Genetic markers for differentiating aspirin-hypersensitivity

Aspirin-induced asthma (AIA) and aspirin-induced urticaria/ angioedema (AIU) are two major aspirin-related allergies. We summarize recent findings related to their molecular genetic mechanisms in order to identify genetic susceptibility markers for differentiating AIU and AIA. The overproduction of cysteinyl leukotriene has been suggested as a mechanism in both AIU and AIA. Increased expression of CYSLTR1 with CYLSTR1 and CYSLTR2 polymorphisms are new findings in AIA, while the ALOX5 promoter polymorphism has been noted in AIU. An HLA study suggested that DPB1*0301 is a strong genetic marker for AIA, and that HLA DRB1*1302 and DQB1*0609 are markers for AIU susceptibility. Several single nucleotide polymorphisms (SNPs) in the promoters of EP2, TBX21, COX-2, Fc epsilon RIbeta, and TBXA2R were associated with AIA, while an Fc epsilon RIalpha promoter polymorphism was associated with AIU. The functional studies of the key genes involved in AIA and AIU are summarized. The identification and functional study of genetic markers for AIA and AIU susceptibility would further elucidate the pathogenic mechanisms and facilitate the development of early diagnostic markers to establish therapeutic targets.     

The human leucocyte antigen-DRB1*1302-DQB1*0609-DPB1*0201 haplotype may be a strong genetic marker for aspirin-induced urticaria

BACKGROUND: Urticaria/angioedema is a common aspirin-induced allergy; however, its pathogenic mechanism is not understood. OBJECTIVE: In order to uncover the genetic mechanism, we studied the associations of the human leucocyte antigen (HLA) genotypes in patients with aspirin-induced urticaria compared with aspirin-intolerant asthma and normal control in a Korean population. METHODS: Ninety-four aspirin-induced urticaria patients presenting urticaria/angioedema-induced by both ASA and NSAID (50 had underlying chronic urticaria) and showing positive responses on oral aspirin challenge test, 76 aspirin-intolerant asthmatics with positive responses on lysine-aspirin bronchoprovocation test, and 185 normal healthy controls were enrolled. HLA-DRB1, DQB1, and DPB1 genotypings were performed by direct DNA sequencing analysis. RESULTS: The allele frequencies of HLA-DRB1(*)1302 (18.1%) and HLA-DQB1(*)0609 (10.1%) in aspirin-induced urticaria were significantly higher than in aspirin-intolerant asthma (5.3%, P=0.0004; 2.0%, P=0.0024) and in normal controls (8.1%, P=0.0005; 3.2%, P=0.0008), and they remained significant after correcting for multiple comparisons. The patients with these two HLA markers had a significantly younger age than patients without, while no associations were found in with respect to atopic status, a history of previous allergic diseases, total IgE level, or presence of underlying chronic urticaria (P>0.05, respectively). In haplotype analysis, the HLA-DRB1(*)1302-DQB1(*)0609-DPB1(*)0201 was significantly higher in the aspirin-induced urticaria (8.0%) than in the aspirin-intolerant asthma (0.7%, P=0.0014) and normal controls (2.0%, P=0.0006). CONCLUSION: These findings suggest that the HLA-DRB1(*)1302-DQB1(*)0609-DPB1(*)0201 may be a strong genetic marker to determine the aspirin-induced urticaria phenotype.     

Pathogenesis of nonsteroidal antiinflammatory drug-induced asthma

PURPOSE OF REVIEW: To summarize recent findings related to the pathogenic mechanisms of aspirin-induced asthma with emphasis on molecular genetic mechanisms. RECENT FINDINGS: The overproduction of cysteinyl leukotrienes with the increased expression of cysteinyl leukotriene receptor 1 (CYSLTR1) is a consistent finding in aspirin-induced asthma patients. Recent data have suggested a dysregulation of cyclooxygenase-2 and prostaglandin E2, increased levels of 15-hydroxyeicosatetranoic acid, and decreased lipoxin generation as characteristics of the condition. The HLA allele DPB10301 was documented as a strong genetic marker for susceptibility in an Asian population. Leukotriene C4 synthase has been established as a key genetic determinant of aspirin-induced asthma, but recent studies have demonstrated that several single nucleotide polymorphisms in the promoters of prostaglandin E2 receptor subtype 2, CYSLTR1 and CYSLTR2 and T-box expressed in T cells (TBX21) could increase risk for the condition. Although cyclooxygenase-2 and thromboxane A2 receptor polymorphisms were not associated with aspirin-induced asthma phenotype, they may exert functional effects. SUMMARY: The identification of genetic markers for aspirin-induced asthma susceptibility along with in-vitro functional studies would help to elucidate the pathogenesis of the condition. Further studies of the interactions among genes and between genes and the environment will be essential.     

