Title: HLA association in aspirin-intolerant asthma
Abstract: Aspirin (ASA)-intolerant asthma (AIA) affecting 10% to 20% of adults with asthma is characterized by ASA hypersensitivity, bronchial asthma, and chronic rhinosinusitis with nasal polyposis.1Szczeklik A Stevenson DD Aspirin-induced asthma: advances in pathogenesis, diagnosis and management.J Allergy Clin Immunol. 2003; 111: 913-921Abstract Full Text PDF PubMed Scopus (415) Google Scholar Although the pathogenic mechanism is not fully understood, a possible involvement of immunologic mechanisms in association with HLA alleles, particularly DPB1∗0401 and DPB1∗0301, was suggested in a white population with AIA.2Lympany PA Welsh KI Christie PE Schmitz-Schumann M Kemeny DM Lee TH An analysis with sequence-specific oligonucleotide probes of the association between aspirin-induced asthma and antigens of the HLA system.J Allergy Clin Immunol. 1993; 92: 114-123Abstract Full Text PDF PubMed Scopus (1) Google Scholar, 3Dekker JW Nizankowska E Schmitz-Schumann M Pile K Bochenek G Dyczek A et al.Aspirin-induced asthma and HLA-DRB1 and HLA-DPB1 genotypes.Clin Exp Allergy. 1997; 27: 574-577Crossref PubMed Scopus (120) Google Scholar However, these data have focused on whites and are required to be confirmed in other ethnic populations. In this study, to evaluate HLA associations in AIA development in a Korean population, we defined HLA-DRB1, DQB1, and DPB1 alleles and haplotypes by high-resolution genotypings in a larger number of patients with AIA compared with patients with ASA-tolerant asthma (ATA) and normal control subjects. Seventy-six patients with AIA (34 men; mean age, 45.2 years), 73 with ATA (21 men; mean age, 46.5 years), and 91 control subjects (74 men; mean age, 30.7 years) were enrolled. Twenty-nine patients with AIA (38.2%) and 38 with ATA (30.5%) had atopy. Fifty-nine patients with AIA (77.6%) and 38 with ATA (53.4%) had chronic rhinosinusitis (P < .01). Twenty-eight (68.3%) among 41 patients with AIA undergoing rhinoscopy had nasal polyps. AIA versus ATA was classified on the basis of lysine-ASA bronchoprovocation test results.4Park HS Early and late onset asthmatic responses following lysine-aspirin inhalation in aspirin sensitive asthmatic patients.Clin Exp Allergy. 1995; 25: 38-40Crossref PubMed Scopus (70) Google Scholar All subjects gave informed consent, which was approved by the ethics committee of Ajou University Hospital, Suwon, Korea. Genomic DNA from the study subjects was extracted with the use of an Extraction Kit (Intron Biotechnol, Seoul, Korea). HLA-DQB1 and HLA-DPB1 high-resolution genotypings were obtained from amplified gene products with the use of locus-specific primers5Tilanus MGJ Hansen JA Hurley CK IHWG Technical Manual. International Histocompatibility Working Group, Seattle2000Google Scholar and direct sequencing with the ABI 3100 Genetic analyzer (Applied Biosystems, Foster City, Calif). In the case of DRB1, the polymorphic exon 2 was amplified from each sample, using 8 sets of allele group–specific primers.5Tilanus MGJ Hansen JA Hurley CK IHWG Technical Manual. International Histocompatibility Working Group, Seattle2000Google Scholar The allele and haplotype frequencies were calculated with an E-M algorithm,6Long CJ Williams RC Urbanek M An E-M algorithm and testing strategy for multiple-locus haplotype.Am J Hum Genet. 