IL-4R、IL-13、ADAM33基因多态性与中国皖南地区汉族人群支气管哮喘的相关性研究

目的:探讨IL-4受体基因Arg551Gln(rs1801275)、IL-13基因Arg130Gln(rs20541)、ADAM33基因T1(rs2280091)位点基因多态性与中国皖南地区汉族人群支气管哮喘的相关性。方法:采用病例-对照的方法,用聚合酶链反应及直接基因测序法比较116例支气管哮喘组与70例正常人对照组之间基因型、等位基因频率的差异。结果:哮喘组和对照组IL-4受体基因Arg551Gln位点和IL-13基因Arg130Gln位点的基因型和等位基因型频率的差异有统计学意义,ADAM33基因T1位点基因型哮喘组和对照组差异有统计学意义,等位基因型频率在哮喘组和对照组差异无统计学意义。结论:提示IL-4R Arg551Gln(rs1801275)位和IL-13基因Arg130Gln(rs20541)位的多态性可能与中国皖南地区汉族哮喘有相关性;ADAM33基因(rs2280091)T1位点位的多态性可能与中国皖南地区汉族哮喘无相关性。     

内蒙古地区汉族支气管哮喘与ADAM33基因多态性的关系

为研究内蒙古地区汉族人群ADAM33基因T1、T2、V4、S2位点不同基因型及等位基因频率的分布并探讨ADAM33基因多态性与支气管哮喘的关系,选用聚合酶链反应-限制性片段长度多态性技术对汉族哮喘患者178例进行ADAM33基因多态性的检测,与195例健康汉族(对照组)进行比较,筛选有意义的基因,同时根据病情严重程度将哮喘组分为轻、中、重度组,比较不同程度组基因型分布差异。结果显示内蒙古地区汉族人群均可检出T1、T2、V4、S2位点的3种基因型,T2、V4位点基因型及等位基因的两组比较差异无统计学意义,而T1、S2位点基因型及等位基因的两组比较差异有统计学意义,各位点基因型在轻、中、重度组分布频率差异无统计学意义。由此证明ADAM33基因T1、S2位点多态性在中国内蒙古地区汉族哮喘人群中可能发挥作用,而V4、T2位点多态性可能与内蒙古地区汉族人群哮喘无关;各位点基因多态性可能与汉族哮喘严重程度无关。     

TLR7基因单核苷酸多态性与江苏淮安哮喘患者易感性的相关性研究

目的:探讨Toll样受体7(TLR7)基因rs179009、rs179019、rs5935436位点多态性与江苏淮安地区汉族人群支气管哮喘的相关性。方法:采用病例对照方法,以聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法比较158例支气管哮喘组与137例健康对照组之间基因型、等位基因频率的差异。结果:哮喘组TLR7基因rs179009、rs170019位点基因型及等位基因型频率与对照组相比差异有统计学意义(P<0.05)。rs5935436位点基因型及等位基因型频率在哮喘组和对照组间差异均无统计学意义(P>0.05)。结论:TLR7基因rs179009位点和rs179019位点的多态性可能与江苏淮安地区汉族人群哮喘相关;而rs5935436位点的多态性可能与江苏淮安地区汉族人群哮喘无关。     

TGF-β1和ADAM33基因交互作用与儿童哮喘易感性及严重程度相关性

目的:探讨转化生长因子β1(TGF-β1)和解整合素金属蛋白酶33(ADAM33)基因单核苷酸多态性与儿童哮喘易感性及严重程度相关性。方法:采用以医院为基础的病例对照研究(110例哮喘患儿和144例对照)方法,三个多态性位点(V4、T2、T869C)用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)技术进行基因分型,应用MDR软件分析基因各位点之间交互作用。结果:TGF-β1基因的T869C位点基因型及等位基因频率分布在哮喘组和对照组比较差异均无统计学意义(P>0.05)。哮喘组ADAM33基因V4位点C和T2位点A等位基因频率显著高于对照组(P<0.01),而V4位点的CC基因型及T2位点的GA基因型分布在轻中度哮喘组与对照组比较差异无统计学意义(P>0.05),T2位点的AA基因型分布在重度哮喘与对照组比较无显著性差异(P>0.05)。MDR交互作用分析显示,ADAM33基因V4和T2位点构成的2个位点最佳模型;ADAM33基因位点V4、T2和TGF-β1位点T869C构成的3个位点最佳模型两组比较均有统计学差异(P<0.05)。结论:ADAM33基因V4和T2位点与儿童哮喘发生及其严重程度相关,同时TGF-β1基因T869C位点与ADAM33基因V4和T2位点均具有明显交互作用     

