哮喘人群STAT6基因多态性的研究

目的 研究信号转导和转录激活因子6（STAT6）基因3’非翻译区G2964A位点多态性与重庆哮喘人群的易感性及血浆IgE水平的关系。方法用聚合酶链反应和单链构像多态性（PCR-SSCP）的方法对42例哮喘患者及42例对照进行了STAT6基因G2964A位点多态性分析。结果哮喘组与对照组STAT6基因G2964A位点的基因型频率之间无显著性差异（P〉0．05）,并且哮喘组各基因型之间均与血浆IgE升高无确定关系（P〉0．05）。结论G2964A位点多态性与重庆人群哮喘易感性可能无明显相关性。     

Lack of association between the IL13 variant Arg110Gln and susceptibility to cedar pollinosis in a Japanese population

BACKGROUND: Interleukin (IL)-13 has come to be appreciated as a molecule critically involved in allergic inflammatory responses. Recent studies revealed that a common variant in the coding region of the IL13 gene, Arg110Gln, has been implicated in the development of asthma and atopy. METHODS: To assess whether the IL13 variant Arg110Gln is associated with cedar pollinosis, one of the most common atopic diseases in the Japanese population, we examined the Arg110Gln variant using PCR-RFLP to compare the genotype and allele frequencies between 95 patients with cedar pollinosis and 95 healthy control subjects. Relationships between the Arg110Gln variant and the pollinosis-related traits, e.g. rhinitis severity, eosinophil counts in nasal secretion and serum total and allergen-specific IgE levels, were also investigated. RESULTS: The frequencies of the minor allele Gln110 were 25.8% in patients with cedar pollinosis and 30.9% in healthy control subjects (p > 0.05). There was also no significant difference in the genotype frequencies between cases and controls (p > 0.05). In addition, we found no significant association of the Arg110Gln variant with any of the pollinosis-related phenotypes (p > 0.05). CONCLUSIONS: Our data suggest lack of evidence for identifying the variant Arg110Glnat the IL13 locus as a genetic risk factor involved in the development of Japanese cedar pollinosis.     

Gene Polymorphism of Interleukin-4, Interleukin-4 Receptor and STAT6 in Children with Atopic Dermatitis in Taif,Saudi Arabia

Aim of study: This work was performed to evaluate the level of IL-4, and to clarify the role of IL-4 gene polymorphism at position cytosine –590-to-thyamine (C-590T), IL-4Rα gene polymorphism at position adenine +4679-to-guanine (A+4679G) [isoleucine-50-valine (I50V)] and STAT6 gene polymorphism at position guanine 2964-to-adenine (G2964A) in Saudi children with non-atopic dermatitis (non-AD) and atopic dermatitis (AD) to identify their role in the pathogenesis of these diseases.

Subjects and methods: This study included 150 children: 50 healthy children as controls, 50 with non-AD, and 50 with AD. They were subjected to full clinical examination, complete blood picture, skin prick test, and determination of serum interleukin-4 (IL-4) and total immunoglobulin-E (IgE) levels. Detection of interleukin-4 gene (C-590T), interleukin-4 receptor alpha gene (A+4679G) (I50V), and STAT6 gene (G2964A) polymorphisms were performed by PCR-based restriction fragment length polymorphism (PCR-RFLP).

Results: There was a significant (P < 0.01) association between genotype and allele frequencies of IL-4Rα (A+4679G) (I50V) polymorphism in the AD group (but not non-AD group). Moreover, there was a significant association between genotype and allele frequencies of the STAT6 (G2946A) polymorphism in the non-AD (P < 0.05) and AD (P < 0.01) groups. On the other hand, there was no significant association between genotype and allele frequencies of the (C-590T) polymorphism in the non-AD group and AD group. There was a significant (P < 0.001) higher total IgE level in patients compared to the controls. Moreover, the mean values of total IgE were significantly different among the different allelic variants of (C-590T), (I50V), (G2964A) polymorphisms of IL-4, IL-4Rα, and STAT6 genes, respectively, in all the studied groups. On the other hand, there was no significant difference of serum IL-4 levels among all the studied patients, or among the different allelic variants of (C-590T), (I50V), (G2964A) polymorphisms of IL-4, IL-4Rα, and STAT6 genes, respectively.

