KR101172593B1 - SMAP1L gene polymorphism associated with asthma - Google Patents

Abstract

The present invention discloses that the SMAP1L gene polymorphism is associated with aspirin-sensitive asthma, and is used for predicting or diagnosing the possibility of developing aspirin-sensitive asthma.

Description

SMAP1L gene polymorphism associated with asthma

The present invention relates to SMAP1L gene polymorphisms associated with aspirin hypersensitivity asthma.

Asthma, caused by inflammation of the lungs, is triggered by interactions between genetic factors and environmental factors such as antigens. Aspirin-intolerant asthma refers to a clinical syndrome in which asthma patients show acute bronchial contraction after administration of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). This clinical syndrome has clinical symptoms such as eosinophilic rhinosinusitis, nasal polyposis, aspirin hypersensitivity and asthma. Aspirin-sensitive asthma patients account for 5-15% of asthma patients and are more likely to develop in women.

The inventors found a relationship between aspirin-sensitive asthma and stromal membrane-associated protein 1-like (SMAP1L) gene polymorphism. Or we will offer a variety of applications, including diagnostic kits and methods for providing information to predict or diagnose aspirin-sensitive asthma.

One aspect of the invention is selected within the SMAP1L (Stromal membrane-associated protein 1-like) genomic gene, set forth in SEQ ID NO: 77, is +32,831 from the translation start point (2,066 base of SEQ ID NO: 77), and C or T Provided is a polymorphic marker for predicting or diagnosing Aspirin Intolerant Asthma (AIA) comprising a polynucleotide consisting of 20-100 consecutive nucleotides including a phosphorus base (rs2982510C> T).

Another aspect of the invention is selected within the Smalmal membrane-associated protein 1-like (SMAP1L) genomic gene, set forth in SEQ ID NO: 77, is + 40,160th from the translation start point (2,066th base of SEQ ID NO: 77), T or Provided is a polymorphic marker for predicting or diagnosing Aspirin Intolerant Asthma (AIA) comprising a polynucleotide consisting of 20-100 contiguous nucleotides comprising a base that is G (rs2294752T> G).

Another aspect of the present invention provides a kit for predicting or diagnosing aspirin-sensitive asthma, including a primer capable of amplifying the aspirin-sensitive asthma predictive or diagnostic polymorphic marker.

Another aspect of the present invention provides an aspirin-sensitive asthma diagnosis kit comprising a probe capable of detecting the aspirin-sensitive asthma predictive or diagnostic polymorphic marker.

Another aspect of the present invention comprises the steps of extracting genomic DNA from a blood sample isolated from the subject; Detecting the polymorphic marker present on the genomic DNA extracted in the step; The present invention provides a method for providing information for predicting or diagnosing aspirin-sensitive asthma, including comparing the polymorphic marker detection result obtained in the step with the polymorphic site detection result of the normal group.

The present inventors have confirmed that the SMAP1L gene polymorphism is closely associated with aspirin-sensitive asthma, and this association can be usefully used for predicting or diagnosing aspirin-sensitive asthma. For example, a polynucleotide comprising the SMAP1L gene polymorphism site can be used for aspirin hypersensitivity asthma prediction or diagnostic polymorphism markers, and aspirin hypersensitivity asthma prediction including a primer capable of amplifying the polymorphic marker or a detectable probe Or as a diagnostic kit. It can also be used to provide information for predicting or diagnosing aspirin-sensitive asthma.

1 to 3 show maps, haplotypes, and LDs of the SMAP1L gene.
1 is a schematic genetic map and SNP (single nucleotide polymorphism) of the SMAP1L gene on chromosome 1p35.3-p34.1. Black blocks represent coding exons and white blocks represent 5'UTR and 3'UTR. UTR refers to the untranslated region and the first nucleotide of the translation site is referred to as +1.
2 is a haplotype of the SMAP1L gene.
3 is the LD coefficient (| D '|) of the SMAP1L SNP.

Asthma is known to be caused not only by smooth muscle dysfunction but also by new airway remodeling of asthma development, specifically airway inflammatory responses. Moreover, altered transport and lost airway reactivity are responsible for allergic airway remodeling.

