-
dation; 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 inde-
pendent 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 report-
ing recommendations framework (STrengthening the REport-
ing 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 repli-
cation, for which further research is very likely to have an
impact on the estimates of risk association. Adequate popula-
tion size was defined with a study power 1-b = 0.9 and
a = 0.05, a genotype relative risk at 2.0, and a disease preva-
lence at 0.01, assuming both allelic and additive models, accord-
ing to the algorithm of Skol et al. (11). Table S1 reports the
study power calculation according to disease-related allele fre-
quency 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 publi-
cations dealing with evaluation of genetic predictors of imme-
diate-type immune and nonimmune reactions to drugs were
selected. Of these 53 studies, eleven were excluded for the fol-
lowing 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 hyper-
sensitivity, 19 were related to BLs (12–30) (Table 1), 12 to
Genetics of IgE-mediated AR and NAR to drugs Oussalah et al.

Table 1 (continued)

Study design
First author, year, STREGA Geographical and Cases, Cases, Controls, Controls,
journal score Rate region approach (n) phenotype (n) phenotype

(Huang et al., 2012, NA B China Case–control 242 BL allergy 220 Healthy

Int J Clin Pharmacol (candidate controls
Ther) gene)
(Nam et al., 2012, J 14/25 C Korea Case–control 153 HCWs who 86 HCWs
Korean Med Sci) (candidate had unexposed
gene) been exposed healthy
to antibiotics controls
(Cornejo-Garcia 15/25 A Spain Case–control 340 Atopy with BL 340 Healthy
et al., 2012, Allergy) Replication of allergy controls
Gueant-
Rodriguez
et al.,
2006
(candidate
gene)
(Bursztejn et al., 13/25 A Italy Spain Case–control Italy: 210 BL allergy Italy: 368 Healthy
2013, Allergy) (candidate Spain: 387 Spain: 326 controls
gene)

(Gueant et al., 2014, 22/25 A Spain Italy Case–control Initial: 387 BL allergy Initial: 1124 Healthy
J Allergy Clin GWAS Replication: Replication: controls
Immunol) (Immunochip) 299 362

(Cornejo-Garc
ıa 15/25 A Spain Italy Case–control Initial: 395 BL Initial: 310 Healthy
et al., 2015, (candidate Replication: allergy Replication: controls
Pharmacogenomics gene) 198 339
J)

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.
*Updated genes nomenclature according to the Human Gene Nomenclature Committee, Human Genome Organization (HUGO).
†
Significant after Bonferroni’s multiple testing correction.

NARs to NSAIDs have been classified in three categories
(European Academy of Allergy and Clinical Immunology
classification): (i) NSAIDs-exacerbated respiratory disease
(NERD), defined as hypersensitivity reactions manifesting
primarily as bronchial obstruction, dyspnea, and nasal con-
gestion/rhinorrhea, occurring in patients with an underlying
chronic airway respiratory disease (asthma/rhinosinusitis/
nasal polyps). Previously used synonyms for this condition
are as follows: aspirin triad, asthma triad, Samter’s syn-
drome, Widal syndrome, aspirin-induced asthma or aspirin-
sensitive rhinosinusitis/asthma syndrome, aspirin-intolerant
asthma, and aspirin-exacerbated respiratory disease; (ii)
NSAIDs-exacerbated cutaneous disease (NECD), defined as
hypersensitivity reactions manifesting as wheals and/or
angioedema occurring in patients with a history of chronic
spontaneous urticaria. Previously used synonyms for this
condition are as follows: aspirin-induced urticaria and
aspirin-exacerbated cutaneous disease; and (iii) NSAIDs-
induced urticaria/angioedema (NIUA), defined as hypersensi-
tivity reactions manifesting as wheals and/or angioedema
occurring in otherwise healthy subjects (without history of
chronic spontaneous urticaria). Symptoms are induced by at
least two NSAIDs with different chemical structure (not
belonging to the same chemical group) (54). On the other

448 Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Genetics of IgE-mediated AR and NAR to drugs Oussalah et al.

Table 1 Studies that reported genetic predictors in association with immediate-type hypersensitivity to beta-lactam antibiotics (19 studies)

Study design
First author, year, STREGA Geographical and Cases, Cases, Controls, Controls,
journal score Rate region approach (n) phenotype (n) phenotype

(Spengler & de Weck, 6/25 C Switzerland Cases only 46 BL allergy 0 –

1977, Monogr (candidate
Allergy) gene)
(Qiao et al., 2004, 9/25 B Korea Case–control 448 BL allergy 101 Healthy
Allergy) (candidate controls
gene)
(Qiao et al., 2005, 10/25 B China Case–control 245 BL allergy 101 Healthy
Allergy) (candidate controls
gene)

(Yang et al., 2005, Eur 10/25 C China Case–control 158 BL allergy 89 Healthy
J Clin Pharmacol) (candidate controls
gene)
(Gueant-Rodriguez 16/25 B Italy Case–control 210 BL allergy 265 Healthy
et al., 2006, (candidate controls
Pharmacogenet gene)
Genomics)

[Yang et al., 2006, NA C China Case–control 113 BL allergy 87 (101) Healthy

Chin Med J (Engl)] (candidate (248) controls
gene)
(Guglielmi et al., 12/25 C France Case–control 44 BL allergy 44 Healthy
2006, (candidate controls
Allergy) gene)

(Qiao et al., 2007, Eur 12/25 C China Case–control 102 BL llergy 86 Healthy
J Clin Pharmacol) (candidate controls
gene)
(Apter et al., 2008, J 16/25 C USA Case–control 23 BL allergy 39 Healthy
Allergy Clin (candidate controls
Immunol) gene)

(Gueant-Rodriguez 12/25 B Italy Case–control 167 BL allergy 260 Healthy

et al., 2008, (candidate controls
Pharmacogenomics gene)
J)
(Gao et al., 2008, Eur 11/25 C China Case–control 144 BL allergy 88 Healthy
J Clin Pharmacol) (candidate controls
gene)
(Huang et al., 2009, 12/25 B China Case–control 242 BL allergy 240 Healthy
Eur J Clin (candidate controls
Pharmacol) gene)