Efficacy of leukotriene receptor antagonist in bronchial hyperresponsiveness and hypersensitivity to analgesic in aspirin-intolerant asthma

BACKGROUND: Albeit its exact pathogenesis is still ambiguous; aspirin-intolerant asthma is one of several types of asthma for which antileukotriene therapy is useful, because it is widely accepted that bronchial over-production of leukotrienes may be involved in its pathogenesis. Pranlukast (8-[p-(4-phenylbutyloxy) benzol] amino-2-(tetrazol-5-yl)-4-oxo-4H-1-benzopyran hemihydrate), a selective cysteinyl leukotriene receptor antagonist, is now widely used in the treatment of asthma. OBJECTIVE: This study was designed to investigate the protective effect of pranlukast on airway sensitivity to sulpyrine provocation testing, bronchial responsiveness to methacholine provocation testing, and to investigate whether this protective activity is associated with a reduction in aspirin-induced excretion of urinary LTE4 (uLTE4), a marker of the cysteinyl leukotriene (LT) overproduction that participates in the pathogenesis of aspirin-induced asthma. METHODS: We assessed the effects of pretreatment with pranlukast on bronchoconstriction precipitated by inhalation of methacholine and sulpyrine in 16 adult patients with mild or moderate aspirin-intolerant asthma; those who were in stable clinical condition and were hypersensitive to sulpyrine provocation testing were allocated to this study. A double-blind, randomized, crossover design was used. uLTE4 was measured using combined reverse-phase high-performance liquid chromatography (rp-HPLC)/enzyme immunoassay. RESULTS: Pranlukast protected against analgesic-induced bronchoconstriction through mechanisms that were not related to the bronchodilator property, but were related to the improvement both of bronchial hyperresponsiveness and hypersensitivity to analgesic (P < 0.005 and P < 0.0001). Pranlukast showed little effect on excretion of uLTE4. CONCLUSION: These results support the hypothesis that cysteinyl leukotriene is one of the most important components in the pathogenesis of aspirin-intolerant asthma. Pranlukast improves not only hypersensitivity to analgesic, but also bronchial hyperresponsiveness in aspirin-intolerant asthma. It is also possible that pranlukast has another anti-asthmatic effect besides that of a leukotriene receptor antagonist.     

Pathogenesis, diagnosis, and treatment of aspirin intolerance.

OBJECTIVES: To provide an overview of aspirin intolerance (AI), to summarize the latest genetic and pathophysiologic findings, and to discuss the current therapeutic recommendations, including aspirin desensitization. DATA SOURCES: Using the PubMed database, a systematic search of articles published between 1968 and 2006 was performed to evaluate the current literature on AI. The bibliographies of selected articles served as a source of additional literature. STUDY SELECTION: Included articles were selected for their relevance to the pathogenesis, diagnosis, and management of AI. RESULTS: The prevalence of AI is approximately 0.3% to 0.9%, but AI is often overlooked. It can display a wide range of clinical pictures, such as acute asthma attacks, urticaria, angioedema, chronic rhinitis, myocardial ischemia, and anaphylactic shock. Regarding the pathogenesis of AI, modifications of eicosanoid metabolism are supposed to underlie AI, including aspirin-induced asthma and aspirin-induced urticaria. However, the pathogenesis of AI has not yet been clearly elucidated. Associations of several HLA alleles with subtypes of AI, such as aspirin-induced urticaria and aspirin-induced asthma, and single nucleotide polymorphisms in genes encoding enzymes involved in arachidonic acid metabolism have been shown. CONCLUSIONS: Because aspirin therapy should be avoided in AI patients, the use of alternative drugs is recommended. Patients intolerant of alternative drugs and those with therapy-resistant asthma or sinusitis benefit from aspirin desensitization.     

