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.     

Cysteinyl leukotriene receptor 1 promoter polymorphism is associated with aspirin-intolerant asthma in males

BACKGROUND: Cysteinyl leukotrienes (CysLTs) play important roles in the pathogenesis of eosinophilic airway inflammation characterized by bronchoconstriction, mucus secretion and airway hyper-responsiveness via cysteinyl leukotriene receptor 1 (CysLTR1)-mediated mechanism. CysLTR1-selective antagonists have anti-bronchoconstrictive and anti-inflammatory effects in asthma, particularly aspirin-intolerant asthma (AIA). METHODS: To investigate the association of CysLTR1 with AIA development, we identified three single nucleotide polymorphisms (SNPs), -634C>T, -475A>C, -336A>G, in the 5' upstream region of CysLTR1 gene using a direct sequencing method in 105 AIA patients, 110 ASA-tolerant asthma (ATA) patients and 125 normal healthy controls (NC). RESULTS: Significant differences were observed in allele frequencies of the three SNPs within male subjects; Male AIA patients had higher frequencies of the minor alleles of these three SNPs than male control groups (P=0.03 for AIA vs. NC; P=0.02 for AIA vs. ATA). Moreover, three-SNP haplotype, ht2 [T-C-G], was associated with increased disease risk (odds ratio (OR)=2.71, P=0.03 for AIA vs. NC; OR=2.89, P=0.02 for AIA vs. ATA) in males. CysLTR1 haplotypes were also associated with altered gene expression; luciferase activity was significantly enhanced with the ht2 [T-C-G] construct in comparison with the ht1 [C-A-A] construct in human Jurkat cells (P=0.04). CONCLUSION: These results suggest that genetic variants of CysLTR1 are associated with AIA in a Korean population, and may modulate CysLTR1 expression.     

Effects of pranlukast on aspirin-induced bronchoconstriction: differences in chemical mediators between aspirin-intolerant and tolerant asthmatic patients.

BACKGROUND: Aspirin inhibits cyclooxygenase activity and modifies production of the arachidonate cascade in aspirin-induced asthma. The aim of the present study was to examine the effects of leukotriene (LT) receptor antagonist on aspirin challenge on eosinophil activity and chemical mediators released into the airway of asthmatic patients. METHODS: Aspirin oral provocation test was performed in aspirin-intolerant asthmatic patients (AIA; N = 7) and aspirin-tolerant asthmatic patients (ATA; N = 7). In AIA, LT receptor antagonist (pranlukast) was administered orally 2 hours before the test, and its inhibitory effects on sputum LTC4+C4, eosinophil cationic protein (ECP), eosinophil count, urinary LTE4/creatinine (Cr), 11-dehydrothromboxane (11-dhTX) B2/Cr, serum LTC4+D4, ECP, and peripheral blood eosinophil count were compared with the findings in ATA subjects. RESULTS: In AIA, aspirin induced an immediate reaction associated with increased urinary LTE4/Cr and sputum ECP and a fall in urinary 11-dhTXB2/Cr. Pranlukast inhibited the bronchial reaction and an increase in sputum ECP after threshold dosed of ASA, but failed to change aspirin-induced LT production in sputum and urine. In ATA, aspirin challenge was only associated with a fall in urinary 11-dhTXB2. CONCLUSIONS: Our results indicated that aspirin-induced asthma is associated with overproduction of LT with a shift to the 5-lipoxygenase series of the arachidonate cascade and that leukotriene receptor antagonist are useful for AIA through inhibition of production of LT and eosinophilic inflammation in the airway.     

Genetic variability of prostaglandin E2 receptor subtype EP4 gene in aspirin-intolerant chronic urticaria