446 Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Oussalah et al. Genetics of IgE-mediated AR and NAR to drugs

Replication Potentially causal Positive drug-specific

cohort variants Effect size Functional validation IgE References

No None NR Lymphocyte culture NR (12)

with penicillin

No FceR1b E237G NR Specific IgE 261/448 (58.3%) (13)

(FceR1b = MS4A2)* antibodies

No IL-4Ralpha*Q576 NR Specific IgE to 141/245 (57.6%) (14)

penicillins (eight
(IL-4Ralpha = IL4R)* types); Serum
levels of IL 4, IL-13
and IFN-gamma
No IL4 NR Serum levels of IL-4 NR (15)
IL13 and IL-13

No IL13 R130Q 130 (RQ+QQ); OR = 1.44 Serum IgE levels NR (16)

IL4RA I50V (0.95–2.18); P = 0.0881
(IL4Ralpha = IL4R)* 50II; OR = 1.65 (1.06–
IL4RA S478P 2.57); P = 0.0272
IL4RA Q551R 478 SS; OR = 1.82 (1.07–
3.12); P = 0.0271
551QQ; OR = 1.67 (1.02–
2.74); P = 0.0426
No HLA-DR9 HLA-DR14.1 NA Specific IgE NA (17)
HLA-DR17 HLA-DR4 antibodies

No IL4RA Ile75Val OR = 5.4 (1.16–27.7); None NR (18)

(IL-4Ralpha = IL4R)* P = 0.012
IL10 -819C>T OR = 17.5 (1.26–533.07);
IL10 -592 C>A P = 0.023
No IL10 -1082 G/A NR Specific IgE and IgG NR (19)
IL10 –819 C/T (eight types); Serum
IL-10 level
No IL4 rs2070874; OR = 3.33 (1.09 Penicillin metabolism NR (20)
IL4R –10.21); P = 0.035 (LACTB)
LACTB 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
No TNFA -308G>A Minor allele; OR = 4.29 Specific IgE 110/169 (65.1%) (21)
(TNFA = TNF) (1.11–16.5); P = 0.0343 antibodies

No IFNR1 NR Specific IgE and IgG 88/144 (61.1%) (22)

(IFNR1 = IFNGR1)* (eight types)

No IL-4RA Q576R Minor allele; OR = 1.67 Specific IgE (eight 146/242 (60.3%) (23)
(IL4RA = IL4R)* (1.17–2.38); P = 0.003 types)
IL-4RA I75V Minor allele; OR = 1.21
(0.93–1.57); P = 0.19

Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 447
Genetics of IgE-mediated AR and NAR to drugs Oussalah et al.

Table 1 (continued)

Study design
First author, year, STREGA Geographical and Cases, Cases, Controls, Controls,
journal score Rate region approach (n) phenotype (n) phenotype

(Huang et al., 2012, NA B China Case–control 242 BL allergy 220 Healthy

Int J Clin Pharmacol (candidate controls
Ther) gene)
(Nam et al., 2012, J 14/25 C Korea Case–control 153 HCWs who 86 HCWs
Korean Med Sci) (candidate had unexposed
gene) been exposed healthy
to antibiotics controls
(Cornejo-Garcia 15/25 A Spain Case–control 340 Atopy with BL 340 Healthy
et al., 2012, Allergy) Replication of allergy controls
Gueant-
Rodriguez
et al.,
2006
(candidate
gene)
(Bursztejn et al., 13/25 A Italy Spain Case–control Italy: 210 BL allergy Italy: 368 Healthy
2013, Allergy) (candidate Spain: 387 Spain: 326 controls
gene)

(Gueant et al., 2014, 22/25 A Spain Italy Case–control Initial: 387 BL allergy Initial: 1124 Healthy
J Allergy Clin GWAS Replication: Replication: controls
Immunol) (Immunochip) 299 362

(Cornejo-Garc
ıa 15/25 A Spain Italy Case–control Initial: 395 BL Initial: 310 Healthy
et al., 2015, (candidate Replication: allergy Replication: controls
Pharmacogenomics gene) 198 339
J)

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.
*Updated genes nomenclature according to the Human Gene Nomenclature Committee, Human Genome Organization (HUGO).
†
Significant after Bonferroni’s multiple testing correction.

NARs to NSAIDs have been classified in three categories
(European Academy of Allergy and Clinical Immunology
classification): (i) NSAIDs-exacerbated respiratory disease
(NERD), defined as hypersensitivity reactions manifesting
primarily as bronchial obstruction, dyspnea, and nasal con-
gestion/rhinorrhea, occurring in patients with an underlying
chronic airway respiratory disease (asthma/rhinosinusitis/
nasal polyps). Previously used synonyms for this condition
are as follows: aspirin triad, asthma triad, Samter’s syn-
drome, Widal syndrome, aspirin-induced asthma or aspirin-
sensitive rhinosinusitis/asthma syndrome, aspirin-intolerant
asthma, and aspirin-exacerbated respiratory disease; (ii)
NSAIDs-exacerbated cutaneous disease (NECD), defined as
hypersensitivity reactions manifesting as wheals and/or
angioedema occurring in patients with a history of chronic
spontaneous urticaria. Previously used synonyms for this
condition are as follows: aspirin-induced urticaria and
aspirin-exacerbated cutaneous disease; and (iii) NSAIDs-
induced urticaria/angioedema (NIUA), defined as hypersensi-
tivity reactions manifesting as wheals and/or angioedema
occurring in otherwise healthy subjects (without history of
chronic spontaneous urticaria). Symptoms are induced by at
least two NSAIDs with different chemical structure (not
belonging to the same chemical group) (54). On the other

448 Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Oussalah et al. Genetics of IgE-mediated AR and NAR to drugs

Replication Potentially causal Positive drug-specific

cohort variants Effect size Functional validation IgE References

No STAT6 in2SNP3 NA Specific IgE (eight NA (25)

types)

No FceR1b -109T > C TT genotype; OR = 3.55 Specific IgE and IgG; 31/153 (20.3%) (26)
(FceR1 = MS4A2)* (1.32–9.53); P = 0.036 In vitro functional
assay

Yes IL4RA I50V NR Specific IgE against NR (27)

