IL-4和IL-4受体基因多态性与成人变应性哮喘的关系

目的　研究白细胞介素 4 (IL 4 )、IL 4受体α链的 2个基因多态性位点与中国成人变应性哮喘的关系。方法　采用病例对照方法 ,用聚合酶链反应 限制性片段长度多态性方法 (PCR RFLP)对IL 4启动子区C - 5 89T和IL 4Rα链Q5 76R进行基因分型。结果　IL 4C - 5 89T与中国成人变应性哮喘无关 ,然而 ,变应性哮喘组IL 4Rα链 5 76R R频率显著性高于对照组 (χ2 =9.36 9,P <0 .0 1;OR =3.797) ,且与血浆高IgE相关。结论　IL 4Rα链 5 76R R基因型是中国成人变应性哮喘的基因危险因子     

IFN-γ与 IL-4基因多态性与儿童哮喘易感性及外周血IFN-γ、IL-4和IgE的关系

目的: 探讨IFN-γ和 IL-4 基因多态性与儿童哮喘易感性及血浆IFN-γ、IL-4和IgE的相关性。方法: 用聚合酶链反应-限制性酶切片段长度多态性(PCR-RFLP)法检测100例哮喘儿童和122例对照儿童IFN-γ基因-179G/T、 IL-4 基因-33C/T和-589C/T位点基因型;等位基因特异性-聚合酶链反应(AS-PCR)法检测IFN-γ基因+874A/T位点基因型;毛细管电泳法检测IFN-γ基因CA重复序列基因型;ELISA法测定血浆IFN-γ、IL-4和IgE。结果: 100例哮喘儿童和122例对照儿童IFN-γ基因-179位点均为GG纯合子,未检测到突变基因型。IFN-γ基因+874A/T位点和CA重复序列的基因型和等位基因频率分布在哮喘组和对照组间无显著差异(P>0.05);+874位点多态性与血浆IFN-γ水平相关,AA基因型IFN-γ含量低于AT基因型(P<0.05)。 IL-4 基因-33C/T和-589C/T位点的基因型和等位基因频率分布在哮喘组和对照组间有显著差异(P<0.05);-33和-589位点TT基因型外周血IL-4和总IgE浓度均高于CT基因型,只有-33位点与血浆IL-4水平存在相关性(P<0.05)。结论: IFN-γ基因+874A/T和CA重复序列多态性可能与儿童哮喘无相关性,+874A/T位点多态性与IFN-γ水平相关。 IL-4 基因-33TT和-589TT基因型可能为儿童哮喘的易感基因型,-33位点多态性与IL-4表达水平相关。     

白细胞介素4受体Q576R基因多态性与支气管哮喘的相关性

目的　探讨白细胞介素4受体(inlerleukin- 4 receptor,IL- 4 R)基因Q5 76 R多态性与儿童支气管哮喘的相关性。方法　用聚合酶链反应-限制性片段长度多态性分析方法检测94例哮喘儿童和6 8名正常对照儿童IL - 4 R Q5 76 R的多态性,并进行χ2 检验。结果　IL - 4 R杂合突变基因型Q5 76 R、突变等位基因R5 76的分布频率在哮喘儿童及正常对照儿童中差异有统计学意义(P<0 .0 5 )。结论　IL - 4 R突变等位基因R5 76可能是儿童易感哮喘的一个候选基因。     

白细胞介素4受体基因多态性与哮喘、过敏症研究进展

支气管哮喘是复杂的多基因遗传性疾病。白细胞介素4(IL鄄4)在哮喘发病机制中发挥重要作用。白细胞介素4受体基因(IL鄄4R)有6种错义突变致表达的氨基酸发生替换。IL鄄4R基因多态性与哮喘、过敏症有关。本文综述了IL鄄4R基因多态性与哮喘、过敏症相关性研究进展。     

白细胞介素4受体基因多态性与哮喘、过敏症研究进展

支气管哮喘是复杂的多基因遗传性疾病。白细胞介素4（IL-4）在哮喘发病机制中发挥重要作用。白细胞介素4受体基因（IL-4R）有6种错义突变致表达的氨基酸发生替换。IL-4R基因多态性与哮喘、过敏症有关。本文综述了IL-4R基因多态性与哮喘、过敏症相关性研究进展。     