Differential Contribution of the CysLTR1 Gene in Patients with Aspirin Hypersensitivity

In this study, we compared the roles of CysLT receptor type 1 (CysLTR1) and leukotriene C4 synthase (LTC4S) gene polymorphisms in two major aspirin-related allergic diseases, aspirin-intolerant asthma (AIA) and aspirin-induced chronic urticaria/angioedema (AICU). CysLTR1-634C>T and LTC4S-444A>C polymorphisms were genotyped and its functional effect on the promoter activity was compared. As in vivo functional study, changes of peripheral mRNA level of CysLTR1 were measured by real-time PCR before and after aspirin challenge. A significant association was found for the CysLTR1 promoter polymorphism and the AIA phenotype compared to AICU (P = 0.015). In U937 cells, the variant genotype reporter construct showed significantly higher promoter activity than the common genotype (P < 0.05). The CysLTR1 mRNA levels increased significantly after aspirin challenge in AIA patients (P = 0.013). In conclusion, the CysLTR1 polymorphism may contribute to develop to the AIA phenotype and be used as a genetic marker for differentiating two major aspirin hypersensitivity phenotypes.     

Leukotriene-related gene polymorphisms in patients with aspirin-intolerant urticaria and aspirin-intolerant asthma: differing contributions of ALOX5 polymorphism in Korean population

The pathogenesis of aspirin (acetylsalicylic acid, ASA)-intolerant urticaria (AIU) is still poorly understood but it has recently been suggested that it is associated with the overproduction of leukotriene (LT). This is supported by evidence that cyclooxygenase 2 inhibitor is given safely to patients with AIU. The present study was designed to investigate the role of genetic polymorphism of LT related genes in the pathogenesis of AIU via a case-control study. We screened single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in leukotriene synthesis in the Korean population with AIU (n = 101), ASA-intolerant asthma (AIA, n = 95) and normal healthy controls (n = 123). Genotype was determined by primer extension reactions using the SNapShot ddNTP primer extension kit. Among 8 SNPs of four LT related genes, the polymorphism of ALOX5 at positions of -1708 G > A showed significant difference in genotype frequency between AIU and AIA (p = 0.01). Furthermore, there were significant differences observed in the frequencies of two ALOX5 haplotypes between the AIU group and AIA group (p < 0.05). However, there were no differences in allele, genotype, or haplotype frequencies of ALOX5 between the AIU group and the normal control group. These results suggested that ALOX5 has a differing contribution in two major clinical pathogenesis related to ASA-sensitivity.     

Exhaled eicosanoids following oral aspirin challenge in asthmatic patients

BACKGROUND: Biochemical analysis of expiratory breath condensate is an emerging non-invasive technique for assessment of airway inflammation. OBJECTIVE: We wondered whether application of expiratory breath condensate could facilitate diagnosis of aspirin-intolerant asthma and reproduce eicosanoids mediators' abnormalities described in this disease. METHODS: We measured prostaglandins (PGs) E(2), F(2 alpha), 9 alpha 11 beta F(2) and iso-F(2) by gas-chromatography/mass-spectrometry and cysteinyl leukotrienes (cys-LTs) by radioimmunoassay in breath condensates of asthmatic patients undergoing oral aspirin challenge. Fourteen patients with aspirin-induced asthma and 20 aspirin-tolerating asthmatics, most of them on chronic inhaled corticotherapy, were studied and compared with 10 healthy subjects. Additionally, plasma 9 alpha 11 beta PGF(2), the metabolite of PGD(2) and urinary leukotriene (LT) E(4) were measured before and following the challenge. RESULTS: At baseline, PG did not differ between the groups, except for lower 9 alpha 11 beta PGF(2) in aspirin-intolerant asthma. Their concentrations were not changed by the challenge. Breath condensate cys-LTs were similar in the groups studied at base, and after aspirin challenge increased only in aspirin-intolerant patients. Elevated baseline urinary LTE(4) and its further increase following aspirin challenge was highly diagnostic for aspirin-intolerant asthma. The discriminatory value of cys-LTs increase in breath condensates was lower (72.8%) than either basal (99%) or post-challenge increase (94%) of urinary LTE(4). CONCLUSIONS: In asthmatic patients on chronic corticotherapy measurement of urinary LTE(4) excretion rather than cys-LTs in breath condensate is of greater value for diagnosis of aspirin hypersensitivity.     

LTC4-synthase A-444C polymorphism: lack of association with NSAID-induced isolated periorbital angioedema in a Spanish population.