IL4RA Q551R prevalent allergens;
(IL4Ralpha = IL4R)* Prevalence of atopy

Yes NOD2 rs2066845 NOD2 CT/TT, rs2066845; Specific IgE NR (28)

rs5743293 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)
Yes Initial study rs4958427; OR = 1.85; Skin test NR (29)
ZNF300 rs4958427 C5 P = 1.8910-8†
rs17612 HLA-DRA | rs17612; OR = 0.27;
HLA-DRB5 rs7754768 P = 4.4910-7
HLA-DRA|HLA-DRB5 rs7754768; OR = 0.63;
rs9268832 HLA-DRA P = 1.4910-6†
rs7192 rs9268832; OR = 0.64;
Replication study P = 4.1910-6†
HLA-DRA rs7192 rs7192; OR = 0.65;
HLA-DRA rs8084 P = 8.1910-6†
Yes LGALS3 rs11125 rs11125; OR = 3.98 (2.70– Serum level of total NR (30)
6.00); P < 0.0001† (Initial: IgE
Spain)
rs11125; OR = 5.1 (3.58–
7.31); P < 0.0001†
(Replication: Italy)

hand, immunologically mediated (non-cross-reactive) hyper- Genetic predictors of NAR to aspirin

sensitivity reactions to NSAIDs encompass two categories
(EAACI classification): (i) single-NSAID-induced urticaria/
angioedema or anaphylaxis (SNIUAA), which corresponds
to an immediate hypersensitivity reactions to a single
NSAID or to several NSAIDs belonging to the same chemi-
cal group, manifesting as urticaria, angioedema and/or ana-
phylaxis; and (ii) single-NSAID-induced delayed
hypersensitivity reactions (SNIRD), which is defined by
hypersensitivity reactions to a single NSAID appearing usu-
ally within 24–48 h after drug administration and manifest-
ing by either skin symptoms (54).
Studies that have assessed the genetic variants potentially
associated with immediate-type hypersensitivity to aspirin
were predominantly conducted in Korea. They highlighted
the involvement of genes that can be grouped into four
pathogenic groups: (i) the membrane-spanning 4A gene
family (FCER1A (formerly, FceR1a), MS4A2 (formerly,
FceR1b), and FCER1G (formerly, FceR1c); (ii) the his-
tamine production pathway (HNMT) (34, 35, 38); (iii) the
inflammatory cytokines (TGFB1, TNF, and IL18) (36, 37,
40); and (iv) the arachidonic acid pathway (ALOX5, LTC4S,
TBXA2R, and PTGER4) (33, 39, 41, 42) (Table 2 and

Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 449
Genetics of IgE-mediated AR and NAR to drugs Oussalah et al.

Table 2 Studies that reported genetic predictors in association with immediate-type hypersensitivity to aspirin (12 studies)

Cases 1
phenotype
according to
First author, year, STREGA Geographical Study design Cases 1, EACCI Cases 2,
journal score Rate region and approach Cases 1, (n) phenotype classification* (n)

(Kim et al., 2005, 16/25 C Korea Case–control 101 Aspirin-intolerant NIUA 95

J Korean Med (candidate urticaria
Sci) gene)
(Choi et al., 2005, 16/25 C Korea Case–control 110 Aspirin-induced NIUA 53
J Korean Med (candidate urticaria/
Sci) gene) angioedema

(Mastalerz et al., 13/25 C Poland Family study – Aspirin-induced NIUA –

2006, Br J (candidate urticaria
Dermatol) gene)
(Bae et al., 2007, 14/25 B Korea Case–control 105 Aspirin-intolerant NECD 154
J Allergy Clin (candidate chronic urticaria
Immunol) gene)

(Palikhe et al., NA B Korea Case–control 119 Aspirin-intolerant NECD 154

2008, Allergy (candidate chronic urticaria
Asthma Proc) gene)

(Park et al., 2008, 14/25 B Korea Case–control 112 Aspirin-intolerant NECD 153
J Clin Pharm (candidate chronic urticaria
Ther) gene)
(Choi et al., 2009, 16/25 B Korea Case–control 239 AIU (120 patients NECD/NIUA –
J Clin Pharm (candidate with aspirin-
Ther) gene) intolerant chronic
urticaria and 119
with aspirin-
intolerant acute
urticaria)
(Kim et al., 2009, 16/25 B Korea Case–control 111 Aspirin-intolerant NECD 154
Allergy) (candidate chronic urticaria
gene)
(Sanchez-Borges 13/25 B Venezuela Case–control 110 Aspirin-induced NIUA –
et al., 2009, J (candidate urticaria
Investig Allergol gene)
Clin Immunol)

450 Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Oussalah et al. Genetics of IgE-mediated AR and NAR to drugs

Cases 2, Controls, Controls, Replication Potentially causal Functional

phenotype (n) phenotype cohort variants Effect size validation References

Asirin-intolerant 123 Healthy No ALOX5 1708 G>A NR None (31)

asthma (NERD) controls

53 patients 99 Healthy No None – None (32)

without aspirin controls
hypersensitivity
who had
various drug
allergies
presenting as
exanthematous
skin symptoms
– – – No LTC4S NR None (33)
GSTM1

Aspirin-tolerant 222 Healthy No FceR1a 344C>T NR Luciferase (34)

chronic controls (FceR1a = FCER1A)† reporter assay;
urticaria electrophoretic
mobility shift
assay; Total IgE
concentrations;
Rate of atopy;
anti-IgE-
mediated
histamine
release
Aspirin-tolerant 224 Healthy No FceR1b E237G NR Release of (35)
chronic urticaria controls FceR1c 237A>G histamine
(FceR1b = MS4A2)†
(FceR1c = FCER1G)†
Aspirin-tolerant 457 Healthy No TGFb1 509C>T NR Serum TGFbeta1 (36)
chronic controls (TGFb1 = TGFB1)† levels
urticaria
– 524 Healthy No TNF 1031T>C NR None (37)
controls TNF 863C>A

Aspirin-tolerant 152 Healthy No HNMT 939A>G NR Histamine (38)

chronic controls release from the
urticaria basophils
– 165 Healthy No LTC4S 444C AC+CC vs Total and mite- (39)
controls AA; specific IgE
OR = 1.95
(1.26–3.03);
P = 0.002

Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 451
Genetics of IgE-mediated AR and NAR to drugs Oussalah et al.