白介素13基因多态性与湖北汉族人群哮喘的关系

目的：为了探讨IL-13基因编码区精氨酸(Arg)110谷氨酰胺(Gln)多态性是否与湖北地区汉族人群哮喘及血浆总IgE水平升高相关。方法：采用PCR-RFLP方法，检测湖北地区43名哮喘患儿、45名成人哮喘患者、31名非哮喘儿童和46名体检健康成人的IL-13外显子4Arg110Gln的等位基因频率和基因型频率。用化学发光法测定血浆总IgE。结果：IL-13基因4257应等位基因a在儿童、成人中的频率分别为0．39、0．32。IL-13基因Arg110Gln多态性的GlnGln型与儿童哮喘和血浆总IgE升高相关(P分别为0．030、0．0009)，但与成人哮喘、血浆总IgE水平之间无统计学意义(P分别为0．219、0．174)。结论：研究显示IL-13外显子4Arg110Gln g/a单核苷酸多态性与湖北汉族儿童哮喘和血浆总ISE水平相关，但与成人哮喘、血浆总IgE水平之间无统计学意义。     

支气管哮喘患者白细胞介素-4、13检测的临床意义

目的 探讨哮喘患者外周血白细胞介素-4（IL-4）和白细胞介素-13（IL-13）的变化及其在哮喘发病机制中的作用。方法 采用ELISA法检测30例支气管哮喘患者及25例正常对照组的血浆IL-13的含量。结果 支气管哮喘急性期患者的血浆IL-4、IL-13均明显高于正常对照组（P均〈0。01）。结论 IL-4、IL-13等因子多与支气管哮喘发病的病理生理过程，可为判断病情提供较好的实验室参数。     

白细胞介素-4受体基因多态性与RSV毛细支气管炎相关性的病例对照研究

目的检测白细胞介素-4(IL-4)受体α链(IL-4Rα)I50V和Q576R基因多态性与呼吸道合胞病毒(RSV)毛细支气管炎的相关性。方法采用聚合酶链-限制性片段长度多态法检测130例RSV毛细支气管炎患儿和108例健康儿童IL-4Rα/I50V、Q576R基因多态性,应用化学发光法和酶联免疫吸附法检测血清总IgE和鼻咽分泌物(NPS)IL-4R水平。结果病例组II、IV和VV基因型频率为24.6%、51.5%和23.9%,对照组为27.8%、40.7%和31.5%,差异无统计学意义(χ2=2.960,P0.05);病例组I、V等位基因频率为50.4%、49.6%,对照组为48.1%、51.9%,差异无统计学意义(χ2=0.236,P0.05),II基因型NPS中IL-4R高于IV和VV基因型(Z=2.031,2.034,P0.05)。病例组QQ和QR基因型频率为72.3%、27.7%,对照组为64.8%、35.2%,差异无统计学意义(χ2=0.521,P0.05);病例组Q、R等位基因频率为86.2%、13.8%,对照组为82.4%、17.6%,差异无统计学意义(χ2=1.261,P0.05),R等位基因携带者NPSIL-4R高于Q等位基因携带者(Z=2.205,P0.05)。两个位点基因型间血清总IgE差异无统计学意义(F=1.021,t=0.452,P0.05);基因型频率与病情间亦无关联(χ2=0.322,1.393,P0.05)。结论 IL-4Rα/50II基因型及576R等位基因携带者与RSV毛细支气管炎NPSIL-4R水平增高相关。     

Toll样受体9基因启动子单核苷酸多态性与儿童变应性哮喘的相关性

目的 研究Toll样受体9(toll-like receptor 9,TLR9)基因启动子区单核苷酸多态性在浙江汉族儿童中的分布,探讨其与哮喘易感性及其表型之间的相关性.方法 对312例变应性哮喘患儿(哮喘组)和339名健康儿童(对照组)采用DNA直接测序法检测TLR9基因-1486(rs187084)和-1237(rs5743836)单核苷酸多态性;采用ELISA法检测两组不同基因型血清干扰素γ(interferon-γ,IFN-γ)、白细胞介素12(interleukin-12,IL-12)和白细胞介素4(interleukin-4,IL-4)水平;采用化学发光法检测血清总免疫球蛋白E(immunoglobulin E,IgE)水平;采用酶免疫荧光法检测血清变应原特异IgE.结果 (1)哮喘组和对照组均存在-1486位点T→C突变,哮喘组TT、TC和CC 3种基因型的频率分别是3 8.8%、48.4%和12.8%,对照组分别是41.0%、44.3%和14.7%;未发现-1237位点存在多态性.(2)哮喘组和对照组-1486位点各基因型的频率分布差异无统计学意义(P＞0.05),年龄分层后比较差异也无统计学意义(P＞0.05).(3)哮喘组-1486位点3种基因型的血清IFN-γ和IL-4水平差异有统计学意义(P＜0.01),CC基因型的IFN-γ水平较低而IL-4水平较高;对照组2种细胞因子的差异无统计学意义(P＞0.05).哮喘组和对照组血清IL-12水平在3种基因型间差异均无统计学意义(P＞0.05).(4)哮喘组-1486位点不同基因型血清总IgE水平差异无统计学意义(P＞0.05).结论 浙江汉族儿童不存在TLR9基因-1237位点多态性.TLR9基因-1486 C/T位点单核苷酸多态性与浙江汉族儿童哮喘易感性、血清IL-12及总IgE水平无关;-1486 C/T位点多态性与哮喘患儿血清IFN-γ和IL-4水平有关联,CC基因型的IFN-γ水平较低而IL-4水平较高.