The number of intracellular signaling proteins is responsible for the inflammatory processes involved in asthma development, and these proteins are targets for the treatment of asthma. Several factors involved in the inflammatory response are related to protein invasion of the airways that interferes with the action of surfactants. When asthma interferes with the cellular storage capacity and physical activity of alveolar surfactants, their synthesis is hindered.

Alveolar type II (ATII) cells synthesize alveolar surfactant, which is an interfacial-active lipoprotein complex. Many hormones, pharmaceutical agents and physiochemical elements are known to increase or decrease alveolar surfactants in ATII cells. Endositosis in ATII cells is associated with the recycling of related protein lamellar bodies (LB) or uptake of surfactant in the extracellular space. In particular, this relates to the absorption of surfactants that depend on clathrin.

On the other hand, Ca ^{2 +} may be associated with endocytosis in endothelial cell type, the Ca ^{2 +} is mediated protein complexing to start the accumulation of Cloud trim in different cell types. In addition, Ca ^{2 +} concentration change in the epithelial cell plasma membrane protein composition is adjusted by controlling the endocytosis. Ca ^{2 +} concentration in the cell ATⅡ rise yen, as well as trigger the SAT SOCIETE sheath (exocytosis), matseonda the endocytosis mechanism. After ATⅡ cells respond to physical apryeokreul feel, Ca ^{+ 2-dependent} surface-active substance release. These facts indicate that disruption of endocytosis disrupts the function of surfactant materials.

SMAP1L (stromal membrane-associated protein 1 like), also known as SMAP2, exhibits GAP (GTPase-activating protein) activity and interacts with clathrin heavy chain and clathrin assembly lymphoid-myeloid (CALM). SMAP1L is co-lacalized with adapter proteins for clathrin AP-1 and EpsinR in the early endosomal / trans-Golgi network (TGN). SMAP1L overexpression also delays the accumulation of TGN38 / 46 molecules in TGN. This fact indicates that SMAP1L acts on the early endosomal-TGN pathway in clathrin- and AP-1-dependent methods.

The SMAP1L gene is a homologue of SMAP1, recently discovered, and its function and mechanism are not exactly known. It is associated with endocytosis and plays an important role in the secretion of molecules associated with various diseases, such as asthma. Specifically, the SMAP1L gene interacts directly with clathrin and regulates clathrin-dependent endocytosis of the transferrin receptor in the plasma membrane. Given the direct interaction of clathrin with SMAP1L, the SMAP1L polymorphism is believed to be related to asthma and its phenotypes, such as aspirin-sensitive asthma.

The present invention reveals that the SMAP1L gene polymorphism is associated with aspirin-sensitive asthma, and thus provides a polymorphic marker for predicting or diagnosing aspirin-sensitive asthma including the SMAP1L gene polymorphism marker. Another aspect of the invention provides a polymorphic marker for aspirin hypersensitivity asthma prediction or diagnosis comprising a polynucleotide comprising a SMAP1L gene polymorphism marker.

The inventors obtained SMAP1L genomic sequence (Accession No. NT_032977.9) from the National Center for Biotechnology Information (build 36).

In one aspect of the invention, the SMAP1L gene polymorphism marker is selected from within the SMAP1L (Stromal membrane-associated protein 1-like) genomic gene as set forth in SEQ ID NO: 77, and from the translation start point (2,066 base of SEQ ID NO: 77) And a base (rs2982510C> T) which is 32,831 th and C or T.

In one aspect of the invention, the SMAP1L gene polymorphism marker is selected from within the SMAP1L (Stromal membrane-associated protein 1-like) genomic gene as set forth in SEQ ID NO: 77, and from the translation start point (2,066 base of SEQ ID NO: 77) 40th and 160th, and may include a base (rs2294752T> G) that is T or G.

In one aspect of the invention, the polynucleotide comprising the SMAP1L gene polymorphism marker is selected within the SMAP1L (Stromal membrane-associated protein 1-like) genomic gene as set forth in SEQ ID NO: 77, and the translation start point (2,066 of SEQ ID NO: 77). The base is +32,831 from the base) and includes a base (rs2982510C> T) that is C or T or a base that is +40,160 from the start of translation (2,066 base in SEQ ID NO: 77) and a T or G (rs2294752T> G) It may contain 20-100 consecutive nucleotides. In another aspect of the invention the polynucleotide is selected from within the SMAP1L (Stromal membrane-associated protein 1-like) genomic gene, set forth in SEQ ID NO: 77, and +32,831 from the translation start point (2,066 base of SEQ ID NO: 77) 20-30 contiguous nucleotides comprising a base that is C or T (rs2982510C> T) or a + 40,160th base from the translation start point (2,066 base in SEQ ID NO: 77) and a base that is T or G (rs2294752T> G) It may include.