Table 2 (continued)

Cases 1
phenotype
Cases 1, according to
First author, year, STREGA Geographical Study design EACCI Cases 2,
journal score Rate region and approach Cases 1, (n) phenotype classification* (n)

(Kim et al., 2011, 14/25 C Korea Case–control 275 Aspirin-induced NIUA –

Br J Dermatol) (candidate urticaria
gene)

(Palikhe et al., 16/25 B Korea Case–control 167 Aspirin-intolerant NIUA 149

2011, Clin Exp (candidate acute urticaria
Allergy) gene)
(Palikhe et al., 13/25 B Korea Case–control 141 Aspirin-intolerant NECD 153
2012, J Hum (candidate chronic urticaria
Genet) gene)

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.
*Nomenclature according to the European Academy of Allergy and Clinical Immunology (EAACI) classification of hypersensitivity to
nonsteroidal anti-inflammatory drugs (54).
†
Updated genes nomenclature according to the Human Gene Nomenclature Committee, Human Genome Organization (HUGO).

Fig. 3). Two groups of genes showed functional and/or phys-
ical interactions; two genes involved in the arachidonic acid
pathway, ALOX5, LTC4S; and 3 genes involved in the
FceRI pathway FCER1A, MS4A2, and FCER1G (Fig. 3).
Genetic predictors of NAR to NSAIDs, including aspirin
Studies that have assessed the genetic variants potentially
associated with immediate-type hypersensitivity to NSAIDs
were predominantly conducted in Spain (41–48). They
reported an association with genes belonging to HLA genes
(HLA-DRB1, HLA-B44, and HLA-Cw5) (43, 44) or to the
arachidonic acid pathway (ALOX5, ALOX5AP, ALOX15,
TBXAS1, PTGDR, and CYSLTR1) (46, 49) (Table 3). A
case–control study evaluated the histamine-producing path-
way and showed a weak association with the diamine oxidase
gene (DAO) (43). Only one study used a GWAS approach
and suggested the potential implication of the CEP68 gene
(encoding centrosomal protein of 68 KDa) in the develop-
ment of hypersensitivity reactions to NSAIDs (48).
Genetic predictors of immediate-type hypersensitivity to
other drugs
A GWAS in children with acute lymphoblastic leukemia
(ALL) found an association of GRIA1, a gene encoding the
glutamate receptor AMPA1 with the risk of allergy to
asparaginase (49). The GRIA1 gene is on chromosome 5q33,
a region previously associated with asthma and atopy (55,
56). Two studies have evaluated the genetic determinants of
immediate-type hypersensitivity reactions to biological thera-
pies, namely EGFR inhibitors (52) and infliximab (53) and
pointed out HLA genes (HLA-A) and inflammatory cytoki-
nes pathway (FASLG, TNFRSF1B), respectively (Table 4).
Discussion
In the present systematic review regarding genetic variants
associated with drugs-induced immediate hypersensitivity
reactions, aspirin and other NSAIDs were the most fre-
quently studied drugs in NAR, while BLs were most fre-
quently involved in AR.
Genetic predictors of IgE-mediated AR: the example of beta-
lactams
Genetic predictors at the cross-point between inflammation and
allergy
Tumor necrosis factor-alpha (TNF-a) is a master pro-inflam-
matory cytokine, which plays also a role in allergy through
its release from mast cells via an IgE-dependent mechanism.
The variant G>A at 308 of TNF is part of an extended
haplotype HLA-A1-B8-DR3-DQ2 and influences the gene
expression. In central Italy, TNF 308GG genotype was a
significant independent predictor of the primary risk for BL

452 Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Oussalah et al. Genetics of IgE-mediated AR and NAR to drugs

Cases 2, Controls, Controls, Replication Potentially causal Functional

phenotype (n) phenotype cohort variants Effect size validation References

– 196 Healthy No IL18 607A/C C-607/G 137 Luciferase (40)

controls haplotype; reporter assay;
OR = 1.46 Electrophoretic
(1.06–2.00); mobility shift
P = 0.02 assays;
Neutrophil
chemotaxis
assays
Aspirin-intolerant 265 Healthy No TBXA2R 4684T NR Electrophoretic (41)
chronic urticaria controls mobility shift
(NECD) assay
Aspirin-tolerant 174 Healthy No PTGER4 1254 G>A NR Dual-luciferase (42)
chronic urticaria controls system;
electrophoretic
mobility shift
assay; PTGER4
mRNA
expression

allergy, concurrently with total IgE level, in a large case–con-
trol study (21). In addition, cases with TNF 308AA geno-
type had a higher serum level of specific IgE to penicillin
antigens than those with 308GA/GG genotype, suggesting
an ambivalent influence of a genetic determinant of pro-
inflammatory pathways on IgE-mediated hypersensitivity to
beta-lactams (21). Polymorphisms of nucleotide-binding
oligomerization domain genes NOD2 and NOD1, associated
with chronic inflammation and with atopy, are implicated in
immunological and inflammatory diseases such as graft-ver-
sus-host and Crohn’s diseases. They are implicated in the
recognition of intracellular bacterial small molecules and
modulate inflammatory pathways and T-regulator/T-helper 2
cells’ balance (57). NOD2 and NOD1 polymorphisms are
associated with atopy and high total IgE in serum (58, 59).
To evaluate the association of NOD2 and NOD1 polymor-
phisms with BL allergy, three polymorphisms of NOD2 and
one polymorphism of NOD1 were studied in 368 Italian and
387 Spanish patients, compared with 368 and 326 controls,
respectively (28). CT/TT genotypes of rs2066845 of NOD2
predicted a lower risk of immediate-type BL allergy among
Italian, while WT/insC genotype of rs5743293 (also in leu-
cine-rich repeat domain of NOD2) predicted a higher risk
among Spanish. The G allele of rs2066845 was associated
with a higher level of IgE in the Italian population. The mir-
rored influence of these NOD2 polymorphisms on BL allergy
in the two populations suggests a link with inflammation
and/or atopy through mechanisms that remain to be clarified
(28).
Genetic predictors of IgE production
The several studies reported in Europe, China, and US con-
verged in showing that AR to BLs are influenced by genes
that are involved in IgE production, including those of the
IL13 and IL4 pathways (14, 16, 18, 20, 60). The association
between immediate allergic reactions to BLs and polymor-
phisms of IL13 (R130Q and 1055C>T variants), IL4R
(I50V, S478P, and Q551R variants) has been evaluated in
patients and their matched control subjects from central Italy
and the south of Spain (16). The combination of the minor
allele of the IL13 R130Q polymorphism with any of the pre-
dominant homozygous genotypes of the three polymorphisms
of IL4R was more significantly associated with the risk of
BL allergy than any other polymorphism considered alone
(16). The same associations were observed with serum IgE
levels. On the contrary, in Spain, IL13 and IL4R had no epi-
static influence and only IL4R I50V and Q551R were predic-
tors of BL AR (27). These gene variants were also associated
with IgE against prevalent allergens and total IgE, respec-
tively. The contrasted influence of IL4R on the risk of BL
allergy could be related to differences in allele frequencies
and gene-environment interactions (27, 61). IL4RA predicted
not only BL AR but also the concentration of total IgE and
the positivity of specific IgE against prevalent allergens, in

Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 453
 Table 3 Studies that reported genetic predictors in association with immediate-type hypersensitivity to NSAIDs (eight studies)

454
Cases 1 Intermediate
phenotype phenotype
Study according to Cases Potentially and
First author, year, STREGA Geographical design and Cases 1 Cases 1 EACCI 2 Cases 2 Controls Replication causal functional
journal score Rate region approach (n) phenotype classification* (n) phenotype Controls (n) phenotype cohort variants Effect size validation References

(Quiralte et al., 14/25 C Spain Case– 21 Urticaria and/or NIUA 47 Patients who 167 Tolerant No HLA-DRB1*11 OR = 7.3 None (43)
1999, J Allergy control angioedema had control (2.8–19.0);
Clin Immunol) (candidate plus exclusively subjects (29 P = 0.02
gene) hypotension cutaneous of whom
and/or reactions had also
laryngeal during had an IgE-
edema after single-blind, mediated
NSAID placebo- anaphylaxis
administration controlled to different
oral agents)
challenges
with NSAIDs
(SNIRD)
(Pacor et al., 12/25 C Italy Case– 69 Chronic NECD – – 200 Healthy No None – None (44)
2006, Mediators control idiopathic controls
Inflamm) (candidate urticaria
gene) associated
Genetics of IgE-mediated AR and NAR to drugs

with aspirin
and/or NSAIDs
hypersensitivity
(Agundez et al., 18/25 B Spain Case– 442 Urticaria + NIUA – – 441 Healthy No DAO Minor allele None (45)
2012, PLoS control angioedema controls rs10156191 OR = 1.59
One) (candidate Anaphylaxis (1.27–2.00);
5
gene) Respiratory P = 6.0 9 10
symptoms
Mixed
symptoms
(Cornejo-Garcia 17/25 A Spain Case– Initial: 486 NSAIDs-induced NIUA – – Initial: 536 Healthy Yes ALOX15 Minor allele, None (46)
et al., 2012, Clin control Replication: acute urticaria Replication: controls (rs7220870) OR = 0.77
Exp Allergy) (candidate 195 212 PTGDR (0.61–0.99);
gene) (rs8004654) P = 0.041
CYSLTR1 (Malaga);
(rs320995) 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)
(Ayuso et al., 17/25 B Spain Case– 442 Hypersensitivity NIUA – – 414 Healthy No None – None (47)
2013, control to NSAIDs controls
Pharmacogenomics) (candidate
gene)
Oussalah et al.

Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
 Table 3 (continued)
Cases 1 Intermediate
phenotype phenotype
Study according to Cases Potentially and
First author, year, STREGA Geographical design and Cases 1 Cases 1 EACCI 2 Cases 2 Controls Replication causal functional
journal score Rate region approach (n) phenotype classification* (n) phenotype Controls (n) phenotype cohort variants Effect size validation References
Oussalah et al.

(Cornejo-Garcia 18/25 B Spain Case– 232 cases NSAIDs-induced NIUA – – 225 (124 Healthy Yes None – None (48)
et al., 2013, China control (112 acute urticaria/ Spanish and controls
Pharmacogenomics) (GWAS) Spanish and angioedema 101 Han
120 Han Chinese).
Chinese)
(Vidal et al., 2013, J 15/25 B Spain Case– 563 Isolated acute NECD – – 551 Healthy No ALOX5 Minor allele None (49)
Allergy Clin control cutaneous controls (rs4948672) OR = 1.82
Immunol) (candidate NSAID ALOX5 (1.25–2.65);
gene) hypersensitivity (rs1565096) P = 6.64 9 10 3
ALOX5 (recessive)
(rs4948672) OR = 1.83
ALOX5 (1.28–2.62);
(rs7894352) P = 8.60 9 10 4
PPARG (dominant)
(rs2938392) OR = 2.22
ALOX5AP (1.41–3.49);
P = 6.10 9 10 4
(rs11147439) (recessive)
TBXAS1 OR = 1.78
R (1.24–2.57);
(s10487667) P = 1.70 9 10 3
TBXAS1 (dominant)
rs6962291) OR = 0.58
(0.39–0.85);
P = 4.52 9 10 3
(recessive)
OR = 0.73
(0.59–0.91);
P = 4.66 9 10 3
(additive)
OR = 0.58
(0.44–0.79);

Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
P = 3.4 9 10 4
(dominant)
OR = 0.62
(0.49–0.77);
P = 1.6 9 10 5
(additive)
(Cornejo-Garcia et al., 18/25 B Spain Case– 399 NSAIDs-induced NIUA 110/ Airway 425 Healthy No CEP68 Not significant None (50)
2014, PLoS One) control acute urticaria/ 126 exacerbation/ controls (53 common after multiple
(candidate angioedema blended variants) testing
gene) pattern correction