Prostaglandin E2 receptor subtype EP4 (PTGER4) is one of the four subtypes of receptors for prostaglandin E2 (PGE2). Overproduction of cysteinyl leukotriene in mast cells may be related with suppression of PGE2 in patients with aspirin hypersensitivity. Considering the association of PTGER4 in mast cells, urticaria- and aspirin-related disease, we hypothesized the genetic variability of PTGER4 may be associated with aspirin-intolerant chronic urticaria (AICU). The case-control study was performed in 141 with AICU, 153 with aspirin-tolerant chronic urticaria (ATCU) and 174 with normal controls (NCs). PTGER4 promoter single-nucleotide polymorphism was genotyped using a primer extension method with the SNAPshot ddNTP primer extension kit. The functional variability of PTGER4 promoter polymorphism was carried out by dual-luciferase system and electrophoretic mobility shift assay (EMSA) in human mast cells (HMC-1). Furthermore, the effect of aspirin was performed for PTGER4 mRNA expression using real-time PCR, and PGE2 production was checked in HMC-1 cells using ELISA. AICU patients carrying GG genotype at -1254?G>A showed significantly higher frequency compared with NC (P=0.032). Similarly, the minor allele frequency, G allele was significantly higher in AICU compared with NC (P=0.031). In vitro functional study demonstrated that the -1254?G allele had lower luciferase activity (P<0.001) in HMC-1 cells. EMSA finding showed that PTGER4 -1254?G produced a specific band. Significantly decreased PTGER4 expression (P=0.008) and PGE2 production by aspirin exposure was confirmed in in vitro HMC cell line model (P=0.001). The PTGER4 -1254?G allele demonstrated a higher frequency in AICU patients and lower promoter activity with decreased expression of PTGER4 and contributes to the development of AICU.     

The role of LTA4H and ALOX5AP polymorphism in asthma and allergy susceptibility

Background: Leukotrienes (LTs) have been identified as central mediators in asthma and allergy. Pharmacological inhibition of cysteinyl‐LT activity improves asthma symptoms and control. Accumulating evidence suggests a role for the dihydroxy leukotriene LTB₄ in airway disease. LTA₄ hydrolase and 5‐lipoxygenase activating protein have key roles in LTB₄ production. Single nucleotide polymorphism (SNPs) and haplotypes spanning the LTA4H and ALOX5AP genes have been associated with LTB₄ production and myocardial infarction (MI). Objective: To assess the contribution of LTA4H and ALOX5AP polymorphism to asthma and allergy susceptibility. Methods: Three hundred and forty‐one Caucasian families (two asthmatic siblings) were genotyped for eight SNPs spanning ALOX5AP and five SNPs spanning LTA4H. Association analyses of asthma and related phenotypes (total IgE, atopy, bronchial hyper‐responsiveness, FEV₁) were undertaken using the Family Based Association Test. Results: Single point analyses identified association (P < 0.05) between SNPs SG13S114, SG13S89, SG13S41 (ALOX5AP), rs1978331 (LTA4H) and asthma and/or related phenotypes. Haplotype analyses using all LTA4H SNPs identified a single key risk haplotype for the development of asthma (P = 0.006) and related phenotypes (P = 0.042–0.005). Haplotype analyses using all ALOX5AP SNPs identified several asthma and atopy risk and protective haplotypes. There was limited correlation with previously identified MI risk haplotypes in both genes. Carriers of both ALOX5AP SG13S41 and LTA4H rs1978331 alleles had an increased risk of developing asthma (OR 2.17, CI 1.41–3.32). Conclusions: These data provide evidence for the role of SNPs spanning the ALOX5AP and LTA4H genes in asthma and atopy susceptibility in the Caucasian population and support a role for LTB₄ in disease pathogenesis.     

Polymorphisms of Aspirin-Metabolizing Enzymes CYP2C9, NAT2 and UGT1A6 in Aspirin-Intolerant Urticaria

Acetyl salicylic acid (ASA) is metabolized by UDP-glucuronosyltransferase 1A6 (UGT1A6), cytochrome P4502C9 (CYP2C9), and N-acetyl transferase 2 (NAT2). Variations in the activities of these enzymes may modulate adverse ASA-related symptoms such as urticaria. We examined whether polymorphisms in the UGT1A6, CYP2C9, and NAT2 genes are related to ASA-intolerant urticaria (AIU). The genotypes of 148 subjects with AIU (AIU group) and 260 normal healthy control subjects (NC group) were analyzed with respect to the following single nucleotide polymorphisms: CYP2C9 -1188T>C and CYP2C9(*)3A1075C; UGT1A6 T181A A>G and UGT1A6 R184S A>C; and NAT2 9796A>T, NAT2 197G>A, NAT2 286G>A, NAT2 9601A>G, and NAT2 9306A>G. There were significant differences in the allele frequencies for the CYP2C9 polymorphisms between the two groups. The frequency of the minor allele CYP2C9 -1188T>C was significantly higher in the AIU group than in the NC group (P=0.005). The frequency of the variant genotype CC was higher in the AIU group compared with the controls in both the co-dominant (P=0.007) and recessive models (P=0.012). The frequency of haplotype 2 [CA] was also significantly higher in the AIU group in both the co-dominant (P=0.006) and dominant models (P=0.012). There was no significant difference in genotype frequencies for any of the UGT1A6 or NAT2 polymorphisms between the two groups. Clinical parameters did not differ according to genotype. These results suggest that the C allele of CYP2C9 -1188T>C may be associated with AIU.     

