Single nucleotide polymorphisms in TNF are associated with susceptibility to aspirin-exacerbated respiratory disease but not to cytokine levels: a study in Mexican mestizo population.

AIM: To evaluate the association of three single nucleotide polymorphisms in TNF and one in LTA in Mexican patients with aspirin-exacerbated respiratory disease (AERD) and the correlation of those single nucleotide polymorphisms with serum levels of TNF-α. PATIENTS & METHODS: Case-control study including 133 patients with AERD, 135 patients with asthma (aspirin-tolerant asthmatics) and 182 healthy subjects. RESULTS: GA genotype of rs1800629 in TNF was found to be associated with the risk of developing AERD (p < 0.05; odds ratio = 2.36) and by dominant model (p < 0.05; odds ratio = 2.51). Furthermore, there was a difference in the serum levels between the aspirin-tolerant asthmatics group and the other groups (p < 0.001). CONCLUSION: The GA genotype of rs1800629 is associated with genetic susceptibility to AERD, but it does not correlate to protein serum levels.

Plasma 15-Hydroxyeicosatetraenoic Acid Predicts Treatment Outcomes in Aspirin-Exacerbated Respiratory Disease.

BACKGROUND: Aspirin desensitization followed by daily aspirin provides therapeutic benefits to patients with aspirin-exacerbated respiratory disease (AERD). It is not well understood how eicosanoid levels change during aspirin treatment. OBJECTIVE: To investigate associations between clinical outcomes of aspirin treatment and plasma eicosanoid levels in patients with AERD. METHODS: Thirty-nine patients with AERD were offered aspirin treatment (650 mg twice daily) for 4 weeks. Respiratory parameters and plasma levels of multiple eicosanoids were recorded at baseline and after 4 weeks of aspirin therapy using the Asthma Control Test and Rhinoconjunctivitis Quality of Life Questionnaire. Respiratory function was evaluated using the FEV1 and nasal inspiratory peak flow. RESULTS: After aspirin treatment, respiratory symptoms improved in 16 patients, worsened in 12 patients, and did not change in 4 patients. Seven patients were unable to complete the desensitization protocol. Patients with symptom improvement had higher baseline plasma 15-hydroxyeicosatetraenoic acid (15-HETE) levels than did patients with symptom worsening: 7006 pg/mL (interquartile range, 6056-8688 pg/mL) versus 4800 pg/mL (interquartile range, 4238-5575 pg/mL), P = .0005. Baseline 15-HETE plasma levels positively correlated with the change in Asthma Control Test score (r = 0.61; P = .001) and in FEV1 after 4 weeks of aspirin treatment (r = 0.49; P = .01). It inversely correlated with Rhinoconjunctivitis Quality of Life Questionnaire score (r = -0.58; P = .002). Black and Latino patients were more likely to have symptom worsening on aspirin or fail to complete the initial desensitization than white, non-Latino patients (P = .02). CONCLUSIONS: In patients with AERD, low baseline 15-HETE plasma levels and black or Latino ethnicity are associated with worsening of respiratory symptoms during aspirin treatment.

Association of TRPM3 Polymorphism (rs10780946) and Aspirin-Exacerbated Respiratory Disease (AERD).

INTRODUCTION: Aspirin-exacerbated respiratory disease (AERD) refers to the combination of asthma rhinosinusitis and poliposis; ingestion of aspirin or other non-steroid anti-inflammatory drugs exacerbate asthma-like symptoms. The pathogenesis of AERD is unknown, and genetic and environmental factors contribute to the disease. Our objective is identifying polymorphisms associated with susceptibility in a Mexican mestizo population. METHODS: Primarily we performed custom Illumina goldengate array-based genotyping of 1512 SNPs, carefully selected from a variety of acute/chronic inflammatory lung conditions previously reported. Four SNPs in TRPM3 gene showed the lowest p-values (rs10780946, rs7025694, rs1889915, and rs7047645). We further selected rs10780946 and rs7025694 for validation using Taqman genotyping (n = 743; 288 AERD, 272 ATA, and 183 HC). RESULTS: rs10780946 showed association when compared between AERD and ATA groups under co-dominant (p = 0.006), dominant (p = 0.002), overdominant (p = 0.01), and log-additive (p = 0.03) genetic models. AERD showed increased heterozygous TC (rs10780946-rs7025694) haplotype compared to ATA and HC (p < 0.05). We could not confirm any association between rs7025694 and AERD. CONCLUSION: rs10780946 TRPM3 polymorphism is associated with AERD susceptibility.

Effect of diffuse panbronchiolitis critical region 1 polymorphisms on the risk of aspirin-exacerbated respiratory disease in Korean asthmatics.