clock基因rs1801260多态性与抑郁症的关联分析

目的:探讨clock基因与汉族人群抑郁症的关联。方法:用Snapshot SNP分型技术对155例抑郁症患者(其中包括133名抑郁症睡眠障碍者)和150名正常对照进行clock基因rs1801260位点分型,比较两组该基因多态性基因型和等位基因频率的差异。结果:与对照组相比,患者组rs1801260多态性的基因型和等位基因的频率差异无统计学意义(P0.05);对rs1801260多态性二种基因型C/T、T/T抑郁症的临床资料比较,显示HAMA总分差异具有统计学意义(t=2.012,P=0.047),其他各项没有明显差异(P0.05)。结论:clock基因rs1801260多态性可能与中国汉族抑郁症的发病无关联,但与抑郁症的焦虑程度可能关联。     

TBX21基因rs16947078位点的多态性与哮喘易感性的研究

目的研究TBX21基因的rs16947078位点的多态性与哮喘易感性的关系。方法应用基质辅助激光解吸附电离飞行时间质谱(MALDI-TOF-MS)平台及MassARRAY-IPLEX技术,分别对重庆地区汉族人群中199名正常对照组和223名哮喘患者组的TBX21基因rs16947078位点进行检测并分析其基因型及等位基因分布情况,研究TBX21基因rs16947078位点的多态性与哮喘易感性间的关系。结果 TBX21基因rs16947078位点基因型和等位基因在病例组与对照组间均存在显著差异,P值分别为0.010和0.011;对年龄和性别进行校正后,相对于AA基因型,AG基因型的人群患哮喘的风险增加(OR=9.433,95%CI:1.170~76.022);等位基因G的携带者患哮喘的风险也有所增加(OR=9.232,95%CI:1.152~74.006)。结论研究结果提示TBX21基因中rs16947078位点与哮喘的易感性相关。     

IL-10基因启动子多态性与皖南地区汉族人群支气管哮喘的相关性研究

目的:探讨IL-10基因启动子-1082G/A(rs1800896)、-819C/T(rs1800871)、-592C/A(rs1800872)位点多态性与安徽皖南地区汉族人群支气管哮喘的相关性。方法:采用病例-对照方法,用聚合酶链反应及直接基因测序法比较183例支气管哮喘组与151例正常人对照组之间基因型、等位基因频率的差异。结果:哮喘组IL-10基因启动子-1082G/A、-592C/A位点基因型与对照组相比有差异(P<0.05),其等位基因型频率在哮喘组和对照组间亦有差异(P<0.05)。而-819C/T位点基因型及等位基因型频率在哮喘组和对照组间均无差异(P>0.05)。结论:IL-10基因启动子rs1800896(-1082G/A)位点和rs1800872(-592C/A)位点的多态性可能与安徽皖南地区汉族哮喘相关;而rs1800871(-819C/T)位点的多态性可能与安徽皖南地区汉族哮喘无相关。     

TLR5rs5744168基因多态性与广西壮、汉族人系统性红斑狼疮的相关性研究

目的:探讨TLR5rs5744168基因单核苷酸多态性与广西壮、汉族系统性红斑狼疮易感性的相关性以及种族间差异,初步阐明其在壮、汉族SLE发生发展中的作用.方法:采用聚合酶链反应PCR技术和直接测序的方法对33例壮族、44例汉族系统性红斑狼疮患者和72名壮、汉族健康对照者的TLR5rs5744168C/T基因多态性进行分析,比较组间基因型和等位基因频率的差异,并与主要临床指标进行相关性分析.结果:(1)广西地区壮、汉族SLE的TLR5 rs5744168的TT基因型均缺失;CC基因型频率在各组中均在90.0％～100.0％之间.(2)广西壮族SLE患者TLR5基因rs5744168 CC、CT基因型频率分别是0.939、0.061,汉族SLE患者相应基因型频率分别是0.977、0.023,与相应民族正常对照组间以及壮、汉族SLE间差异均无统计学意义(分别x2 =2.001 x2=2.235和x2 =0.723;均P＞0.05);壮族SLE患者的TLR5rs5744168 C、T等位基因频率分别是0.970、0.030,汉族SLE相应的C、T等位基因频率分别是0.989、0.011,与相应民族正常对照组间以及壮、汉族SLE间差异均无统计学意义(分别x2=1.970、x2 =2.166和x2=0.708;均P＞0.05).(3)TLR5rs5744168 CC、CT基因型及C、T等位基因与广西壮汉族SLE患者ds-DNA、ANA、肾损害临床表现和实验室检查均无相关性(均P＞0.05).结论:TLR5rs5744168基因多态性与广西壮、汉族SLE的易感性以及ds-DNA、ANA、肾损害临床实验室主要指标均无明显相关性,壮、汉族间亦不存在明显民族差异性.     