A polymorphism of MS4A2 (−109T>C) encoding the β-chain of the high-affinity immunoglobulin E receptor (FcɛR1β) is associated with a susceptibility to aspirin-intolerant asthma

BACKGROUND AND OBJECTIVE: The MS4A2 gene, the beta chain of the high-affinity receptor for immunoglobulin (Ig)E, has previously been linked to atopy and asthma. The beta-chain of FcepsilonR1 enhances receptor maturation and signal transduction capacity, leading to the release of proinflammatory mediators and cytokines that can exacerbate the symptom of asthma. This study was performed to evaluate whether two genetic polymorphisms of the FcepsilonR1beta gene (FcepsilonR1beta-109T > C and FcepsilonR1beta E237G) are associated with aspirin-intolerant asthma (AIA). The MS4A2 gene polymorphisms (FcepsilonR1beta-109T > C and FcepsilonR1beta E237G) were determined by SNP-IT assays in patients with AIA (N = 164), aspirin-tolerant asthma (ATA, N = 144) and normal controls (NC, N = 264) recruited from a Korean population. RESULTS: The genotype frequencies of FcepsilonR1beta-109T > C and E237G polymorphisms were not significantly associated with the pathogenesis of AIA. However, FcepsilonR1beta-109T > C polymorphism was significantly associated with the presence of specific IgE to Staphylococcal enterotoxin B (SEB); the number of subjects carrying both homozygous TT genotype of FcepsilonR1beta-109T > C and specific IgE to SEB was significantly higher in the AIA group when compared with the other control groups (P = 0.01, odds ratio (OR) = 7.723, 95% confidence interval (CI) = 1.327-39.860 for AIA vs. ATA; P = 0.02, OR = 6.364, 95% CI = 1.149 approximately 35.229 for AIA vs. NC). In addition, luciferase reporter assays also showed that the FcepsilonR1beta-109T allele was associated with higher promoter activity of MS4A2 in both RBL-2H3 and A549 cell lines. CONCLUSION: FcepsilonR1beta-109T > C polymorphism may increase expression of MS4A2 by mast cells, leading to enhanced release of proinflammatory mediators in the asthmatic airway, contributing to increased susceptibility to AIA.     

Genetic mechanism of aspirin-induced urticaria/angioedema

PURPOSE OF REVIEW: Aspirin-induced urticaria/angioedema is a major aspirin-related hypersensitivity often associated with aspirin-intolerant asthma. Genetic studies on aspirin-intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes. The genetic analysis of aspirin-induced urticaria/angioedema is limited, however. RECENT FINDINGS: A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin-induced urticaria/angioedema. A polymorphism study that examined nine single-nucleotide polymorphisms of five leukotriene-related genes [ALOX5 (encoding 5-lipoxygenase), ALOX5AP (5-lipoxygenase-activating protein), PTGS2 (cyclooxygenase 2), LTC4S (leukotriene C4 synthase), and CYSLTR1 (cysteinyl leukotriene receptor 1)] found that promoter polymorphisms of ALOX5 (-1708A>G) and CYSLTR1 (-634C>T) were significantly different between aspirin-intolerant asthma and aspirin-induced urticaria/angioedema, suggesting different contributions to the lipoxygenase pathway. A second polymorphism study, conducted on histamine-related genes, did not find any significant associations with aspirin-induced urticaria/angioedema for the genes HNMT (encoding histamine N-methyltransferase), HRH1 or HRH2 (encoding histamine receptor types 1 and 2 respectively), or the gene encoding high-affinity IgE receptor Ibeta (FcepsilonRIbeta); however, the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin-induced urticaria/angioedema. This finding has been supported by in vitro functional studies. SUMMARY: The HLA alleles DRB11302 and DQB10609, and the ALOX5 and FcepsilonRIalpha promoter polymorphisms, may contribute to the pathogenesis of aspirin-induced urticaria/angioedema. Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition.     