1995; 56: 799-810PubMed Google Scholar with the use of SAS/Genetics software (SAS Institute Inc; Cary, NC), and the frequencies between two groups were compared by means of allele and haplotype procedures of the software, which are based on χ2 statistics. P values were corrected for multiple comparisons by multiplying by 10, as 9 common alleles/haplotypes and all others considered as one were tested. The clinical characteristics between the two groups were compared by means of χ2 and Student t tests. Significance level was <.05. Twenty-nine DRB1 alleles, 16 DQB1 alleles, and 21 DPB1 alleles were noted in this study. The alleles in the DRB1 locus were in Hardy-Weinberg equilibrium, whereas the alleles in DQB1 and DPB1 loci were not (P < .05) when tested by χ2 test. Table I summarizes the allele frequencies showing significant differences between two groups. The frequency of HLA-DPB1∗0301 was 13.8% in patients with AIA, compared with 4.1% in patients with ATA (odds ratio [OR] = 5.2, 95% CI = 1.8 to 14.7, P = .004) and 2.2% in control subjects (OR = 8.3, 95% CI = 2.7 to 25.5, P < .0001). These results remained significant after P values were corrected for multiple comparisons (Pc = .04, Pc < .001). The frequencies of DRB1∗0101, DRB1∗0301, DRB1∗0901, and DQB1∗0501 were significantly increased or decreased in patients with AIA than in patients with ATA or control subjects; however, P values were not significant after correction for multiple comparisons. When clinical features of patients with AIA were compared according to DPB1∗0301 genotype, the patients with DPB1∗0301 (n = 21) tended to have lower FEV1 levels (76.4 ± 18.9% vs 83.1% ± 23.3%, P = .14), higher ratio of women (71.4% vs 49.1%, P = .08), and higher prevalence of rhinosinusitis and/or nasal polyps (90.5% vs 72.7%, P = .13) than those without it (n = 55).Table IAllele frequencies of HLA-DRB1, DQB1, and DPB1 in study subjectsP value (OR)AlleleAIA (%) n = 76ATA (%) n = 73NC (%) n = 91AIA vs ATAAIA vs NCDRB1∗01013 (2.0)8 (5.5)12 (6.6).042 (0.3)∗03019 (5.9)2 (1.4)4 (2.2).037 (9.7)∗090128 (18.4)14 (9.6)19 (9.4).028 (2.3).037 (2.2)DQB1∗05015 (3.3)10 (6.8)16 (8.8).039 (0.4)DPB1∗030121 (13.8)6 (4.1)4 (2.2).004 (5.2)<.001 (8.3) Open table in a new tab For HLA DRB1-DQB1-DPB1 loci, 31 haplotypes were observed with >1% frequencies. Table II shows the most common haplotypes in the AIA group. The frequency of DRB1∗0901-DQB1∗0303-DPB1∗0501 haplotype was significantly higher in patients with AIA (12%) than in patients with ATA (3.8%, P = .006, Pc = .06). The frequency of DRB1∗0901-DQB1∗0303-DPB1∗0201 haplotype was much higher in patients with AIA (4.9%) than in control subjects (0%, P = .006, Pc = .06). In 2-locus haplotype analysis, DRB1∗0901-DPB1∗0501 and DQB1∗0303-DPB1∗0501 haplotypes showed a significant association with AIA (AIA vs ATA, P = .01, Pc = .1). DRB1∗0901-DPB1∗0201 and DQB1∗0303-DPB1∗0201 haplotypes also showed a significant association with AIA (AIA vs NC, P < .0005, Pc < .05). The frequency of DQB1∗02-DPB1∗0301 haplotype was significantly higher in patients with AIA than in those with ATA (P = .004, Pc = .04) and control subjects (P= .008, Pc = .08).Table IIHaplotype analysis of HLA-DRB1, DQB1, and DPB1Haplotype frequencies (%)P valueHaplotype∗Five frequent 3-locus haplotypes in A1A group are listed in frequency order.AIA (n = 76)ATA (n = 73)NC (n = 91)AIA vs ATAAIA vs NCDRB1-DQB1-DPB11.0901-0303-050112.03.87.4.006.102.0901-0303-02014.92.20.0.23.0063.1501-0602-02014.62.72.5.59.194.0406-0302-02014.52.52.0.27.185.0301-02-03013.30.00.6.03.05DRB1-DQB11.0901-030317.89.610.4.04.05DRB1-DPB11.0901-050111.64.17.3.01.242.0901-02015.22.60.0.26.0023.0301-03013.90.00.5.02.02DQB1-DPB11.0303-050112.84.67.2.01.032.0303-02016.22.40.5.09.0043.02-03015.00.00.5.004.008∗ Five frequent 3-locus haplotypes in A1A group are listed in frequency order. Open table in a new tab This is the first study to demonstrate a strong association between DPB1∗0301 allele and AIA development in an Asian population, which is comparable to a Polish study,3Dekker JW Nizankowska E Schmitz-Schumann M Pile K Bochenek G Dyczek A et al.Aspirin-induced asthma and HLA-DRB1 and HLA-DPB1 genotypes.Clin Exp Allergy. 