aspirin - exacerbated respiratory disease ( aerd ) refers to the development of bronchoconstriction in asthmatics following the ingestion of aspirin or other nonsteroidal anti - inflammatory drugs .
it is defined by a clinical syndrome associated with moderate - to - severe asthma and eosinophil inflammation in the upper and lower airways , resulting in chronic rhinosinusitis and asthma .
additionally , the airways of aerd show epithelial disruption , cytokine production , and the upregulation of inflammatory molecules .
the prevalence of aspirin hypersensitivity in the general population ranges from 0.6 to 2.5% and is higher in asthmatics .
metabolites involved are prostaglandins ( pgs ) , leukotrienes ( lts ) , and thromboxane ( tbx ) .
inhibition of coxs by acetyl salicylic acid ( asa ) in the respiratory tract alters arachidonic acid metabolism , leading to a reduction in pge2 .
the lipoxygenase ( lox ) pathway produces the leukotrienes lta4 , ltb4 , and ltc4 as metabolites .
15-lipoxygenase ( 15-lo ) is one of the lox family members and catalyses the conversion of arachidonic acid to 15-hydroxyperoxyeicosatetranoic acid ( 15-hpete ) .
15-hydroxyeicosatetranoic ( 15-hete ) , a more stable derivative of 15-hpete , is another important product , which acts as an anti - inflammatory mediator and functional antagonist of lts .
further products of 15-hpete include eoxins ( exs ) exa4 and 15-hete can be conjugated with glutathione , leading to the formation of exc4 , exd4 , and exe4 .
aerd has also been correlated with increased cyslt receptors : cysltr1 and cysltr2 [ 79 ] .
the third cyslt receptor , the g protein - coupled receptor 17 ( gpr17 ) , is located at an intermediate phylogenetic position between two distinct receptor families : the purinergic receptor ( p2y ) and cyslt receptor for extracellular nucleotides and cyslts , respectively , .
overexpression of cysltr1 was detected in the nasal mucosa of patients with aerd , compared with aspirin - tolerant asthma ( ata ) .
considering the pathogenic mechanism of aerd , various genetic markers have been suggested in various ethnic groups and are summarized in this paper .
based on evidence showing a close association of leukotrienes and aerd , initial research was performed on the association between ltc4s 444a  >  c promoter polymorphism and aerd . in
the population investigated ( polish ) , the c allele was identified as a risk factor ; however , this finding was not replicated in japanese , american , or korean populations [ 1215 ] .
snps of 5-lipoxygenase ; alox5 at 1708 g  >  a , 21c  >  t , 270 g  >  a , and 1728 g  >  a and alox5 activating protein ( alox5ap , 218a  > 
g ) were studied in a korean population where it was discovered that the haplotype alox5 ht1 [ g - c - g - a ] was significantly higher in aerd than in ata , suggesting a possible contribution of alox5 in aerd .
we identified three snps ( 634c  >  t , 475a  >  c , and 336a  >  g ) in the promoter region of cysltr1 , and mutant variants of these snps were associated with the aerd phenotype .
the mutant variants showed higher promoter activity , suggesting that these polymorphisms may modulate cysltr1 expression increasing aerd susceptibility . in the case of cysltr2 ,
the frequencies of minor alleles for 819 t  >  g , 2078c  >  t , and 2534a  >  g were significantly higher in the aerd group   when compared with ata .
decreased production of prostaglandin e2 ( pge2 ) by nasal epithelial cells of aerd has been observed .
pge2 production in airway smooth muscle cells has been shown to downregulate cox2 mrna expression .
two snps of tbxa2r , 4684 t  >  c , and + 795 t  >  c , were shown to be associated with the phenotype of aerd in a korean population [ 22 , 23 ] .
the prostaglandin e2 receptor subtype 2 gene ( ptger2 ) was associated with the risk of aerd by decreasing the level of transcription , resulting in a reduction of the  pge2 braking  mechanism of inflammation and involvement in the molecular mechanism underlying aerd in the japanese population . a further report in
the korean population showed that prostaglandin e2 receptor subtype 3 ( ptger3 ) may be an important genetic factor for aspirin intolerance in korean asthmatics .
the human leukocyte antigen ( hla ) allele dpb1 * 0301 was identified as a strong marker for aerd , because patients with this allele showed typical characteristics of aerd including a decreased forced expiratory volume in 1  s ( fev1 ) and increased prevalence of rhinosinusitis with nasal polyps , as previously noted in a polish population .
increased numbers of eosinophils and mast cells have been observed in the bronchial mucosa of aerd [ 28 , 29 ] .
recent studies demonstrated that the chemoattractant receptor molecule expressed in th2 cells , the crth2 466 t  >  c polymorphism , could increase serum and cellular eotaxin-2 production by lowering crth2 expression , leading to eosinophilic infiltration in aerd patients .
a further study indicated that the chemokine cc motif receptor ( ccr3 ) may be related to eosinophil migration .
the ccr3 520 t  >  c was significantly associated with aerd patients where mrna expression was also significantly increased after asa provocation . il-13
polymorphisms at 1510a  >  c and 1055c  >  t are associated with the development of rhinosinusitis in aerd patients .
il-13 arg110gln may be associated with an increased eosinophil count and eotaxin-1 level , leading to an increase in eosinophilic inflammation in the upper and lower airways of patients with aerd   ( table 1 ) .