STREGA, STrengthening the REporting of Genetic Association Studies); NSAIDs, nonsteroidal anti-inflammatory drugs; OR, odds ratio; NIUA, NSAIDs-induced urticaria/angioedema; NECD, NSAIDs-exacerbated cutaneous disease; SNIR, Single-NSAID-induced delayed hypersensitiv-
ity reactions.
*Nomenclature according to the European Academy of Allergy and Clinical Immunology (EAACI) classification of hypersensitivity to nonsteroidal anti-inflammatory drugs (54).
Genetics of IgE-mediated AR and NAR to drugs

455
Genetics of IgE-mediated AR and NAR to drugs Oussalah et al.

Table 4 Studies that reported genetic predictors in association with immediate-type hypersensitivity to other drugs (three studies)

First author, year, STREGA Geographical Study Cases 1

journal score Rate Disease region design (n)

(Chen et al., 2010, Clin 14/25 C Asparaginase USA GWAS 500K 322 (discovery
Pharmacol Ther) hypersensitivity (Time to allergy cohort)
survival analysis) 163 (validation
cohort)

(Fuerst et al., 2012, 17/25 C Skin rash arising Germany Cases only 105
Pharmacogenomics) from treatment (Development of
with skin rash was
EGFRIs rated during the
first 4 weeks of
therapy with
EGFRIs)
(Steenholdt et al., 2012, 16/25 C Acute severe Denmark Observational, 125
Aliment Pharmacol infusion reactions retrospective and
Ther) to explorative cohort
infliximab study

STREGA, STrengthening the REporting of Genetic Association Studies); EGFRIs, EGF receptor inhibitors; OR, odds ratio; HR, hazard ratio

the Spanish population. This suggested that IL4RA was asso-
ciated with BL allergy through its influence on atopy in
South Spain, where the exposure to house dust mite was high
(27). The IL4R R551 allele was associated with penicillin
allergy in China (23). Another study performed in the South
of France found a significant association of BL AR with
IL4R I50V and IL10 promoter ( 819C>T and 592C>A), in
female patients with atopy (18). In consistence with these
results, the 1082G allele in IL10 promoter was associated
with specific IgE positive antibodies in patients with BL
allergy, in China (19).
IL4 and IL13 bindings to receptor subunits activate the
signal transducer and activator of transcription (STAT) 6 sig-
naling pathway, which plays an important role in the induc-
tion of IgE synthesis. Consistently, an association between
STAT6 variants and penicillin allergy has been found in
China (25), however, not in Spain (27).
IL18 activates T cells and increases interferon (IFN)-c,
but it can also stimulate the production of Th2 cytoki-
nes, suggesting a potential influence in allergy. IL18
607A/C and 137G/C promoter polymorphisms were
associated with susceptibility to penicillin AR, in China
(24).
The high-affinity receptor for IgE (FceR1-b, renamed
MS4A2 according to the updated Human Gene Nomencla-
ture Committee nomenclature) plays a central role in the
induction and maintenance of IgE sensitization and is associ-
ated with elevated total and specific IgE levels. The FceR1b
109T>C polymorphism influences the promoter activity and
may be a potential genetic risk factor for increased IgE sensi-
tization to cephalosporins in occupational allergy of health
care workers (26). Another study reported an association of
the FceR1b E237G polymorphism with penicillin AR in the
Chinese population (13).
The MHC-encoded susceptibility genes
A fine-mapping genomewide association study of the genetic
predictors of BL allergy was recently performed in patients
with immediate allergic reactions to BLs from Spain and was
replicated in patients from Italy (29). This study found signif-
icant associations of HLA-DRA rs7192 and rs8084 with
allergy to penicillins and amoxicillin but not to cephalospor-
ins. A haplotype block in HLA-DRA and HLA-DRA |
HLA-DRB5 inter-region encompassed a motif involved in
balanced expression of a-chain and b-chains of MCH class
II, while rs7192 was predicted to influence a-chain conforma-
tion (29). These gene variants of HLA-DRA and HLA-DRA |
HLA-DRB5 intergenic region have been also associated with
IgE-mediated sensitization to prevalent allergens (29), sug-
gesting complex gene-environment interactions of BL allergy,
in which genetic susceptibility of HLA type 2 antigen presen-
tation could play a central role. An increased frequency of
HLA-DR9 has also been reported in the Chinese population,
which has not been replicated (29).
Genetic predictors of NAR: the examples of nonspecific
reactions against Aspirin and NSAIDs
The MHC-encoded susceptibility genes
Between 1999 and 2014, eight studies, mainly from Spain, eval-
uated potential genetic predictors in association with NAR to
NSAIDs (43–50). The first report by Quiralte et al. evaluated

456 Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Oussalah et al. Genetics of IgE-mediated AR and NAR to drugs

Intermediate
phenotype
Potentially and
Cases 1 Controls Controls causal functional
phenotype (n) phenotype variants Effect size validation References

Asparaginase – – GRIA1 Minor allele None (51)

hypersensitivity (rs4958381) Discovery:
OR = 1.73 (1.35–2.21);
P = 1.8 9 10 5
Validation:
OR = 1.93 (1.25– 2.98);
P = 0.0029
Cancer patients – – HLA-A*02:01 HR = 0.28 (0.12–0.63); None (52)
HLA- P = 0.002
A*03:01 HR = 0.29 (0.11–0.75);
P = 0.011