1997; 27: 574-577Crossref PubMed Scopus (120) Google Scholar and to perform haplotype analysis in patients with AIA. In addition, clinical manifestations of patients with AIA with DPB1∗0301 are more identical to typical manifestation of AIA described previously.1Szczeklik A Stevenson DD Aspirin-induced asthma: advances in pathogenesis, diagnosis and management.J Allergy Clin Immunol. 2003; 111: 913-921Abstract Full Text PDF PubMed Scopus (415) Google Scholar Consistency of DPB1∗0301 as a positive factor in two different ethnic populations suggested that genes controlling AIA susceptibility are closely related to the HLA-DPB1 locus. On the basis of these findings and the previous study demonstrating higher incidences of circulating autoantibodies in patients with AIA,7Szczeklik A Nizanlowska E Serafin A Dyczek A Duplaga M Musial J Autoimmune phenomena in bronchial asthma with special reference to aspirin intolerance.Am J Respir Crit Care Med. 1995; 152: 1753-1756Crossref PubMed Scopus (68) Google Scholar it can be speculated that autoimmunity is one pathogenesis of AIA development. Furthermore, the HLA gene region contains a series of disparate genes such as TNF-α, complement 4, and so forth.8Acton RT The major histocompatibility complex.in: Rich RR Fleisher TA Shearer WT Kotzin BL Schroeder Jr, HW Clinical immunology. 2nd edition. Mosby, London2001: 6.1-6.13Google Scholar The polymorphisms of TNF gene have been reported to be associated with variation in the expression of TNF-α and the presence of asthma.9Li Kam Wa TC Mansur AH Britton J Williams G Pavord I Richards K et al.Association between -308 tumour necrosis factor promoter polymorphism and bronchial hyperreactivity in asthma.Clin Exp Allergy. 1999; 29: 1024-1028Crossref Scopus (97) Google Scholar However, polymorphisms of many other genes in the HLA gene region have not been investigated for a role in asthma. Further studies will be needed to investigate other markers and genes in the context of linkage disequilibrium with the DPB1∗0301 allele. The HLA haplotype analysis in this study demonstrated that two of the DRB1∗0901-associated haplotypes appeared to be significant in AIA susceptibility, although the P values did not remain significant after multiple comparisons (Pc = .06). However, further studies with a larger sample size will be needed to elucidate a borderline association of these haplotypes with AIA. The frequency of DQB1∗02-DPB1∗0301 haplotype in AIA was lower than that of DPB1∗0301, although the haplotype showed significant association with AIA, which would be more evidence that the single allele of DPB1∗0301 is an independent risk factor for AIA development. In conclusion, we suggest that DPB1∗0301 may be involved in AIA development. A possible involvement of DRB1∗0901-associated haplotypes was also suggested.
Publication Year: 2004
Publication Date: 2004-03-01
Language: en
Type: letter
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 83
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