One aspect of the invention provides a composition for predicting or diagnosing aspirin hypersensitivity asthma comprising the polymorphic marker. Another aspect of the invention provides a medical or pharmaceutical composition for predicting or diagnosing aspirin-sensitive asthma comprising the polymorphic marker.

The present invention provides a kit for aspirin hypersensitivity asthma prediction or diagnosis comprising a primer capable of amplifying the SMAP1L gene polymorphism marker.

In one aspect of the invention, the primers in the kit used to amplify the SMAP1L gene polymorphism may include any that can amplify the SMAP1L gene polymorphism. In another aspect of the present invention, the primer in the kit used to amplify the SMAP1L gene polymorphism may be one or more of the nucleotide sequences set forth in SEQ ID NOs: 1 to 76, but is not limited thereto.

In another aspect of the invention, the aspirin-sensitive asthma prediction or diagnostic kit may further comprise a primer used to amplify another single base polymorphism (SNP). In another aspect of the invention, the kit may further comprise instructions describing how to use the polymorphic marker.

In one aspect of the invention, the aspirin-sensitive asthma prediction or diagnostic kit may comprise a probe (probe) that can detect the polymorphic marker. In another aspect of the present invention, the probe capable of detecting the polymorphic marker may be one or more of the nucleotide sequences set forth in SEQ ID NOs: 1 to 76, but is not limited thereto.

One aspect of the invention comprises the steps of extracting genomic DNA from a blood sample isolated from the subject; Detecting the polymorphic marker present on the genomic DNA extracted in the step; The present invention provides a method for providing information for predicting or diagnosing aspirin-sensitive asthma, including comparing the polymorphic marker detection result obtained in the step with the polymorphic site detection result of the normal group.

In one aspect of the present invention, a method for providing information for predicting or diagnosing aspirin-sensitive asthma may obtain DNA of a subject from all possible sources such as blood, saliva, hair, and skin of the subject.

In one aspect of the present invention, the method for providing information for predicting or diagnosing aspirin-sensitive asthma may include extracting genomic DNA from a blood sample.

In one aspect of the present invention, in the method for providing information for predicting or diagnosing aspirin-sensitive asthma, detecting the polymorphic marker may include sequencing analysis, hybridization by microarray, and allele specific PCR. ), Dynamic allele-specific hybridization (DASH), PCR extension analysis, and TaqMan technique, but are not limited thereto. The methods can use conventional methods for sequencing and can be performed using an automated genetic analyzer.

In a method of providing information for predicting or diagnosing aspirin-sensitive asthma in one aspect of the present invention, comparing the polymorphic marker detection result with the detection of the polymorphic site of the normal group in a conventional comparison method, for example, a statistical method. It may be, but is not limited to.

Another aspect of the present invention provides a composition for inhibiting or treating aspirin-sensitive asthma including the SMAP1L gene polymorphism expression promoter or inhibitor as an active ingredient. In a composition for inhibiting or treating aspirin-sensitive asthma containing the SMAP1L gene polymorphism expression promoter as an active ingredient, the promoter generally includes all substances capable of promoting the expression of the SMAP1L gene polymorphism. In a composition for inhibiting or treating aspirin-sensitized asthma comprising the SMAP1L gene polymorphism expression inhibitor as an active ingredient, the inhibitor generally includes all substances capable of inhibiting the expression of the SMAP1L gene polymorphism. The materials can be extracted from natural products or artificially synthesized, for example.

In another aspect of the present invention, the composition for inhibiting or treating aspirin-sensitized asthma may be added to pharmaceutical supplements such as preservatives, stabilizers, hydrates or emulsifiers, salts and / or buffers for controlling osmotic pressure, and other therapeutically useful substances. And may be formulated in various oral or parenteral dosage forms according to conventional methods. In addition, the pharmaceutically acceptable dose, ie dosage, of the active ingredient will vary depending on the age, sex, weight of the subject to be treated, the particular disease or pathology to be treated, the severity of the disease or pathology, the route of administration and the judgment of the prescriber. will be. Dosage determination based on these factors is within the level of skill in the art.