Crohn’s disease – – FASLG OR = 4.0 (1.1–22.4); None (53)

patients (rs763110) P = 0.041
under infliximab TNFRSF1B OR 0.2 (No CI
(rs652625) reported); P = 0.043

in a case–control study design 114 HLA-DRB1 and 26 HLA-
DQB1 alleles in patients with cutaneous and anaphylactoid
reactions caused by NSAIDs (43). The frequency of HLA-
DR11 alleles was 58.8% in the anaphylactoid reaction group,
compared with 15.9% in the NSAID-tolerant healthy control
subjects (OR, 7.3; 95% CI, 2.8–19.0; P = 0.02) and 6.3% in the
group of the patients with a tolerance for NSAIDs and with
IgE-mediated anaphylaxis (OR, 18.75; 95% CI, 4.3–81.1;
P = 0.004). This study did not show at the functional level that
HLA-DRB1*11 alleles themselves were directly responsible for
disease risk, although the strength of association suggested that
HLA-DRB1*11 alleles could be an important determinant of
this specific reaction to NSAIDs in susceptible individuals,
unraveling MHC-encoded susceptibility in NSAID-induced
anaphylactoid reactions (43).
The prevalence of HLA class I phenotypes and HLA-
DRB1 genotype was assessed in 69 patients with aspirin and/
or NSAIDs hypersensitivity and 200 healthy subjects and did
not identify any significant difference between patients and
controls as regards to HLA-DRB1* genotypes (44). This
study was potentially underpowered for demonstrating a sta-
tistically significant difference for HLA-DRB1*11 alleles, but
it showed that carriers of HLA-B44 phenotype had a higher
risk of chronic idiopathic urticaria associated with aspirin
and/or NAR to NSAIDs (44).
The histamine-producing pathway genes
Histamine is released and is responsible for some of the clini-
cal symptoms, in NAR to aspirin and NSAID. A case–con-
trol study evaluated 7 SNPs using the TaqManÒ assays on
three histamine-producing pathway genes (HDC, HNMT,
and DAO) in 442 unrelated Caucasian patients with hyper-
sensitivity to NSAIDs and 414 healthy unrelated controls
ethnically matched with patients and from the same geo-
graphic area in Malaga and Madrid (Spain) (45). The non-
synonymous variant on the diamine oxidase gene (DAO
rs10156191, p.Thr16Met) was moderately but significantly
associated with cross-intolerance to NSAIDs (OR, 1.59; 95%
CI, 1.27–2.00; P = 6 9 10 5 for the minor allele) (45). In
contrast, HNMT was the only significant predictor of this
pathway in NAR to aspirin (32, 33, 36). Results from these
studies suggest that mutations in genes encoding histamine-
metabolizing enzymes may increase the risk, or modify the
clinical presentation, of NAR, in which histamine plays an
important role. The potential influence of variants of genes
encoding histamine receptors (HRH gene family) on the
expression of allergic diseases has been evaluated in a case–
control study (47). The authors analyzed copy number varia-
tions (CNVs) and common functional SNPs in genes HRH1,
HRH2, and HRH4 in 442 unrelated patients with hypersensi-
tivity to NSAIDs and in 414 healthy unrelated controls and
found no influence of HRH genes variants on the primary
risk for developing NSAIDs hypersensitivity (47).
The arachidonic acid pathway genes
A large case–control study from the Spanish network RIR-
AAF assessed 15 relevant genes encoding both enzymes and
receptors from the arachidonic acid pathway in 486 patients
with NIUA and 536 unrelated controls (46). Among the 31
tested variants, seven were associated with NIUA risk in the
initial study (46). In the replication study, only three SNPs
from the six initially significant variants were replicated

Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 457
Genetics of IgE-mediated AR and NAR to drugs
Figure 2 Functional (in blue) and physical (in brown) interaction
networks of genes involved in IgE-mediated beta-lactam allergy
using the GeneMANIA prediction server (http://www.genema
nia.org/). Both physical and functional interaction networks show a
ALOX15 (rs7220870, c.-272G>T), PTGDR (rs8004654, c.-
549T>C), and CYSLTR1 (rs320995, c.927C>T, Phe309Phe),
suggesting the potential implication of genetic variants of the
arachidonic acid pathway in NIUA (46).
In a case–control study, 563 adult patients with NIUA and
551 healthy control subjects without a history of NSAID
hypersensitivity were enrolled (49). This study investigated
potential SNPs associated with isolated NECD from a prede-
fined list of 217 SNPs in 48 genes involved in cyclooxygenase
or lipoxygenase pathways or in inflammation (49). The most
significant association with NECD was found for the intronic
variant rs6962291 on the TBXAS1 (thromboxane A synthase
1) gene (OR, 0.62; 95% CI, 0.49–0.77; P = 1.6 9 10 5),
which remained significant after multiple testing correction
(49). One intronic SNP on the ALOX5 (arachidonate 5-lipox-
ygenase) gene (rs4948672) was associated with an increased
risk for isolated NECD (OR, 1.82; 95% CI, 1.25–2.65;
P = 6.64 9 10 3) but did not reach multiple testing signifi-
cance (49). TBXAS1 catalyzes the conversion of prostaglan-
458 Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Oussalah et al.
clustering of genes belonging to HLA type 2 antigen presentation
genes, cytokines (e.g., IL4, IL4R, IL13, IL18, IL10), and the produc-
tion and release of preformed mediators (LGALS3).
din H2 to thromboxane A2 which induces platelet
aggregation and smooth muscle contraction (49). The
ALOX5 gene encodes a member of the lipoxygenase gene
family and plays a dual role in the synthesis of leukotrienes
from arachidonic acid. By comparison, the case–control stud-
ies performed on NAR to aspirin showed an association with
three other genes of the arachidonic acid pathway, LTC4S,
TBXA2R, and PTGER4, and only one, ALOX5, which was
also associated with NAR to NSAIDs (33, 39, 41, 42). This
is consistent with the fact that aspirin and NSAIDs inhibit
distinct enzymes of this pathway.
Other potential pathways
A genomewide association study compared 232 NIUA cases
(112 Spanish and 120 Han Chinese) with 225 unrelated con-
trols (124 Spanish and 101 Han Chinese) using the Affyme-
trixÒ Genome-Wide Human SNP Array 6.0 (Affymetrix, CA,
USA) (48). Although no variant reached genomewide signifi-
cance, possibly due to the limited study power, suggestive
Oussalah et al. Genetics of IgE-mediated AR and NAR to drugs

Figure 3 Functional interaction network of genes involved in nonspeci- spond to cytokines (TGFB1, TNF, IL18), production and release of neo-
fic reactions to aspirin using the GeneMANIA prediction server (http:// formed mediators (LTC4S, TBXA2R, PTGER4), and production and
www.genemania.org/). Three gene clusters are individualized and corre- release of preformed mediators (FCER1A, MS4A2, FCER1G, HNMT).