Conclusion: IL-4Rα gene (I50V) and STAT6 gene (G2964) polymorphisms may play a role in development of eczema; however, the IL-4 gene polymorphism (C-590T) had no relationship with susceptibility to the disease among Saudi children.     

Association of IFN-gamma and IFN regulatory factor 1 polymorphisms with childhood atopic asthma

BACKGROUND: IFN-gamma and related molecules play important roles in the differentiation and function of TH2 cells. OBJECTIVE: We sought to determine whether IFNG and related genes contribute to any susceptibility to atopic asthma, a representative TH2-dominant disorder. METHODS: We investigated the association of IFNG (CA repeat polymorphism within the first intron), IRF1 (GT repeat polymorphism within the intron 7), IFNGR1 (Val 14 Met), and IFNGR2 (Gln 64 Arg) gene polymorphisms with atopic asthma in the Japanese child population. RESULTS: A significant association (P =.0018) was observed between IFNG gene polymorphism and atopic asthma. The tendency was more prominent in patients with age of onset of 3 years or younger (P =.0004) or patients with a family history of allergic diseases (P =.0038). Furthermore, there was a significant association between IRF1 gene whole-allele distribution and atopic asthma (P =.044). The tendency was more prominent in patients with onset at 3 years of age or less (P =.0058). On the other hand, IFNGR1 and IFNGR2 gene polymorphisms showed no association with atopic asthma. CONCLUSION: These results suggested that among IFNG and related genes, IFNG and IRF1 genes confer genetic susceptibility to atopic asthma in Japanese children.     

Association between an interleukin-13 promoter polymorphism and atopy.

Several studies indicate genetic involvement of Th2 cytokines in allergic diseases. Interleukin (IL)-13 has been mapped to the cytokine cluster on chromosome 5q31-33, which has been associated with atopic conditions. Recently, an association was reported between the T allele in a promoter polymorphism in the IL-13 gene (C to T exchange) at position -1055 and allergic asthma in a population study in the Netherlands. This observation was apparently confirmed in a case-control study using probands and spouses from a Dutch asthma family study, but the polymorphism in that study was reported to occur at position -1111. In the present study, we established that this polymorphism is located at position -1024 relative to the ATG translation initiation codon, and investigated whether it confers a genetic predisposition to atopic conditions and the Th1 condition multiple sclerosis (MS) in Caucasian subjects. We confirmed the association between the IL-13 -1024TT genoype and inhalation allergy (P = 2.4E-02). By combining the data from the three studies, we demonstrated a strong association (P = 1.09E-05) between the IL-13 -1024 marker and inhalation allergy. Furthermore, we showed for the first time that this association also exists in atopic dermatitis (P = 2.0E-02). No association with MS was found.     

Novel polymorphism in the coding region of the IL-13 receptor alpha' gene: association study with atopic asthma in the Japanese population

Interleukin (IL)-4 and IL-13 play key roles in the development of atopic asthma. The IL-13 receptor (R) alpha' chain is a component of both IL-4R and IL-13R complexes. By screening the whole coding region of the IL-13Ralpha' gene for polymorphisms, we identified a new polymorphism at nucleotide position 1050 from the ATG start codon. The allelic frequency of the C/T polymorphism in the Japanese population was found to be 0.97:0.03. Because of the low frequency of the T allele, the association study failed to indicate any significant association between this polymorphism and atopic asthma in the Japanese population. Further studies are required in other racial groups with higher frequencies of this polymorphism to elucidate the association.     