Another aspect of the present invention provides a method for screening a composition for inhibiting or treating aspirin-sensitive asthma, including confirming whether a test substance promotes or inhibits expression of the SMAP1L gene polymorphism. In the screening method for inhibiting or treating aspirin-sensitive asthma, the test substance includes all substances that are likely to be used as compositions for inhibiting or treating aspirin-sensitive asthma. In another aspect of the invention, the screening method may further comprise the step of treating, binding or reacting the test substance to the SMAP1L gene polymorphism in a conventional manner in the art. In another aspect of the screening method of the present invention, when the test substance promotes or inhibits the expression of the SMAP1L gene polymorphism, the method may further include determining that it is usable as a composition for inhibiting or treating aspirin-sensitive asthma. In another aspect of the screening method of the present invention, when the test substance inhibits or promotes expression of the SMAP1L gene polymorphism, the data may be used as an adjuvant judgment data on the availability of the aspirin-sensitive asthma inhibitor or its therapeutic composition. have.

In one aspect of the present invention, since the SMAP1L gene polymorphism is closely related to the development of aspirin-sensitive asthma, in addition to the above, it is possible to apply it to various inventions for predicting, diagnosing, regulating, and controlling aspirin-sensitive asthma. .

In one aspect of the invention, the aspirin hypersensitivity asthma prediction or diagnostic polymorphism markers, aspirin hypersensitivity asthma prediction or diagnostic kit comprising a primer or a probe that can amplify the polymorphic marker, aspirin hypersensitivity asthma prediction or diagnosis Methods for providing hazard information, compositions for inhibiting or treating aspirin-sensitive asthma and screening compositions for inhibiting or treating aspirin-sensitive asthma are applicable to humans as well as animals. That is, the object of application of the present invention may be an animal or a human.

Hereinafter, the configuration and effects of the present invention will be described in more detail with reference to test examples. However, these test examples are provided only for the purpose of illustration to help the understanding of the present invention is not limited to the scope and scope of the present invention.

[Test Example]

1. Selection and analysis of test target

A total of 592 subjects were selected for this test. All of these subjects were diagnosed with asthma according to GINA criteria. Each patient had an increased expiratory volume of FEV ₁ by more than 15% for one second with bronchodilator inhalation and / or overreacted to stimulating concentrations of P20 methacholine. Patients with hypertension / diabetes and those taking angiotensin converting enzyme (ACE) inhibitors were excluded. Of the subjects, the test group (163 patients) were diagnosed as aspirin-sensitive asthma patients among asthmatic patients, and the control group (429 patients) were asthmatic patients diagnosed as not aspirin-sensitive. Their characteristics are summarized in Table 1 below.

all Test group Control group Number of people 592 163 429 Age of onset (average) 46.15 43.13 * 47.30 Gender (male / female) 206/386 59/104 147/282 Weight (kg) 62.81 ± 0.84 61.25 ± 0.38 63.40 ± 0.97 % Of smokers 27.70 21.47 * 30.07 FEV ₁ Decrease After Aspirin Dosing 9.27 ± 13.24 24.63 ± 16.11 ** 3.54 ± 4.85 Blood Eosinophil (%) 6.01 ± 5.73 5.96 ± 5.21 6.03 ± 5.92 FEV ₁ (% predicted) 90.54 ± 6.97 90.35 ± 14.04 * 91.66 ± 16.87 PC20 Methacholine (mg / ml) 6.43 ± 8.67 5.02 ± 7.83 * 6.91 ± 8.90 Total IgE (IU / ml) 357.65 ± 604.09 348.60 ± 596.44 361.00 ± 607.56 Skin test positive rate (%) 56.42 52.76 57.81

* P <0.05, ** P <0.0001 (vs. control)

As shown in Table 1, the percent decrease in FEV ₁ after the administration of aspirin in the test group was higher than that of the control group (P <0.0001). There were also differences between the two groups in terms of age of onset, body weight, predicted FEV ₁ %, and PC20 methacholine and smoker rates.