Abstract：

Objective To investigate the distribution characteristics of the single nucleotide polymorphisms (SNPs) in the promoter region of the toll-like receptor 9 gene (TLR9)in Chinese Han children from Zhejiang province, and their associations with asthma susceptibility and phenotypes. Methods A case-control study was conducted. A total of 312 asthmatic children aged between 1.9 and 11.6 and 339 age matched healthy controls were enrolled in this study from April 2007 to November 2008. The -1486 C/T in rs187084 and -1237 C/T in rs5743836 loci of the TLR9 gene were genotyped by direct DNA sequencing of the PCR products. Serum levels of IFN-γ, IL-12 and IL-4 were detected by enzyme linked immunosorbent assay. Serum levels of total IgE were detected by chemiluminescence, and serum levels of ildren (P＜0.01). The CC genotype had the lowest levels of serum IFN-γand the highest levels of serum IL-4 among the three genotypes. There were no significant differences in these cytokines among the healthy controls (P＞0.05). No statistical differences of serum IL-12 were found among the three genotypes in the two groups (P＞0.05). (4) There were no significant differences of total IgE (log-transformed) among the three genotypes in the asthmatic children (P＞0. 05). Conclusion The -1237 C/T polymorphism of TLR9 gene was not detected in Chinese Han children in this study. The - 1486 C/T polymorphism was associated with the levels of serum IFN-γ and IL-4 in children with asthma.However, there were no correlations between the -1486C/T polymorphism and serum IL-12 levels, total IgE levels or asthmatic susceptibility.     

IL-2等6种细胞因子与儿童支气管哮喘关系的研究

观察急性发作期、激素治疗后缓解期支气管哮喘患儿血浆细胞因子的变化,探讨儿童支气管哮喘与细胞因子的关系。采用免疫分析技术对64例急性发作期支气管哮喘患儿、45例缓解期患儿及20例正常儿童血浆IL-2、sIL-2R、IL-4、IL-5、IL-8、TNF-α、IgE等细胞因子水平进行测定;用逆转录聚合酶键反应技术（RT-PCR）对外周淋巴细胞IL-4、IL-5mRNA表达进行定量分析。结果:（1）发作期哮喘患儿血浆IL-2、sIL-2R、IL-4、IL-5、IL-8、TNF-α和IgE水平均明显高于正常对照组（P值均<0.001）,以IL-4、IL-5和IgE变化最为明显,缓解期均明显下降,但IL-4、IL-5及IgE水平仍高于正常水平（P<0.01）。（2）发作期患儿外周淋巴细胞IL-4、IL-5mRNA表达增强,治疗缓解后减弱,同时血浆IL-4、IL-5分别与IL-4、IL-5mRNA呈明显正相关关系。结论:（1）本研究结果提示细胞因子的释放与哮喘的发作密切相关。（2）外周淋巴细胞IL-4、IL-5强表达以及血浆IL-4、IL-5高水平提示哮喘发作期Th2亚群的激活;同时IL-8和TNF-α的升高表明中性粒细胞和单核巨噬细胞可能参与哮喘的发作。（3）糖皮质激素抑制多种细胞因子的释放,可能是其治疗哮喘的主要机制。     

Relationships between specific serum IgE, cytokines and polymorphisms in the IL-4, IL-4Ralpha in patients with penicillins allergy