Increase in urinary leukotriene B4 glucuronide concentration in patients with aspirin-intolerant asthma after intravenous aspirin challenge

BACKGROUND: Aspirin challenge of aspirin-intolerant asthma (AIA) patients causes a significant increase in leukotriene E4 (LTE4) concentration in urine. However, knowledge on leukotriene B4 (LTB4) generation in patients with AIA is insufficient. Recent research has demonstrated that exogenously administered LTB4 is excreted as glucuronide into the urine in human healthy subjects. OBJECTIVE: The purpose of this study is to estimate urinary LTB4 glucuronide (LTBG) concentration in the clinically stable condition in healthy subjects and asthmatic patients and to investigate changes in urinary LTBG concentration in patients with AIA after aspirin challenge. METHODS: A provocation test was performed by intravenous aspirin challenge. After urine was hydrolysed by beta-glucuronidase, the fraction containing LTB4 was purified by high-performance liquid chromatography and LTB4 concentration was quantified by enzyme immunoassay. Urinary LTBG concentration was calculated as the difference between the concentration obtained with hydrolysis and that without hydrolysis. RESULTS: (1) After hydrolysis, the presence of urinary LTB4 was verified by gas chromatography-mass spectrometry-selected ion monitoring. (2) The urinary LTBG concentration was significantly higher in the asthmatic patients than in the healthy subjects (median, 5.37 pg/mg creatinine [range 1.2-13] vs. 3.32 pg/mg creatinine [range, 0.14-10.5], P = 0.0159). (3) The patients with AIA (n = 7), but not those with aspirin-tolerant asthma (n = 6), showed significant increases in LTBG and LTE4 excretions after aspirin challenge. (4) When the concentrations after aspirin challenge were analysed simultaneously, a significant linear correlation was observed between urinary LTBG concentration and urinary LTE4 concentration in patients with AIA (Spearman's rank correlation test, r = 0.817, P = 0.0003). CONCLUSION: LTBG is present in human urine, albeit at a concentration lower than urinary LTE4. In addition to a marked increase in cysteinyl-leukotriene production, aspirin challenge induced LTB4 production in AIA patients.     

ALOX5AP基因SG13S114A/T多态性与颈动脉粥样硬化斑块稳定性的相关性

目的 探讨花生四烯酸5-脂氧合酶激活蛋白(arachidonate 5-lipoxygenase acttvating protein,ALOX5AP)基因SG13S114 A/T的多态性与颈动脉粥样硬化斑块稳定程度的关系.方法 应用聚合酶链反应-限制性片段长度多态性分析法检测132例颈动脉易损斑块及152例稳定斑块的急性脑梗死者ALOX5AP基因SG13S114 A/T基因型,比较两组间该位点多态性的差异.结果 易损斑块组ALOX5AP基因SG13S114 AA基因型和A等位基因频率高于稳定斑块组,两组差异有统计学意义(P＜0.01),其中男性和女性上述基因型和等位基因频率的比较,易损斑块组均高于稳定斑块组,两组差异有统计学意义(P＜0.01).结论 ALOX5AP基因SG13S114 A/T多态性可能与动脉粥样斑块的稳定性有关,其中SG13S114 A等位基因可能是易损斑块的风险因素.     

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.     

Release of cysteinyl leukotrienes with aspirin stimulation and the effect of prostaglandin E2 on this release from peripheral blood leucocytes in aspirin-induced asthmatic patients

BACKGROUND: The decrease in prostaglandin E(2) (PGE(2)) release due to aspirin (ASA)-induced cyclooxygenase inhibition and the increment in cysteinyl leukotriene (Cys-LT) release secondary to the removal of the inhibitory effect of PGE(2) on Cys-LT release have been suggested in the pathogenesis of aspirin-induced asthma (AIA). OBJECTIVE: In this study, we aimed to investigate the in vitro release of Cys-LT and to determine the effect of PGE(2) on Cys-LT release from peripheral blood leucocytes of patients with AIA after stimulation by ASA. PATIENTS AND METHODS: Patients with AIA (n = 13), patients with ASA-tolerant asthma (ATA) (n = 12) and healthy volunteers as controls (n = 13) were included to the study. ASA and PGE2 at three different concentrations were applied to the peripheral blood leucocytes of the study group, and Cys-LT levels following stimulants were assessed by enzyme immunoassay method. RESULTS: There was no difference in baseline Cys-LT levels between groups (AIA 353.4 +/- 55.5 pg/mL, ATA 354.7 +/- 40.3 pg/mL, and control group 368.5 +/- 30.2 pg/mL; P > 0.05). Though not present in other groups, the Cys-LT level of 453.6 +/- 70.0 pg/mL following ASA stimulation was higher than baseline in patients with AIA (P = 0.04). When PGE(2) was added to the ASA-stimulated samples of patients with AIA, Cys-LT levels were measured as 298.7 +/- 78.6 pg/mL, 279.8 +/- 79.9 pg/mL, and 243.4 +/- 51.3 pg/mL at PGE(2) 10(-7) m, 10(-6) m and 10(-5) m concentrations, respectively. These levels were lower than the ASA-stimulated Cys-LT values (P = 0.03, P = 0.01 and P = 0.01, respectively). The inhibitory effect of different PGE(2) concentrations on Cys-LT release was also present in patients with ATA and in controls. CONCLUSION: The increase in Cys-LT levels following ASA stimulation seems to be unique to AIA, which was not present in patients with ATA and in healthy controls. The inhibitory effect of PGE(2) on stimulated Cys-LT levels is another important finding to elucidate the role of PGE(2) in the pathogenesis of AIA.     