No association between atopic asthma and a coding variant of FcεR1β in a Japanese population

Susceptibility to atopic diseases is known to involve genetic factors. The Gly237 allele of a polymor-phism (Glu237Gly) of the FcεR1β gene is reportedly associated with atopic asthma in Japanese. To confirm this association, we conducted transmission disequilibrium tests in 76 families identified through atopic asthmatics. A case-control study was also carried out in atopic asth-matic subjects and non-atopic controls. The Gly237 allele was not preferentially transmitted to atopic asthma-affected offspring. Neither the Gly237 allele nor the Gly237/Gly237 + Glu237/Gly237 genotypes were significantly more prevalent in the atopic asthmatics than in the controls. This study failed to confirm a substantial role of the Gly237Glu polymorphism of the FcεR1β gene in the genetic predisposition for atopic asthma in this Japanese population. Received: February 22, 1999 / Accepted: April 16, 1999     

IgE高亲和力受体β链基因多态性与湖北汉族人变应性哮喘易感性的研究

目的探讨IgE高亲和力受体β链( high-affinity IgE receptor β gene, Fc ε RI β)基因启动子-109位C/T和编码区Glu237Gly基因多态性与湖北汉族人变应性哮喘易感性及血浆总IgE的关系. 方法采用聚合酶链反应-限制性片段长度多态性技术检测 Fc ε RI β基因启动子区-109位和编码区Glu237Gly两位点多态性,采用病例-对照法研究了216例变应性哮喘患者和198名对照. 结果 (1)湖北汉族人变应性哮喘患者 Fc ε RI β基因启动子区-109位T/T、T/C和C/C基因型频率是0.403、0.491和0.106;与对照相比差异无显著性(χ2=0.384,P＞0.05),但变应性哮喘组T/T基因型患者血浆总IgE对数值(2.539±0.8325)与T/C基因型的对数值(2.278±1.089)和C/C基因型的对数值(2.323±0.7852)相比差异具有显著性.(2)变应性哮喘患者 Fc ε RI β基因Glu237Gly位点Glu/Glu、Glu/Gly和Gly/Gly基因型频率为0.579、0.370和0.051,与正常对照相比差异具有显著性(χ2=13.62,P＜0.01),变应性哮喘患者Gly/Gly基因型血浆总IgE对数值为(2.622±0.9374),与Glu/Glu和Glu/Gly相比差异具有显著性. 结论 Fc ε RI β基因启动子区-109位T/T基因型与血浆总IgE高度相关,编码区237位Gly/Gly基因型与中国湖北汉族人变应性哮喘及血浆高IgE相关.     

Association between an interleukin‐13 promoter polymorphism and atopy

Several studies indicate genetic involvement of Th2 cytokines in allergic diseases. Interleukin (IL)‐13 has been mapped to the cytokine cluster on chromosome 5q31–33, which has been associated with atopic conditions. Recently, an association was reported between the T allele in a promoter polymorphism in the IL‐13 gene (C to T exchange) at position ?1055 and allergic asthma in a population study in the Netherlands. This observation was apparently confirmed in a case–control study using probands and spouses from a Dutch asthma family study, but the polymorphism in that study was reported to occur at position ?1111. In the present study, we established that this polymorphism is located at position ?1024 relative to the ATG translation initiation codon, and investigated whether it confers a genetic predisposition to atopic conditions and the Th1 condition multiple sclerosis (MS) in Caucasian subjects. We confirmed the association between the IL‐13 ?1024TT genoype and inhalation allergy (P = 2.4E‐02). By combining the data from the three studies, we demonstrated a strong association (P = 1.09E‐05) between the IL‐13 ?1024 marker and inhalation allergy. Furthermore, we showed for the first time that this association also exists in atopic dermatitis (P = 2.0E‐02). No association with MS was found.     

Association of MICA polymorphism with HLA-B51 and disease severity in Korean patients with Behcet's disease

The HLA-B51 allele is known to be associated with Behcet's disease (BD) in many ethnic group. However, it has not yet been clarified whether the HLA-B51 gene itself is the pathogenic gene related to BD or whether it is some other gene in linkage disequlibrium with HLA-B51. Recently, the Triplet repeat (GCT/AGC) polymorphism in transmembrane region of the MHC class I chain-related A (MICA) gene was identified. To investigate the association of MICA with BD, we studied the MICA polymorphism in 108 Korean BD patients and 204 healthy controls in relation to the presence of HLA-B51 and clinical manifestations. The triplet repeat polymorphism was determined by polymerase chain reaction (PCR)-denaturing polyacrylamide gel electrophoresis (PAGE). The phenotype frequency of the MICA*A6 allele (relative risk, RR=2.15, p=0.002) and HLA-B51(RR=1.87, p=0.022) were significantly increased in the Korean patients with BD. A strong linkage disequilibrium was observed between the MICA*A6 and HLA-B51 in both the patients with BD and control subjects. Stratification analysis showed that MICA*A6 homozygosity was strongly associated with BD in the HLA-B51-negative population, and HLA-B51 was also associated with MICA*A6-negative population. In conclusion, MICA*A6 rather than HLA-B51 was strongly associated with Korean patients with BD, and the MICA*A6 allele is a useful susceptibility marker of BD, especially in the HLA-B5-negative     