BACKGROUND: The mechanism of nonsteroidal anti-inflammatory drug (NSAID)-induced reactions is unknown. However, strong evidence supports the hypothesis of an enhanced production of cysteinyl-leukotrienes. The existence of a polymorphism (A-444C) in the promoter region of the leukotriene (LT)C4-synthase gene (the terminal enzyme in the LTC4 production pathway) has been reported. This polymorphism has yielded contradictory results on its association with aspirin-induced asthma. OBJECTIVE: The present study was designed to investigate the possible genetic association of C(-444) allele and a specific clinical phenotype of NSAID sensitivity, the NSAID-induced isolated periorbital angioedema, via a case/control study. METHODS: The polymorphism A-444C was analyzed in 58 patients with NSAID-induced periorbital angioedema and 61 control subjects, who had undergone single-blind, placebo-controlled oral challenge. Genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: We have not found an association of C(-444), allele with NSAID-induced isolated periorbital angioedema. CONCLUSIONS: Further studies are needed to determine whether polymorphisms in the LTC4-synthase gene or other leukotriene-forming enzymes are involved in the pathogenesis of the different subsets of NSAID sensitivity.     

Tacrolimus reduces urinary excretion of leukotriene E(4) and inhibits aspirin-induced asthma to threshold dose of aspirin

BACKGROUND: The exact mechanism of aspirin-induced asthma is not clear. It has been postulated that precipitation of asthma attacks by aspirin is linked to inhibition of COX activity and massive release of cysteinyl leukotriene into the airway. Tacrolimus, a macrolide-derived immunosuppressant, is used for immunosuppression in organ transplantation and also for allergic diseases such as atopic dermatitis. OBJECTIVE: We evaluated the effects of tacrolimus in aspirin-induced asthma by using a double-blind, crossover study design. METHODS: Twelve patients with aspirin-induced asthma (male:female, 3:9; mean age +/- SD, 36.7 +/- 7.2 years) received either tacrolimus (0.1 mg/kg) or placebo 2 hours before the threshold dose of oral aspirin. RESULTS: In the placebo arm, oral aspirin significantly decreased FEV 1 concomitant with significant increases in sputum eosinophilic cationic protein and urinary leukotriene E(4) levels. Tacrolimus significantly inhibited bronchoconstriction and abrogated aspirin-induced increase in both sputum eosinophilic cationic protein and urinary leukotriene E(4) levels. CONCLUSION: The current study suggested that tacrolimus inhibited bronchoconstriction to a threshold dose of aspirin by inhibition of cysteinyl leukotriene excretion.     

Polymorphisms in the 5-lipoxygenase activating protein (ALOX5AP) gene are not associated with asthma in an Australian population

BACKGROUND: The cysteinyl-leukotrienes (cys-LTs) are important pro-inflammatory mediators in asthma, and have been shown to have a role in specific disease subtypes, including asthma severity. Few studies have investigated the role of polymorphisms in the ALOX5AP gene, encoding 5-lipoxygenase activating protein (FLAP), and asthma. We hypothesized that polymorphisms in this gene are associated with asthma and in particular, with asthma severity, in an Australian population. OBJECTIVE: To screen the coding region of the ALOX5AP gene for polymorphisms and to determine the association between previously described polymorphisms and asthma and asthma severity in an Australian population. METHODS: We used PCR-SSCP and PCR-RFLP analysis to examine a previously described promoter polyA variable repeat polymorphism and two intronic polymorphisms (IVS2+12C>A, IVS2+105T>C), and to screen all five exons of the gene for new polymorphisms, in a large Australian population of randomly selected, non-asthmatic controls (n=457), mild asthmatics (n=274), moderate asthmatics (n=231) and severe asthmatics (n=79). RESULTS: We confirmed the presence of two polymorphisms in intron 2 and found no association between these polymorphisms and asthma or asthma severity, nor between a promoter polymorphism in the ALOX5AP gene and asthma or asthma severity. Gene fragment analysis of the promoter polymorphism revealed novel, conserved repeat numbers in our population, and no new polymorphisms were found in the coding region of the gene. CONCLUSION: These findings in a large, well characterized asthma population, reveal that, while FLAP is an important enzyme in cys-LTs biosynthesis, polymorphisms in the ALOX5AP gene are not likely to be functionally associated with the asthma phenotype.     