ADRB2基因rs1042713位点多态性与中国人群哮喘易感性关系的荟萃分析

目的:应用meta分析的方法综合评价ADRB2(β-2肾上腺素能受体)基因的SNP位点[Arg16Gly(A46G,rs1042713)]多态性与中国人群哮喘易感性的关系。方法:检索Pubmed、Embase、Web of Knowledge、中国知网、万方、维普等数据库,收集研究ADRB2基因多态性与中国汉族人群哮喘易感性的相关文献。采用Stata12.0软件对符合纳入标准的研究做meta分析。结果:共纳入12篇文献,累计哮喘病例2 193例,对照组2 033例,所有入选文献均满足Hardy-Weinberg遗传平衡定律。Meta分析结果显示,中国人群ADRB2基因rs1042713位点突变基因G携带者(GG+GA)的哮喘发病风险较野生型纯合子(AA)比较,总体并未显著增加(OR=1.08,95%CI=0.82~1.44),但亚组分析显示,G携带者儿童哮喘的发病风险相对增高(OR=1.69,95%CI 0.99~2.87),而成人哮喘的发病风险则相对降低(OR=0.88,95%CI 0.68~1.15)。结论:ADRB2基因rs1042713位点基因多态性与中国儿童哮喘易感性存在一定的相关性,携带G突变基因者可相对增加儿童哮喘的患病风险。     

A disintegrin and metalloprotease 33 (ADAM33) gene polymorphisms and the risk of asthma: A meta-analysis

Polymorphisms in the ADAM33 gene have been associated with asthma, but the data are controversial. Therefore, we reviewed the related studies and quantitatively summarized the associations between ADAM33 polymorphisms and asthma risk using meta-analysis. A dominant model (AA+Aa vs. aa), recessive model (AA vs. Aa+aa), additive model (AA vs. aa) and allelic model (A vs. a) were used to estimate the association between ADAM33 polymorphism and asthma risk. A total of 29 case–control studies referring to 14 SNPs were identified: rs2280091(T1), rs2787094(V4), rs528557(S2), rs2280090(T2), rs511898(F+1), rs44707(ST+4), rs3918396(S1), rs543749(V−1), rs574174(ST+7), rs597980(ST+5), rs2853209(S+1), rs2280089(T+1), rs612709(Q−1), and rs3746631(V5). The results indicated that S1, V−1, V5, S+1, S2, ST+4, ST+7, ST+5, and Q−1 were not associated with asthma. Significant associations were found with the T1, V4, F+1 and T+1 polymorphisms in the overall population. In the subgroup analysis by ethnicity, a positive result was only found for the T1, V4, F+1 and T2 polymorphisms in Asia but not in Europe or Latin America. This meta-analysis provides evidence that the T1, V4, F+1, T2, and T+1 polymorphisms in the ADAM33 gene are risk factors for asthma, especially in the Asian population.     

Smoke exposure interacts with ADAM33 polymorphisms in the development of lung function and hyperresponsiveness

Introduction:  ADAM33 is the first identified asthma gene by positional cloning, especially asthma combined with bronchial hyperresponsiveness (BHR). Moreover, ADAM33 is associated with early-life lung function and decline of forced expiratory volume in 1 s (FEV₁) in the general population. In utero and postnatal cigarette smoke exposure (CSE) are associated with reduced lung function, and development of BHR and asthma. We hypothesized that this may occur via interaction with ADAM33.
Aim:  To replicate the role of ADAM33 in childhood lung function and development of BHR and asthma. Furthermore, we investigated gene–environment interaction of ADAM33 with in utero and postnatal CSE in the Dutch PIAMA cohort.
Methods:  Six ADAM33 single-nucleotide polymorphisms (SNPs) were genotyped. Rint was measured at age 4 and 8 years, FEV₁ and BHR at age 8 years; asthma was based on questionnaire data at age 8.
Results:  In the total cohort, the rs511898 A, rs528557 C, and rs2280090 A alleles increased the risk to develop asthma (+BHR). There existed interaction between in utero but not postnatal CSE and the rs528557 and rs3918396 SNPs with respect to development of BHR, the rs3918396 SNP with Rint at age 8 and the rs528557 SNP with FEV₁% predicted.
Conclusions:  We confirm associations between ADAM33 and the development of asthma (+BHR). This is the first study suggesting that interaction of in utero CSE with ADAM33 results in reduced lung function and the development of BHR, which needs further confirmation.     