viral respiratory infections have been suggested to contribute to allergic sensitization , leading to the development of asthma and in subjects with established asthma ; they are known to exacerbate allergic disease .
aspirin hypersensitivity is diminished in some aerd patients during acyclovir treatment of herpes simplex infection . moreover ,
elevated levels of igg4 , derived from chronic antigenic stimulation of viral origin , have been noted in aerd patients . a further study investigating the exacerbation of aerd with airway infection of respiratory syncytial virus was reported .
recently , a study indicated that the polymorphisms in the toll - like receptor 3 ( tlr3 ) gene , tlr3 299698 g  >  t and 293391 g  > 
tlr3 recognizes dsrna , activates nuclear factors , and increases interferon - gamma , which is a signal to other cells and increases antiviral defenses . as functional deterioration of tlr3 can predispose individuals to increased susceptibility to viral infections , the detection of tlr3 polymorphisms may be informative for risk assessment in aerd susceptibility .
the suggested mechanism is that specific cytotoxic lymphocytes are produced in response to viral infection .
activity of these lymphocytes is suppressed by pge2 , which is produced by pulmonary alveolar macrophages .
if pge2 levels are decreased , cytotoxic reactions are preceded by cox inhibitors and cytotoxic lymphocyte - mediated attacks lead to the destruction of virus affected cells in the respiratory tract .
reactive oxygen species , toxic metabolites , and mediators released then precipitate asthma attacks . the ubiquitin - proteasome pathway - related gene ( ube3c )
has been recently studied in a korean population and indicated that rs3802122 and rs6979947 is associated with aerd .
a further study indicated that the kinesin family number 3a ( kif3a ) gene and its polymorphism might have an effect on aerd , because rs3756775 revealed a significant association with the percentage decline in fev1 after aspirin provocation .
recently , the genome - wide methylation profile of nasal polyps showed that genes involved in lymphocyte proliferation , cell proliferation , leukocyte activation , cytokine biosynthesis , immune responses , inflammation , and immunoglobulin binding were hypomethylated . in the arachidonic pathways , pgds , alox5ap , and ltb4r
the calcium channel voltage - dependent gamma subunit 6 ( cacng6 ) gene encodes a protein that stabilizes the calcium channel .
cacng6 has been studied in aerd , which revealed that rs192808c  >  t may be associated with the risk of aerd in a korean population .
genome - wide association studies ( gwas ) have recently emerged as a technology that can predict genetic variations across the genome associated with human diseases and clinical responses to drug treatment .
candidate gene approaches have been used for most of the genetic association studies of aerd .
gwas suggested that the nonsynonymous cep68 rs 7572857 g  >  a variant , replacing glycine with serine , showed a higher decline in fev1 due to aspirin provocation than other variants and could be a susceptible gene for aerd .
gene - gene interactions have also been proposed in the pathogenesis of aerd , and a few studies indicated that the genetic effects of cyslts and ltc4s 444a  >  c synthesis increased the lower level of fev1 after lysine asa inhalation .
tbxa2r 795 t  >  c polymorphism was associated with hla   dpb1 * 0301 in aerd patients compared with ata .
recently , a synergistic effect between the tgf - beta1 - 509c / t and il-10 - 1082a / g polymorphisms on the phenotype of aerd was noted when stratified by the presence of rhinosinusitis .
moreover , kim et al . reported a significant epistatic effect with a four - locus genetic interaction in the susceptibility to aspirin intolerance in asthmatic patients .
this model includes four snps : b2adr 46a  >  g , ccr3 520 t  >  g , cysltr1 634c  >  t , and fcer1b 109 t  >  c .
aerd often produces a moderate - to - severe phenotype ; however , diagnosis in these patients is challenging despite the availability of various techniques .
a hypothesis has been put forward , mostly focused on the overproduction of cyslts and arachidonic acid pathways .
most of the genetic studies have been performed using techniques such as gwas and the candidate gene approach .
however , replication studies in different ethnic groups will be essential to validate the reported data and apply this knowledge in clinical practice .
future areas of investigation should focus on identification of biomarkers for early diagnosis with various diagnostic techniques .
these genetic studies will be able to extend our understanding about the molecular genetic mechanism of aerd and to find a genetic marker for predicting drug responses or hypersensitivity reactions .
furthermore , this will be helpful for the determination of new diagnostic tools and therapeutic interventions .
 aspirin - exacerbated respiratory disease ( aerd ) refers to the development of bronchoconstriction in asthmatics following the exposure to aspirin or other nonsteroidal anti - inflammatory drugs . 
 the key pathogenic mechanisms associated with aerd are the overproduction of cysteinyl leukotrienes ( cyslts ) and increased cysltr1 expression in the airway mucosa and decreased lipoxin and pge2 synthesis . 
 genetic studies have suggested a role for variability of genes in disease susceptibility and the response to medication . 
 potential genetic biomarkers contributing to the aerd phenotype include hla - dpb1 , ltc4s , alox5 , cyslt , pge2 , tbxa2r , tbx21 , ms4a2 , il10 , ace , il13 , kif3a , slc22a2 , cep68 , ptger , and crth2 and a four - locus snp set composed of b2adr , ccr3 , cysltr1 , and fcer1b . future areas of investigation need to focus on comprehensive approaches to identifying biomarkers for early diagnosis . 