Pathways
Production and Production and
HLA antigen
Cytokines release of neoformed release of preformed
processing
mediators mediators

IL4R, IL4, IL13, IL10,

Betalactam No gene studied or LGALS3
TNF, IFNGR1, IL18, HLA-DRA
antibiotics discovered
NOD2

No gene studied or LTC4S, TBXA2R, FCER1A, MS4A2,

Aspirin TGFB1, TNF, IL18
discovered PTGER4 FCER1G, HNMT

HLA-DRB1 ALOX5, ALOX5AP,

Nonsteroidal an- No gene studied or No gene studied or
HLA-B44 TBXAS1, PTGDR,
in ammatory drugs discovered discovered
HLA-Cw5 CYSLTR1

Figure 4 Overview of pathogenetic pathways potentially involved retrieved from the systematic review: (i) cytokines signaling, (ii)
in IgE-mediated beta-lactam allergy and nonspecific reactions to HLA antigen processing, (iii) production and release of newly
aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) formed mediators, (iv) and production and release of preformed
(four pathogenic pathways were individualized based on genes mediators).

Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 459
Genetics of IgE-mediated AR and NAR to drugs Oussalah et al.

associations were proposed for three clusters in the Spanish
group (RIMS1, BICC1 and RAD51L 1) and one region in
the Han Chinese population (ABI3BP). A recent genomewide
association study highlighted the influence of the CEP68
(centrosomal protein of 68 KDa) gene on susceptibility to
aspirin intolerance in asthmatics from Taiwan (62). A Span-
ish case–control study assessed the role of this locus in NAR
to NSAIDs by examining 53 common gene variants in a total
of 635 patients with NIUA (n = 399), NERD (n = 110) or
blended pattern (n = 126), compared to 425 controls. Seven-
teen variants on the CEP68 gene, including the nonsynony-
mous Gly74Ser variant (rs7572857) previously identified in
asthmatic cases from Taiwan, were found to be associated
with a reduced susceptibility for NIUA (lowest P-
value = 1.13 9 10 6; OR, 0.33; 95% CI, 0.21–0.52) (50).
Although the functions of the CEP68 protein are not fully
understood, these results suggest that it may play an impor-
tant role in NAR produced by NSAIDs.
arachidonic acid pathways. Other gene predictors suggest the
possible involvement of mechanisms that regulate mediator
release and inflammation. However, this present review also
shows that data on this issue are still too sparse to draw
more specific conclusions. The limited knowledge produced
by the literature on the complex interactions between genetic
variability and environmental exposure illustrates the need
for performing GWAS and replications in contrasted popula-
tions, taking into account worldwide variations of allele fre-
quencies, gene–gene interactions and contrasted situations of
environmental exposure.
Acknowledgments
We thank Jose Antonio Cornejo-Garcia (Research Labora-
tory, IBIMA, Regional University Hospital of Malaga) and
Maria Jose Torres (Allergy Unit, IBIMA, Regional Univer-
sity Hospital of Malaga) for manuscript revision.

Overview and limitations of reported data

Authors’ contributions
The overall analysis of data reported in this systematic review
AO and J-LG performed the literature search and data
highlights some limitations in the studies dedicated to genetic
extraction and wrote the manuscript; CM, MB, J-AC-G,
predictors of IgE-mediated AR and NAR. A first ascertain-
MJT, AB, AN, JC, MG, KB, J-CC, AB, MA, PD, LK, IT,
ment is that most of the studies on genetic prediction of drug
and JLL revised the manuscript; Authors of the ENDA
hypersensitivity have been performed using a gene-candidate
group involved in review and approval of the final draft.
design. Only one GWAS with replication was performed in
IgE-mediated AR. This study showed that genetic susceptibil-
ity of HLA type 2 antigen presentation could play a central Conflicts of interest
role in gene–environment interactions producing IR against
The authors declare that they have no conflicts of interest.
penicillins. A second remark is that only four case–control
studies were replicated, and three of them were related to
AR against BLs. These three replicated studies evidenced the Supporting Information
influence of three genes related to IgE production, atopy,
Additional Supporting Information may be found in the
and inflammation, namely IL4R, NOD2, and LGALS3
online version of this article:
through potential interacting pathomechanisms that should
Table S1. Study power calculation according to disease-
deserve further interest (Figs 2 and 4). Most of the case–con-
related allele frequency assuming both allelic and additive
trol studies performed on NAR against aspirin and NSAIDs
genetic models.
were not replicated, even if they were highly consistent in
Table S2. Detail of the eleven studies excluded from the
identifying genes involved in the arachidonic acid pathways
systematic review.
as predictors (Figs 3 and 4). Among these genes, ALOX5 has
Table S3. Assessment of quality of eligible studies accord-
been reported as a predictor in two studies on NAR against
ing to the STrengthening the REporting of Genetic Associa-
aspirin and NSAIDs, respectively. In addition, these studies
tion Studies (STREGA) recommendations: betalactam
were performed in two contrasting world regions (29, 47).
antibiotics.
The intriguing association of NAR to NSAIDs with atopy
Table S4. Assessment of quality of eligible studies accord-
(47) suggests also a possible influence of genes related to
ing to the STrengthening the REporting of Genetic Associa-
atopy, which should deserve further attention.
tion Studies (STREGA) recommendations: aspirin.
In conclusion, this systematic review shows clear differ-
Table S5. Assessment of quality of eligible studies accord-
ences in the functional influence of the genes, which predict
ing to the STrengthening the REporting of Genetic Associa-
IgE-mediated AR against BLs and NAR against aspirin and
tion Studies (STREGA) recommendations: Nonsteroidal
NSAIDs, respectively. Those predicting AR to BLs are sus-
anti-inflammatory drugs (other than aspirin).
tained by GWAS and replicated studies, which highlight the
Table S6. Assessment of quality of eligible studies accord-
involvement of interacting mechanisms, HLA type 2 antigen
ing to the STrengthening the REporting of Genetic Associa-
presentation, IgE-class switching, and atopy. The strongest
tion Studies (STREGA) recommendations: other drugs.
gene predictors of NAR against aspirin and NSAIDs are
Data S1. Supplementary methods.
related to the synthesis of newly formed mediators of the

460 Allergy 71 (2016) 443–462 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Oussalah et al.
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