2. Identification of single nucleotide polymorphism (SNP) and genotyping

(1) Distribution of SMAP1L Mutations

SMAP1L SNP genotypes of subjects of the National Center for Biotechnology Information (build 36) were determined. Genomic DNA was extracted using the Gentra Puregene kit (Minneapolis, Minn.) According to the manufacturer's protocol. Genotyping was performed with 20 ng of genomic DNA using a TaqMan assay in an ABI prism 7900HT sequence detection system (Biosystems, Calif., USA). Genotyping data was obtained using ABI-PRISM Sequence Detection System (SDS) software version 2.3. The genotyping quality of the retention data was set at 0.25. In the SMAP1L, genotypes of 19 SNPs were determined using a Golden Gate assay with the probe sequences of Table 2. Golden gate analysis is performed by extending and ligation of alleles, amplifying with primers and hybridizing to Universal IlluminaCode Assay.

Genotype results of a total of 19 SNPs determined by SMAP1L are shown in Table 3 below.

SNP ID Allele location frequency Release Bondability HWE rs209573 C> G Promoter 0.304 0.423 0.313 rs1391315 T> G Intron 1 0.132 0.229 0.513 rs209584 A> G Intron 1 0.082 0.151 0.900 rs383228 A> C Intron 1 0.304 0.423 0.313 rs12566885 A> G Intron 1 0.090 0.164 0.131 rs209598 G> A Intron 1 0.340 0.449 0.180 rs4660407 G> C Intron 1 0.169 0.281 0.250 rs2982506 G> A Intron 1 0.060 0.113 0.593 rs393985 A> G Intron 1 0.171 0.283 0.935 rs16827275 C> T Intron 1 0.124 0.217 0.827 rs16827276 C> T Intron 1 0.132 0.229 0.513 rs2982510 C> T Intron 2 0.309 0.427 0.682 rs4660409 C> T Intron 4 0.151 0.256 0.394 rs16827291 G> A Intron 4 0.309 0.427 0.332 rs12068474 C> T Intron 5 0.091 0.166 0.123 rs2294752 T> G Intron 6 0.311 0.428 0.770 rs2294755 C> T Intron 6 0.172 0.284 0.897 rs446738 T> A Intron 9 0.391 0.476 0.802 rs11208057 A> G Intron 9 0.310 0.428 0.350

HWE: Hardy-Weinberg Equilibrium.

As can be seen in Figure 1 and Table 3, only one SNP (rs209573) was located in the promoter region, the rest was located in the intron region. All locus genotype distributions were in the Hardy-Weinberg Equilibrium (P> 0.05). Each haplotype was inferred using the algorithm of PHASE (version 2.0) to select six haplotypes with frequencies greater than 0.5 for analysis. This is shown in FIG. Linkage disequilibrium (LD) coefficients (| D |) and r ² between SMAP1L polymorphisms are calculated for all subjects and are shown in FIG. 3.

As can be seen in Figure 1 and Table 3, two sets of SNPs (rs2982510C> T, rs2294752T> G) in SMAP1L are the absolute LD (| D | = 1 and r ² = 1).

(2) Relationship between polymorphism and aspirin-sensitive asthma

Multiple logistic assays were used to analyze 19 SNPs and 6 haplotypes in SMAP1L between test and control groups. At this time, age, sex, smoking status, and atopy were used as empty variables. The results are shown in Table 4 below.

* P values are logistic analysis with gender, smoking status and atopy adjusted as covariates. ** P values are corrected by complex tests using SNPSpD software.

MAF: minor allel frequency; OR: odds ratio; CI: confidence interval; P corr: calibrated P value

As can be seen in Table 4, two single base polymorphisms (rs2982510 and rs2294752) were significant in the recessive model. The minor allele frequencies (MAF) of rs2982510 and rs2294752 were lower in aspirin-sensitive asthma patients than in aspirin-resistant asthma patients (ATA). In other words, two polymorphisms of rs2982510 and rs2294752 were associated with aspirin-sensitive asthma.

(3) Relationship between polymorphism and decline in FEV ₁ after aspirin dosing

Since a decrease in FEV ₁ after aspirin dosing is an important diagnostic marker for aspirin-sensitive asthma, a regression analysis of the relationship between genotype or haplotype and FEV ₁ drop after SNP and aspirin dosing was performed. The results are shown in Table 5 below.

* P values in regression analysis are co-dominant (Pa), dominant (Pb) and recessive (Pc) values with covariates of gender, smoking status, and atopy, and ** P values are combined using SNPSpD software. The value corrected by the test.