Distribution of HLA‐DRB1 and HLA‐DQB1 families of alleles and haplotypes in Vojvodina population

Major histocompatibility complex encoding human leucocyte antigens (HLA) is a highly polymorphic gene cluster that makes it a valuable tool in the population genetic studies. The aim of our study was to compare HLA class II gene frequencies with other populations from Europe and to determine the relationship between the investigated populations. In this study, one hundred and twenty healthy individuals from Vojvodina, northern Serbia, were studied for 18 of the HLA‐DRB1 and HLA‐DQB1 loci. The HLA families of alleles were analysed by using sequence‐specific primers for polymerase chain reaction (PCR‐SSP). The results showed the increased frequency of HLA‐DRB1*11(0.333), ‐DRB1*04(0.300), ‐DRB1*07(0.250), ‐DQB1*03(0.730) and ‐DQB1* 05(0.391), among the tested families of alleles. The two‐locus haplotype analysis revealed significant positive linkage disequilibrium for DRB1*11DQB1*03 (Δ = 0.0788, χ² = 12.61) and DRB1*04DQB1*03 (Δ = 0.0583, χ² = 8.04). A phylogenetic tree constructed on the basis of the DRB1* gene frequencies derived from other populations revealed the clustering among the Vojvodina population together with other populations in Europe (Croats, Austrians and Hungarians). Close relationship of the Vojvodina population with the populations of Hungarians and Austrians can be the result of their historical influence on the region of Vojvodina.     

Extensive HLA class II studies in 58 non-DRB1*15 (DR2) narcoleptic patients with cataplexy

Narcolepsy is a sleep disorder that has been shown to be tightly associated with HLA DR15 (DR2). In this study, 58 non-DR15 patients with narco-lepsy-cataplexy were typed at the HLA DRB1, DQA1 and DQB1 loci. Subjects included both sporadic cases and narcoleptic probands from multiplex families. Additional markers studied in the class II region were the promoters of the DQA1 and DQB1 genes, two CA repeat polymorphisms (DQCAR and DQCARII) located between the DQA1 and DQB1 genes, three CA repeat markers (G51152, T16CAR and G411624R) located between DQB1 and DQB3 and polymorphisms at the DQB2 locus. Twenty-one (36%) of these 58 non-DR15 narcoleptic patients were DQA1*0T02 and DQBI*0602, a DQ1 Subtype normally associated with DRB1*15 in DR2-positive narcoleptic subjects. Additional microsatellite and DQA1 promoter diversity was found in some of these non-DR15 but DQB1*0602-positive haplotypes but the known allele specific codons of DQA1*0102 and DQB1*0602 were maintained in all 21 cases. The 37 non-DQA1*0102/DQB1*0602 subjects did not share any particular HLA DR or DQ alleles. We conclude that HLA DQA1*0102 and DQB1*0602 are the most likely primary candidate susceptibility genes for narcolepsy in the HLA class II region.     

HLA Dr-Dq haplotypes and the TNFA-308 polymorphism: associations with asthma and allergy

BACKGROUND: The HLA (human leukocyte antigen) class II genes DQB1 and DRB1 and the Tumor Necrosis Factor alpha gene (TNFA) within the HLA complex (chromosome 6p21) have been associated with asthma and allergy. Due to the strong linkage disequilibrium characterizing this complex and the multiple asthma/allergy expressions, we aimed to determine which of these genes were primarily involved in specific asthma/allergy traits. METHODS: The DRB1-DQB1 alleles and TNFA-308 polymorphism were genotyped in 959 children from the Environment and Childhood Asthma study and analyzed for possible associations with allergic and non-allergic asthma (with/without at least one positive skin prick test for allergens) and specific allergic sensitization, as well as bronchial hyperresponsiveness and total IgE, using both allele and extended haplotype analyses. RESULTS: Different genes within the HLA complex were associated with separate asthma and allergy traits. Nonallergic asthma was associated with both the TNFA-308A allele [Odds ratio (OR) 1.7 (1.3-2.3)] and DRB1 03 allele [OR 1.6(1-2.6)], but extended DRB1 03-TNFA-308 haplotype analysis suggested that the DRB1-DQB1 association was secondary to linkage disequilibrium with the TNFA-308 polymorphism. Allergies were associated with HLA class II alleles only; birch sensitization with DQB1 0603-DRB1 13 [OR 2.3 (1.4-4.0)] and mugwort sensitization with DQB1 0609-DRB1 13 [OR 7.1 (1.9-27.0)] and DQB1 0501-DRB1 01 [OR 2.0 (1.0-4.0)]. CONCLUSIONS: Our data suggests that asthma is not associated with DRB1 or DQB1 but rather TNFA or a gene(s) in linkage disequilibrium, while sensitization to specific allergens is associated with particular alleles at the DQ and/or DR loci. A novel association between DQB1 0603-DRB1 13 and birch allergy is identified.     