Association between ADAM33 T1 polymorphism and susceptibility to asthma in Asians

Objective

The aim of this study was to determine whether the ADAM33 (a disintegrin and metalloproteinase domain 33) T1 (rs2280091), T2 (rs2280090), and ST+7 (rs574174) polymorphisms confer susceptibility to asthma.

Methods

A meta-analysis stratified by ethnicity and age was conducted on associations between the ADAM33 T1, T2, and ST+7 polymorphisms and asthma.

Results

Eleven studies, which included 4,124 patients and 7,094 controls, were available for the meta-analysis. Meta-analysis revealed an association between asthma and the ADAM33 T1 GG genotype [odds ratio (OR)?=?2.257, 95?% confidence interval (CI)?=?1.577–3.228, p?=?8.42?×?10^?7]. Stratification by ethnicity indicated an association between this genotype and asthma in Asians (OR?=?2.683, 95?% CI?=?1.799–4.001, p?=?1.31?×?10^?7), and stratification by age indicated an association between it and asthma in adults (OR?=?1.895, 95?% CI?=?1.005–3.573, p?=?0.048). However, no association was found between asthma and the ADAM33 T2 and ST+7 polymorphisms.

Conclusions

This meta-analysis demonstrates that the ADAM33 T1 polymorphism confers susceptibility to asthma in Asians, but no association was found between the ADAM33 T2 and ST+7 polymorphisms and asthma susceptibility.     

Association of ADAM33 gene polymorphisms with asthma in Indian children

Asthma is the most common chronic disorder in childhood, and asthma exacerbation is an important cause of childhood morbidity and hospitalization. In the present study, the relationship between single-nucleotide polymorphisms (SNPs) of the ADAM33 gene and asthma in Indian children has been examined using a case-control study. Five SNPs of the ADAM33 gene, F+1(rs511898) G/A, S2 (rs528557) G/C, ST+4 (rs44707) A/C, ST+5 (rs597980) C/T and V4 (rs2787094) C/G, were analyzed in 211 asthma cases and 137 controls aged 1-15 years using the PCR-restriction fragment length polymorphism method. Data were statistically analyzed using the χ(2)-test and logistic regression model. Haplotype estimation and linkage disequilibrium were conducted using the expectation-maximization algorithm. The genotypes and allele frequencies of SNPs S2 and ST+5 of the ADAM33 gene were significantly associated with asthma risk (P = 0.020 - < 0.001), whereas F+1, ST+4, V4 homozygous mutant genotypes and mutant alleles were significantly associated with increased asthma risk (P = 0.031 - < 0.001). A positive association was also found with haplotypes AGCCT, GGACT and AGCCC (P = < 0.001, odds ratio (OR) = 6.10-6.50), whereas ACAGT, AGCGC, AGCGT, GCAGC and GCCGT showed protective association with asthma (P = 0.019-0.000, OR = 0.50-0.20). Taken together, out results suggest that ADAM33 gene polymorphisms may modify individual susceptibility to develop childhood asthma in the Indian population.     

ADAM33 genetic polymorphisms, smoking, and rhinoconjunctivitis in Japanese women: the Kyushu Okinawa Maternal and Child Health Study

Two previous studies have demonstrated a significant relationship between ADAM33 single nucleotide polymorphisms (SNPs) and allergic rhinitis. Here, we investigated this issue in young adult Japanese women. The study included 393 women who met the criteria of the International Study of Asthma and Allergies in Childhood (ISAAC) for rhinoconjunctivitis. Controls included 767 women without rhinoconjunctivitis according to the ISAAC criteria who had not been diagnosed with allergic rhinitis by a doctor. The GC genotype of rs2787094, the CT genotype of rs628977, and the haplotype containing the rs2787094 C allele, the rs628977 T allele, the rs2853209 T allele, and the rs612709 G allele were significantly inversely associated with rhinoconjunctivitis. The AA genotype of rs2853209, the GA genotype of rs612709, and the haplotype carrying the rs2787094 G allele, the rs628977 C allele, the rs2853209 A allele, and the rs612709 G allele were significantly positively associated with rhinoconjunctivitis. A significant inverse relationship between rs628977 and rhinoconjunctivitis was demonstrated only in women who had never smoked, indicating a significant interaction between rs628977 and smoking. Our results suggest that SNPs and haplotypes in the ADAM33 gene are associated with rhinoconjunctivitis. This study is the first to demonstrate an interaction between rs628977 and smoking that affects rhinoconjunctivitis.     