BACKGROUND: Excessive production of interleukin (IL)-4, IL-13 and interferon (IFN)-gamma is thought to be important in the development of allergic disease and atopy. Several investigators have linked the IL-4 and IL-4R genes to allergic disease and atopy. The aim of this study is to further explore the mechanism of penicillins allergy and evaluate the possible role of the IL-4 C-589T and IL-4RalphaQ576R polymorphisms in modulating the allergic responses to penicillins. METHODS: Radioallergosorbent test (RAST) was used to detect eight kinds of specific immunoglobulin E (IgE) to penicillins in serum. Serum levels of IL-4, IL-13 and IFN-gamma were measured by using enzyme-linked immunosorbent assay (ELISA). The IL-4 C-589T and IL-4RalphaQ576R polymorphisms were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). RESULTS: Compared with control subjects, there were significantly higher levels of IL-4, IL-13 and IFN-gamma in allergic patients with positive specific IgE (P < 0.01), and the lower levels of IL-4 and IFN-gamma were observed in allergic patients with negative specific IgE (P < 0.05). We found a growing trend of IL-4 and IL-13 levels with the kind increasing of positive specific IgE, and even there were significant correlations between the three kinds of cytokines and many kinds of specific IgE (P < 0.05). The IL-4Ralpha*Q576 allele was significantly increased in patients with penicillins allergy compared with control subjects (P < 0.01). Furthermore, the allele was strongly associated with increased serum-specific benzylpenicilloyl (BPO)-, phenoxomethylpenicillanyl (PVA)- or ampicillanyl (APA)-IgE levels in patients with positive specific IgE (P < 0.05). CONCLUSIONS: These data suggest that IL-4, IL-13 and IFN-gamma play an important roles in penicillins allergy. The IL-4RalphaQ576R polymorphism may involve in the development of penicillins allergy, and through modulating specific serum IgE levels.     

The R576 IL-4 receptor alpha allele correlates with asthma severity.

BACKGROUND: Atopic disorders, including asthma, are very prevalent, affecting up to 40% of populations, and their incidence is on the rise. Although environmental factors are important in the development of atopy, there is a strong genetic predisposition. Several genes and chromosomal regions have been linked to atopy and asthma, supporting the polygenic nature of these disorders. IL-4 and IL-13 are T(H)2 cytokines with numerous activities that contribute to allergic inflammation and asthma. Both IL-4 and IL-13 use the IL-4 receptor alpha chain (IL-4Ralpha) as a component of their respective receptor systems. Allelic variants of IL-4Ralpha have been reported, and the R576IL-4Ralpha allele was recently shown to be a risk factor for atopy. OBJECTIVE: We sought to determine whether the R576 allele was associated with the prevalence or clinical severity of asthma. METHODS: We developed a rapid, reliable, PCR-based assay to screen individuals for the R576IL-4Ralpha allele and used this assay to genotype prospectively recruited individuals with asthma (n = 149) and control subjects (n = 57). RESULTS: There was a strong association of R576IL-4Ralpha with the prevalence and clinical severity of asthma. In a prospective cohort, homozygosity for R576 was significantly increased in individuals with asthma (n = 149, P =.03; relative risk 8.2) compared with controls (n = 57). Furthermore, 1 or 2 copies R576IL-4Ralpha correlated with asthma severity establishing a genotype-phenotype relationship and suggesting a gene dosage effect. CONCLUSIONS: Thus R576IL-4Ralpha acts as an allergic asthma susceptibility and disease-modifying gene and may serve as a clinically useful marker of asthma severity.     

IgE高亲和力受体β链基因与中国湖北成人变应性哮喘的关系

目的:探讨IgE高亲和力受体β链基因(FcεRⅠβ)启动子-109位和编码区Glu237Gly基因多态性与湖北成人变应性哮喘及血浆总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FcεRⅠβ基因启动子区-109位和编码区Glu237Gly两位点多态性,采用病例-对照法共研究106例成人变应性哮喘患者和106例相匹配的对照者。结果:①成人变应性哮喘患者FcεRⅠβ基因启动子区-109位T/T、T/C和C/C基因型频率是0.415、0.491和0.094;与对照相比差异无显著(χ²=0.5575,P＞0.05),但成人变应性哮喘组T/T基因型患者血浆总IgE对数值为2.6490±0.9241与T/C基因型的2.2960±1.1040和C/C基因型的2.3130±0.8052相比差异显著。②FcεRⅠβGlu237Gly位点Glu/Glu、Glu/Gly和Gly/Gly基因型频率为0.566、0.377和0.057,与正常对照相比差异显著(χ²=7.31,P＜0.05),Gly/Gly基因型血浆总IgE对数值为2.7220±0.9374,与Glu/Glu和Glu/Gly相比差异显著。结论:IgE高亲和力受体β链启动区-109位T/T基因型与血浆总IgE高度相关,编码区237位Gly/Gly基因型与湖北汉族成人变应性哮喘及血浆高IgE相关。     

Lack of association of atopy/asthma and the interleukin-4 receptor α gene in Japanese