Different contribution of HLA-DR and -DQ genes in susceptibility and resistance to Insulin-dependent diabetes mellitus (IDDM)

Abstract: Previous studies have indicated that certain alleles of HLA-DR and -DQ genes were strongly associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM), and the role of DQ molecule in IDDM has been suggested. To further clarify the association of DQ alleles with IDDM, we determined the nucleotide sequences of full-length cDNA from 13 DQA1 alleles and 14 DQB1 alleles. The sequencing analysis revealed sequence polymorphisms outside the hypervariable region of DQ genes. We then analyzed the DQA1 and DQB1 polymorphisms along with that of DRB genes in 86 B-lymphoblastoid cell lines (B-LCLs) from various ethnic groups and in healthy unrelated Japanese and Norwegian individuals. The allelic and haplotypic distributions in each population revealed the characteristic haplotypic formation in the HLA class II region. HLA genes in 139 Japanese and 100 Norwegian IDDM patients were analyzed. DQB1*0301 was negatively associated with IDDM in both ethnic groups, irrespective of associated DRB1 and DQA1 alleles. In DQB1*0302 positive populations, which represented a positive association with IDDM in both ethnic groups, DRB1*0401, *0404, *0802 haplotypes increased in the patients, whereas DRB1*0406 haplotype decreased. Considering about the hierarchy in DRB1 alleles with IDDM susceptibility (DRB1*0401>*0404>*0403 in Norwegian and DRB1*0802>*0403>*0406 in Japanese), the genetic predisposition to IDDM is suggested to be defined by the combination of DR-associated susceptibility and DQ-associated susceptibility and by the DQ-associated resistance which is a dominant genetic trait.     

Tolerability of meloxicam in patients with histories of adverse reactions to nonsteroidal anti-inflammatory drugs.

BACKGROUND: Adverse reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are frequent, particularly among patients with chronic urticaria or asthma. The need to identify an alternative drug that is safe and reliable is a common problem in clinical practice. OBJECTIVE: To assess the tolerability of meloxicam, a new NSAID that selectively inhibits the inducible isoform of cyclooxygenase, in a group of NSAID-sensitive patients. PATIENTS AND METHODS: We studied 177 patients who had suffered adverse reactions to one or more NSAIDs. Cutaneous reactions were reported by 83.1% of the subjects (urticaria in 55, angioedema in 52, urticaria/angioedema in 39, and maculopapular rash in 1), respiratory symptoms by 3.9%, both cutaneous and respiratory symptoms by 9%, Stevens-Johnson's syndrome by 2.3%, and anaphylactoid reactions by 1.7%. All subjects underwent a single-blind, placebo-controlled oral challenge with divided therapeutic doses of meloxicam (1.9 mg + 5.6 mg 1 hour later = cumulative dose 7.5 mg). RESULTS: Positive reactions were observed in only two cases (1.1%), both manifested exclusively by cutaneous symptoms (urticaria/angioedema in one case and maculopapular rash/facial edema in the second). CONCLUSION: Meloxicam seems to be well tolerated by NSAID-sensitive subjects whose reactions are manifested by urticaria/angioedema. Additional study is needed for a more complete assessment of its tolerability in patients with aspirin-induced asthma and other severe manifestations of NSAID sensitivity.     

Polymorphisms of high-affinity IgE receptor and histamine-related genes in patients with ASA-induced urticaria/angioedema

The pathogenic mechanism of ASA-induced urticaria/angioedema (AIU) is still poorly understood, but it has been known that histamine releasing by cutaneous mast cell activation is considered to be an important role. Considering the importance of histamine in AIU, we speculated that a genetic abnormality of histamine-related genes such as a high-affinity IgE receptor, a metabolic enzyme of histamines and histamine receptors, may be involved in the development of AIU. Enrolled in the study were 110 patients with AIU, 53 patients without ASA hypersensitivity who had various drug allergies presenting as exanthematous skin symptoms, and 99 normal healthy controls (NC). Eleven single nucleotide polymorphisms (SNPs) of the beta chain of the high-affinity IgE receptor (FCER1B) and three histamine-related genes-histamine N-methyltransferase (HNMT), histamine H1 receptor (HRH1), histamine H2 receptor (HRH2)-were screened using the SNP-IT assay based on a single base extension method. No significant differences were observed in allele and genotype frequencies, and haplotype frequencies of all the SNPs of FCER1B, HNMT, HRH1, and HRH2 among the three groups (p>0.05, respectively). These results suggest that the polymorphisms of FCER1B and the three histamine-related genes may not contribute to the development of AIU phenotype in the Korean population.