ADAM33 polymorphisms and phenotype associations in childhood asthma

BACKGROUND: A disintegrin and metalloproteinase (ADAM) 33 has been implicated as an asthma susceptibility gene by using a positional cloning approach. However, genetic linkage of asthma phenotypes to chromosome 20p13 (the location of ADAM33) has not been observed in most asthma genome scans, and it is unclear whether these associations with ADAM33 are broadly generalizable. OBJECTIVE: To examine whether ADAM33 is associated with asthma in a North American population of childhood asthmatic patients. METHODS: We performed a family-based association study by using 652 nuclear families ascertained through asthmatic subjects enrolled in a large randomized clinical trial. Seventeen ADAM33 single nucleotide polymorphisms (SNPs; including 9 associated with asthma in the initial report) were genotyped by mass spectrometry. Single-SNP and haplotype association analysis was performed. RESULTS: Among white and African American subjects, no single-SNP association with asthma was observed. However, a common 16-SNP haplotype (frequency, 14.6% in white subjects) was associated with asthma (P=.006). Two SNPs in strong linkage disequilibrium (T1 and T+1) were marginally associated with asthma in the Hispanic cohort (P=.04). These data provide marginal support for an asthma locus in the ADAM33 genomic region. However, the magnitudes of the observed associations are modest at best and are inconsistent with the original report. CONCLUSIONS: We conclude that either ADAM33 has only modest effects on asthma susceptibility, and the initial reports of association were a result of analysis in a selected population, or the initial findings were a result of chance. It is also possible that the true asthma susceptibility locus in this genomic region is near, but not at, ADAM33.     

ADAM33 polymorphism: association with bronchial hyper-responsiveness in Korean asthmatics

BACKGROUND: A disintegrin and metalloprotease 33 (ADAM33) is expressed in the lung by fibroblasts and bronchial smooth muscle cells. Given its structure and cellular provenance, ADAM33 may be associated with airway remodelling and bronchial hyper-responsiveness. Single nucleotide polymorphisms (SNPs) and haplotypes of the ADAM33 gene have previously been associated with asthma susceptibility in the Caucasian population. OBJECTIVE AND METHODS: To assess whether genetic variants of ADAM33 are related to asthma in a Korean population, we conducted an association study of the ADAM33 gene with asthma susceptibility, bronchial hyper-reactivity and serum IgE in Korean asthmatics (n=326) and normal controls (n=151). Five of the 14 polymorphisms originally reported to be associated with asthma development (S1 G>A, T1 T>C, V-1 C>A, V1 T>A, V4 C>G) were genotyped using single base extension and electrophoresis. Haplotypes and their frequencies were inferred using the algorithm implemented by the software Arlequin. Allele frequencies of each SNP and haplotypes were compared between the patients and the normal controls using logistic regression analysis. RESULTS: There was no significant difference in the distribution of SNPs and the six haplotypes between asthmatics and normal controls. All single SNPs and six haplotypes in ADAM33 were also analysed for the association with level of PC(20) using general linear models. The distribution of the T1 T>C SNP and one haplotype (ht4: GCGG) showed significant association with log-transformed PC(20) methacholine level in the asthma patients (P=0.03 and 0.0007, respectively, using a co-dominant model). CONCLUSION: Polymorphism of ADAM33 may contribute to development of BHR in asthma.     

ADAM33 polymorphisms are associated with asthma susceptibility in a Japanese population

BACKGROUND: Asthma is the most common chronic disorder in childhood, and asthma exacerbation is an important cause of childhood morbidity and hospitalization. Asthma is believed to be a complex disorder involving genetic and environmental factors, and several asthma susceptibility loci have been identified through genome-wide screening. A disintegrin and metalloprotease 33 (ADAM33) was the first asthma susceptibility gene to be discovered by positional cloning in 2002. OBJECTIVE: The aim of the present study was to investigate whether single-nucleotide polymorphisms (SNPs) in ADAM33 are associated with childhood asthma in the Japanese population. METHODS: Twenty-three ADAM33 SNPs were genotyped by fluorescence correlation spectroscopy with the use of DNA from 155 families (538 members) identified through children with atopic asthma. The transmission disequilibrium test (TDT) was performed for family-based association study. RESULTS: TDT revealed that minor alleles of S+1, ST+4, and T2 SNPs were over-transmitted to asthma-affected offspring (P<0.05). According to the haplotype TDT, no haplotype of ADAM33 was transmitted preferentially to asthmatic offspring. CONCLUSION: Our results confirm the involvement of ADAM33 in the development of childhood asthma among the Japanese.