* C / C, C / R and C / R mean homozygotes of common alleles, heterozygous and homozygotes of rare alleles.

As shown in Table 5, it can be seen that the two SNPs (rs2982510 and rs2294752) are associated with the percent decrease in FEV ₁ after aspirin dosing. Asthmatic patients with rs2982510 and / or rs2294752 minor allelic homozygotes showed lower FEV ₁ after dosing aspirin compared to patients with heterozygotes or major allelic homozygotes. On the other hand, the decline in FEV ₁ and the haplotype did not appear to be related.

3. Statistical Method

Lewontin's D '(| D' |) and LD coefficient r ² were calculated between all pairs of alleles. Linkage disequilibrium (LD) was obtained using Haploview v4.1, downloaded from the Broad Institute (http://www.broadinstitute.org/mpg/haploview). Haplotypes were first measured using PHASE software and then logistically analyzed using SAS version 9.1 (SAS Inc., Cary, NC). Subjects without genotype were excluded from SNP and haplotype analysis. Genotype and haplotype distributions include age (continuous value), gender (male = 0, female = 1), smoking status (non-smoker = 0, former smoker = 1, smoker = 2), atopy (none = 0, present = 1) ) And body mass index (BMI) were analyzed by logistic analysis. The difference in FEV ₁ drop after aspirin dosing between genotype and haplotype was calculated using a linear regression model. The data was also analyzed using SAS version 9.1. The significant number of independent marker loci for each gene was calculated by multi-testing calibration using SNPSpD (http://genepi.qimr.edu.au/general/daleN/SNPSpD/) software, which is a pair-wise pairing between SNPs. ) Is based on the spectral decomposition (SpD) of the matrix of associative imbalance (LD).

The results indicate that SNPs associated with aspirin-sensitive asthma are located in introns 2 and 6. This indicates that intron regions can also affect overall transcription in other ways. Recently, it has been known that intron regions can affect transcription, and mutations in intron regions can lead to abnormal splicing and even cause disease. It is also known that SNPs in the intron region may be associated with asthma. Thus, rs2982510 and rs2294752 of the SMAP1L gene may affect the development of aspirin-sensitive asthma by affecting the transcriptional process.

Attach an electronic file to a sequence list

Claims (5)

delete delete Selected from within the SMAP1L (Stromal membrane-associated protein 1-like) genomic gene, set forth in SEQ ID NO: 77,
A base of +32,831, C or T (rs2982510C> T) from the translation start point (2,066 base of SEQ ID NO: 77); Or a polymorphic marker comprising a polynucleotide consisting of 20-100 contiguous nucleotides comprising a base (rs2294752T> G) that is +40,160 th from the translation start point (2,066 base in SEQ ID NO: 77) and is T or G (rs2294752T> G).
Aspirin Intolerant Asthma (AIA) prediction or diagnostic kit comprising a primer that can be amplified. Selected from within the SMAP1L (Stromal membrane-associated protein 1-like) genomic gene, set forth in SEQ ID NO: 77,
A base of +32,831, C or T (rs2982510C> T) from the translation start point (2,066 base of SEQ ID NO: 77); Or a polymorphic marker comprising a polynucleotide consisting of 20-100 contiguous nucleotides comprising a base (rs2294752T> G) that is +40,160 th from the translation start point (2,066 base in SEQ ID NO: 77) and is T or G (rs2294752T> G).
Aspirin hypersensitivity asthma prediction or diagnostic kit comprising a detectable probe (probe). Extracting genomic DNA from blood samples isolated from the subject;
Present on the genomic DNA extracted in the step
Selected from within the SMAP1L (Stromal membrane-associated protein 1-like) genomic gene, set forth in SEQ ID NO: 77
A base of +32,831, C or T (rs2982510C> T) from the translation start point (2,066 base of SEQ ID NO: 77); Or predicting aspirin-sensitive asthma including a polynucleotide consisting of 20-100 contiguous nucleotides comprising a base that is at +40,160 from the start of translation (the 2,066 base of SEQ ID NO: 77) and the base is T or G (rs2294752T> G) or Detecting a diagnostic polymorphic marker; And
A method for providing information for predicting or diagnosing aspirin-sensitive asthma, comprising comparing a polymorphic marker detection result obtained in the step with a polymorphic site detection result of a normal group.

Images