Possible involvement of mast-cell activation in aspirin provocation of aspirin-induced asthma

BACKGROUND: Although there is increasing evidence of the importance of cysteinyl leukotrienes (LT) as mediators of aspirin-induced bronchoconstriction in aspirin-sensitive asthma, the cellular origin of the LT is not yet clear. METHODS: Urinary concentrations of leukotriene E4 (LTE4), 11-dehydrothromboxane B2, 9alpha,11beta-prostaglandin F2, and Ntau-methylhistamine were measured during the 24 h following cumulative intravenous administration of increasing doses of lysine aspirin to asthmatic patients. In addition, the urinary concentrations of these metabolites were measured on 5 consecutive days in a patient who suffered an asthma attack after percutaneous administration of nonsteroidal anti-inflammatory drugs. RESULTS: In aspirin-induced asthma patients (AIA, n=10), the basal concentration of urinary LTE4, but not the other metabolites, was significantly higher than that in aspirin-tolerant asthma patients (ATA, n=10). After intravenous aspirin provocation, the AIA group showed a 13.1-fold (geometric mean) increase in excretion of LTE4 during the first 3 h, and 9alpha,11beta-prostaglandin F2 also increased in the AIA group during the first 0-3 h and the 3-6 h collection period. Ntau-methylhistamine excretion was also increased, but to a lesser degree. Administration of aspirin caused significant suppression of 11-dehydrothromboxane B2 excretion in both the AIA and ATA groups. When the percentage of maximum increase of each metabolite from the baseline concentrations was compared between the AIA group and the ATA group, a significantly higher increase in excretion of LTE4, 9alpha,11beta-prostaglandin F2, and Ntau-methylhistamine was observed in the AIA group than the ATA group. An increased excretion of LTE4 and 9alpha,11beta-prostaglandin F2 has been detected in a patient who suffered an asthma attack after percutaneous administration of nonsteroidal anti-inflammatory drugs. CONCLUSIONS: Considering that human lung mast cells are capable of producing LTC4, prostaglandin D2, and histamine, our present results support the concept that mast cells, at least, may participate in the development of aspirin-induced asthma.     

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.     

纤溶酶原激活剂抑制物-1基因启动子区4G/5G多态性与妊娠高血压综合征的关系

目的　探讨纤溶酶原激活剂抑制物 - 1(plasminogen activator inhibitor- 1,PAI- 1)基因启动子区 4 G/ 5 G多态性与妊娠高血压综合征 (pregnancy- induced hypertension syndrome,PIHs)发病的相关性。方法　应用聚合酶链反应 -限制性片段长度多态性分析 ,检测了 171例 PIHs患者 (PIHs组 )和 193名正常妊娠妇女 (对照组 )的 PAI- 1基因 4 G/ 5 G多态性。结果　 (1) PIHs组 PAI- 1基因型频率分布 :4 G/ 4 G型为4 7.4 % ,4 G/ 5 G型为 4 1.5 % ,5 G/ 5 G型为 11.1% ;PIHs组 4 G等位基因频率 (0 .6 81)和 4 G/ 4 G型频率(47.4 % )显著高于正常对照组孕妇 (0 .4 95和 2 1.2 % ) (P<0 .0 0 1)。 (2 )重度 PIHs患者组 4 G/ 4 G型和 4 G等位基因频率 (6 1.3%和 0 .75 8)显著高于轻度 PIHs组 (35 .8%和 0 .6 2 3) (P<0 .0 0 1) ;中度 PIHs组 (42 .8%和0 .6 5 2 )和轻度 PIHs组比较差异无显著性 (P>0 .0 5 )。 (3) 4 G/ 4 G基因型孕妇发生 PIHs的相对风险率的比数比为 3.34,95 %的可信区间为 2 .14～ 5 .2 2。结论　 PAI- 1基因 4 G/ 5 G多态性参与 PIHs的发病 ,纯合子4 G/ 4 G基因型可能是 PIHs发病的重要危险因素之一。