BACKGROUND: The functional role of the human diffuse panbronchiolitis critical region 1 (DPCR1) gene, located in the major histocompatibility complex class I, has not been widely investigated. However, this gene is a well known genetic marker for diffuse panbronchiolitis, a disease affecting human respiratory bronchioles. In this study we explored the association between polymorphisms in DPCR1 and aspirin-exacerbated respiratory disease (AERD), an asthma phenotype. METHODS: Genotyping of 6 polymorphisms was carried out in a total of 189 Korean asthmatic patients stratified into 93 AERD cases and 96 aspirin tolerant asthma controls. Subjects who exhibited significant decrease of FEV(1) by aspirin provocation were identified as AERD subjects. Logistic and regression analyses were performed to investigate the association between DPCR1 polymorphisms and the risk of AERD as well as FEV(1) decline. RESULTS: Initial analysis revealed significant association of rs2517449 with AERD, with a P value of .03 via a recessive model; however, the association signal disappeared after multiple testing corrections. In addition, rs2517449 and rs2240804 also showed association signals with decline of FEV(1) after aspirin provocation (P = .007 and .03, respectively, in a recessive model). After testing for multiple comparisons, only the association signal from rs2517449 was retained (P(corr) = .04), while other polymorphisms showed no associations with the risk of AERD and FEV(1) decline. CONCLUSIONS: Our results show that polymorphisms in DPCR1 are not associated with the risk of AERD.

Genetic association analysis of TAP1 and TAP2 polymorphisms with aspirin exacerbated respiratory disease and its FEV1 decline.

Aspirin exacerbated respiratory disease (AERD) induces bronchoconstriction in asthmatic patients characterized with a clinical condition of severe decline in forced expiratory volume in one second (FEV1) after ingestion of aspirin. Two genes consisting a heterodimer, transporter 1 and 2, ATP-binding cassette, sub-family B (MDR/TAP) (TAP1 and TAP2) within the major histocompatibility complex (MHC) region, have been implicated in immunodeficiency and bronchiectasis development. To investigate the associations of TAP1 and TAP2 genetic polymorphisms with AERD and phenotypic FEV1 decline, a total of 43 common single-nucleotide polymorphisms (SNPs) including 12 SNPs of TAP1 and 31 SNPs of TAP2 were genotyped in 93 AERD patients and 96 aspirin-tolerant asthma controls. Interestingly, regression analysis revealed that polymorphisms and haplotypes of TAP2 were associated with FEV1 decline by aspirin provocation (P=0.002-0.04), with about twofold decline rate of FEV1 in most of minor homozygotes compared with major homozygotes. In addition, nominal evidences of association between TAP2 and AERD development were observed (P=0.02-0.04). However, TAP1 polymorphisms showed no relations to both AERD and FEV1 decline after aspirin challenge (P>0.05). Although further functional evaluations and replications are required, our preliminary findings provide supporting information that variants of TAP2 might be predisposing factors for FEV1 decline-related symptoms.

Positive association between aspirin-intolerant asthma and genetic polymorphisms of FSIP1: a case-case study.

BACKGROUND: Aspirin-intolerant asthma (AIA), which is caused by non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, causes lung inflammation and reversal bronchi reduction, leading to difficulty in breathing. Aspirin is known to affect various parts inside human body, ranging from lung to spermatogenesis. FSIP1, also known as HDS10, is a recently discovered gene that encodes fibrous sheath interacting protein 1, and is regulated by amyloid beta precursor protein (APP). Recently, it has been reported that a peptide derived from APP is cleaved by alpha disintegrin and metalloproteinase 33 (ADAM33), which is an asthma susceptibility gene. It has also been known that the FSIP1 gene is expressed in airway epithelium. OBJECTIVES: Aim of this study is to find out whether FSIP1 polymorphisms affect the onset of AIA in Korean population, since it is known that AIA is genetically affected by various genes. METHODS: We conducted association study between 66 single nucleotide polymorphisms (SNPs) of the FSIP1 gene and AIA in total of 592 Korean subjects including 163 AIA and 429 aspirin-tolerant asthma (ATA) patients. Associations between polymorphisms of FSIP1 and AIA were analyzed with sex, smoking status, atopy, and body mass index (BMI) as covariates. RESULTS: Initially, 18 SNPs and 4 haplotypes showed associations with AIA. However, after correcting the data for multiple testing, only one SNP showed an association with AIA (corrected P-value = 0.03, OR = 1.63, 95% CI = 1.23-2.16), showing increased susceptibility to AIA compared with that of ATA cases. Our findings suggest that FSIP1 gene might be a susceptibility gene for aspirin intolerance in asthmatics. CONCLUSION: Although our findings did not suggest that SNPs of FSIP1 had an effect on the reversibility of lung function abnormalities in AIA patients, they did show significant evidence of association between the variants in FSIP1 and AIA occurrence among asthmatics in a Korean population.