Neuronal nitric oxide synthase gene polymorphism and IgE-mediated allergy in the Central European population

BACKGROUND: Several findings suggest that nitric oxide (NO) plays a significant role in the regulation of the Th1/Th2 balance and contributes to the development of allergic diseases. Our study investigates a possible association of C/T transition located 276-bp downstream from the translation termination site in exon 29 of the human nitric oxide synthase type 1 (NOS1) gene with immunoglobulin E (IgE)-mediated allergic diseases in the Czech population. METHODS: The study included 688 subjects - 368 patients with clinically manifested allergic diseases and 320 unrelated controls with negative familial history of asthma/atopy. The NOS1 genotypes were determined by polymerase chain reaction (PCR) and restriction analysis by Eco72I. RESULTS: No significant differences were found for allele or genotype frequencies of the 5266 C/T polymorphism in exon 29 of the NOS1 gene between IgE-mediated allergic diseases (or asthma alone) and healthy subjects. However, this common polymorphism showed a significant association with signs of atopy, especially with total serum IgE levels [log(e) IgE levels (mean +/- SD): CC genotype = 4.34 +/- 1.40; CT genotype = 4.58 +/- 1.53; TT genotype = 5.01 +/- 1.61; P < 0.05). CONCLUSIONS: Our findings suggest that NOS1 gene may participate in the pathogenesis of high total serum IgE levels in allergic diseases in our population. These findings provide support for NOS1 as a candidate gene for IgE-mediated allergy.     

A novel PCR-RFLP assay for the detection of a polymorphism in the 3' of STAT6 gene

We have identified a novel single nucleotide polymorphism at position 2964 (G/A) in the 3' untranslated region of the human STAT6 gene (GeneBank Accession No. U16031). A novel PCR-RFLP method has been devised for this polymorphism using the amplification-created restriction site (ACRS) method. Allele frequencies in the UK Caucasian population were found to be 0.33 for allele A and 0.67 for allele G.     

Prevalence of endothelial nitric oxide synthase gene polymorphisms in patients with atopic asthma

BACKGROUND: Asthma is a common multifactorial disease, the aetiology of which is attributable to both environmental and genetic factors. The endothelial nitric oxide synthase (NOS3) gene has been implicated in asthma pathogenesis. OBJECTIVE: This study investigated associations of 27 base-pair tandem repeat polymorphism in intron 4 and the Glu298Asp (G894T) variant of the NOS3 gene with atopic asthma in a Czech population. METHODS: Polymerase chain reaction was used to determine the NOS3 genotypes in subjects with atopic asthma (n = 163) and random controls (n = 209). RESULTS: The NOS3 allele or genotype distributions did not differ significantly between the control and asthma groups. However, the common genotype (bb) of the NOS3 polymorphism in intron 4 was found to be significantly associated with total IgE levels (P = 0.006), specific IgE levels for feathers (P = 0.0002) and a positive skin prick test for hay (P = 0.004). In one atopic patient, we identified an additional 27-bp repeat in the NOS3 gene (NOS3c), which occurred in heterozygous combination with the NOS3b allele (NOS3b/c genotype). In addition, we describe a new polymorphism (A5495G) in the NOS3 gene, which was in almost complete linkage disequilibrium with the NOS3 repeat polymorphism in intron 4. The Glu298Asp variant was not associated with asthma and/or related atopic phenotypes in our study. CONCLUSION: Neither the NOS3 'b' allele nor the NOS3 'b/b' genotype showed any general association with atopic asthma, but they were associated with atopy-related phenotypes. We conclude that the NOS3 gene polymorphisms may act as disease modifiers in atopic asthma phenotype in our population.