BACKGROUND: Susceptibility to the development of atopic diseases is known to involve genetic factors. Several investigators have reported the interleukin-4 (IL-4) receptor alpha gene to be involved in the development of atopy. Recent study has shown that the R allele of a polymorphism in the IL-4 receptor alpha chain gene (Q576R) to be associated with atopy. OBJECTIVE: The objective of this study was to evaluate the possible role of the IL-4 receptor alpha gene in modulating allergic response and asthma in the Japanese population. METHODS: We conducted linkage analysis using microsatellite markers flanking the IL-4 alpha receptor gene in 82 families ascertained through asthmatic children. The IL-4 receptor Q576R polymorphism was also genotyped by PCR-restriction fragment length polymorphism analysis. RESULTS: We did not find evidence for linkage of the asthma and atopy phenotypes with the markers D16S298 and D16S403 (P = 0.10 and P = 0.56, respectively, for the atopy phenotype and P = 0.17 and P = 0.60, respectively, for the asthma phenotype). The IL-4 receptor R576 allele was not preferentially transmitted to atopy- or asthma-affected children (chi2 = 1.67, P = 0.24 for atopy and chi2 = 0.91, P = 0.40 for asthma). In addition, the prevalence of the R576 allele among parents with and without atopy was similar, 20 of 81 (24.7%) parents with atopy and 22 of 77 (28.6%) parents without atopy. CONCLUSION: Our findings indicate that the IL-4 receptor alpha gene does not exert a substantial influence on the inheritance of atopy or asthma in this Japanese population.     

Molecular analysis of sequence variants in the Fcepsilon receptor I beta gene and IL-4 gene promoter in Italian atopic families

BACKGROUND: The genetic variants in the Fcepsilon receptor I beta gene (Glu237Gly) and the T allele of the (C590T) polymorphism of interleukin (IL)-4 gene promoter were reported to be associated with atopy. But the data of the studies in different populations are contrasting with one another. METHODS: A group of 25 Italian nuclear families were studied. In each family at least two allergic subjects were present. The allergic children were 65 and the allergic relatives were 35. One hundred and three nonallergic unrelated controls included outpatiens with no history of atopy. The (C590T) promoter polymorphism of the IL-4 and the genetic variant Glu237Gly of Fcepsilon RI beta genes were analysed by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: A significant difference was observed in the genotype frequency at codon 237 of the Fcepsilon RI beta gene between allergic children and nonatopic control (P < 0.01) and in the allergic relatives (P < 0.001). In the children, the Glu237Gly polymorphism was also associated with elevated circulating levels of immunoglobulin E. The -590C/T allele of IL-4 promoter gene showed no association with atopy. CONCLUSIONS: In our study, the Glu237Gly polymorphism of the Fcepsilon RI beta gene was associated with atopy. Our results have not pointed out an association between the (C590T) promoter polymorphism of the IL-4 gene and atopy. These data suggest the potential role of the Fc RI beta gene in the development of the allergy.     

A repeat polymorphism in interleukin-4 gene is highly associated with specific clinical phenotypes of asthma.

BACKGROUND: IL-4 is a determining factor in immunologic mechanisms to allergy and inflammation. The authors designed a case-controlled study to investigate the potential association of a repeat polymorphism in IL-4 gene with specific clinical phenotypes of asthma. METHODS: The authors used the polymerase chain reaction to characterize the variation of the IL-4 intron 2 region in 145 unrelated Tunisian patients with asthma and 160 healthy control subjects. In order to strengthen the case-controlled study, analysis of IL-4 polymorphism was performed in families of several asthmatic patients. Asthma scores were determined and correlated with this polymorphism. RESULTS: Analysis of IL-4 polymorphism in patients with allergic asthma and in control subjects demonstrated a significant association between the IL-4 A1 allele and asthma. Further evidence of the strong association found between IL-4 intron 2 polymorphism and asthma was provided by the finding that asthma is transmitted in association with the inheritance of the IL-4 A1 marker. When patients were stratified into two groups according to the degree of the severity of asthma, the IL-4 A1 allele was specifically not associated with mild asthma, but highly associated with the moderate and severe forms of the disease. The relative risk (RR) of severe asthma is especially high in patients carrying the A1/A3 genotype (RR = 3.94, p = 0.0001). Conversely, a major decrease in the frequency of the IL-4 A3/A3 genotype was observed in patients with severe asthma, resulting in a significantly negative RR of this clinical phenotype of asthma (RR = 0.165, p = 0.0001). CONCLUSIONS: Tunisian persons carrying the IL-4 A1/A3 genotype may have an increased risk of severe asthma.     

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.