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

Abstract

SummaryBackground 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 aspirinintolerant 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 5 0.0004; 2.0%, P 5 0.0024) and in normal controls (8.1%, P 5 0.0005; 3.2%, P 5 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 (P40.05, 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 5 0.0014) and normal controls (2.0%, P 5 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.

Genetic mechanism of aspirin-induced urticaria/angioedema

“…We have demonstrated an association between HLA genotype and AIU by using a high-resolution analysis technique, confirming a strong positive association between the HLA DRB1 Ã 1302 and HLA DQB1 Ã 0609 alleles in AIU [14 ]; allelic frequencies of HLA DRB1 Ã 1302 and HLA DQB1 Ã 0609 were significantly higher in AIU patients than in AIA patients or in normal control subjects (Table 1). When clinical parameters were analyzed according to the presence of these two alleles, the patients carrying HLA DRB1 Ã 1302 or HLA DQB1 Ã 0609 (28.2 AE 7.0 and 29.0 AE 6.9 years respectively) were significantly younger (by 10 years) than those without either allele (38.0 AE 13.6 and 36.4 AE 13.4 years respectively), indicating that patients with these alleles develop AIU at an earlier age.…”

Update on the Genetic Basis of Drug Hypersensitivity Reactions

“…Finally, further associations have been found with the adenosine receptor A3 gene (-1050G>T and -564C>T) [117], IL4 (-589T>C) [112,118], IL10 (-1082 G>A) [112], CTLA (49A>G) [112], nitric oxide synthase 2 [119], and the HLA system [120][121][122].…”

A functional promoter polymorphism of the human IL18 gene is associated with aspirin-induced urticaria

“…HLA-DRB1*1302-DQB1*0609 has also been recognized as a genetic marker for AIU. 3 Leukotriene overproduction may be one of the mechanisms responsible for AIU, 1,4 which is supported by genetic studies showing significant association of leukotriene C4 synthase (LTC4S) 5,6 and 5-lipoxygenase (ALOX5). 7 In addition, previous genetic association studies have reported that the IgE high affinity receptor (FCER1A), 8 histamine N-methyltransferase (HNMT) 9 and adenosine A3 receptor (ADORA3) 10 genes are genetic determinants of AIU, which indicates that genetic variation associated with increased histamine release and ⁄or augmented mast cell signalling, leading to the release of proinflammatory mediators, can contribute to the development of AIU.…”

“…AIU was defined by a positive result on an aspirin oral provocation test, which was performed using 500 mg of aspirin (Rhonal; KunWha Pharmaceutical Co., Seoul, Korea) as described previously. 3 Patients with AIU can be classified into two different phenotypes, AIAU and AICU. Aspirin is regarded as a causative factor of urticaria and ⁄or angio-oedema in AIAU, which lasts for < 6 weeks, whereas it exacerbates pre-existing urticaria in AICU, which lasts for more than 6 weeks.…”