A Disintegrin And Metalloprotease 33 Research Articles

Allele-specific micro-RNA-mediated regulation of ADAM33 in childhood allergic asthma.

A disintegrin and metalloprotease 33 (ADAM33) is associated with asthma susceptibility, and its genetic variations impact susceptibility and disease severity. However, the mechanisms remain unclear. This study aimed to investigate ADAM33 single nucleotide polymorphisms (SNPs) in childhood asthma susceptibility and explore their regulatory mechanisms. Eleven selected SNPs in ADAM33 were genotyped and identified the association with asthma susceptibility. In the validation cohort, we measured plasma sADAM33 levels and compared them with disease severity among children with different SNP genotypes. Computational predictions identified miRNAs targeting the SNP, and the impact of the SNP on miRNA regulation was confirmed using a dual luciferase reporter system. Finally, we validated the regulatory role of miRNAs on ADAM33 expression using an in vitro model with upregulated ADAM33 expression. Only rs3918400 was associated with asthma susceptibility. In the validation cohort, children with allergic asthma exhibited higher plasma sADAM33 levels. Among asthmatic children, those with the rs3918400 CT/TT genotype had higher sADAM33 levels, poorer asthma control, more severe airway hyper-responsiveness, lower FEV1% and higher dust mite-specific IgE activity compared to those with the CC genotype. miR-3928-5p bound strongly to the rs3918400 C allele and effectively reduced ADAM33 protein expression in CC genotype cells. However, the binding affinity of miR-3928-5p to the T allele was weaker, resulting in diminished negative regulation of protein expression. The rs3918400 SNP affects the negative regulation of ADAM33 by miR-3928-5p, potentially participating in a complex interplay of processes related to childhood asthma susceptibility.

Evaluation of the association between clinical parameters and ADAM33 and ORMDL3 asthma gene single-nucleotide polymorphisms with the severity of COVID-19

BackgroundCoronavirus Disease of 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients had varying clinical symptoms and disease severity (mild, moderate, severe, and critical). Several risk factors, including genetic polymorphisms, have been reported to be associated with disease risk and severity. This study aimed to investigate the association of two polymorphisms in the orosomucoid1-like 3 (ORMDL3) and a disintegrin and metalloprotease 33 (ADAM33) asthma-related genes with the severity of COVID-19. Material and methodsThe study included 116 COVID-19 patients with a positive polymerase chain reaction (PCR) test for the SARS-CoV-2 Delta variant. 58 patients with moderate symptoms, 28 patients with severe symptoms, and 30 outpatients with mild symptoms. Genotyping of rs7216389 in the ORMDL3 and rs2280091 in ADAM33 genes was performed by polymerase chain reaction-restriction fragment length polymorphism. Furthermore, records of patients were studied for hematological profiles and biochemical markers. ResultsNo significant association was found between rs7216389 and rs2280091 and the severity of COVID-19 between different groups of COVID-19 patients. The serum levels of RBC and neutrophil-to-lymphocyte ratio were significantly increased; the erythrocyte sedimentation rate (ESR), and Aspartate transaminase (SGOT) were significantly decreased during treatment in intensive care unit (ICU) patients. The serum levels of red blood cells, Platelets, Urea, Alkaline phosphatase, ESR, Alanine transaminase (SGPT), and SGOT were significantly increased during treatment in hospitalized patients. The serum levels of inflammatory factors, including C-reactive protein (CRP), D-dimer, and Ferritin at the time of admission, were significantly higher in patients admitted to the ICU patients compared to the other group of patients. ConclusionThe two polymorphisms studied in this research are not suitable markers for predicting the severity of COVID-19. However, there are significant differences in the amounts of some blood factors in different groups of COVID-19 patients (P < 0.05) and these factors can be used as a marker for the disease severity prediction.

Significant Association of Adam 33 Polymorphism with COPD in Javanese Population of Indonesia

Background: Chronic Obstructive Pulmonary Disease (COPD) is one of World health cases that is commonlyknown, which is triggered by the combination of environmental factors especially cigarette smoking andgenetic factors. The association between A disintegrin and metalloprotease 33 (ADAM33) polymorphismsand COPD has been investigated and reported by other researchers. Objective: The main aim of this study isto identify the association between single nucleotide polymorphisms (SNPs) in ADAM 33 gene with COPDin the Javanese population in Lampung, Indonesia. Methods: A randomized cross-sectional study was usedin this research. PCR-Sequencing method was involved to analyze the polymorphic for three SNPs (T1, T2,and Q-1) of the ADAM33 gene. Statistical analysis data was performed in descriptive and comparative aswell as it was measured by parametric/non-parametric tests. Results: The results showed that the T2 GG,and T1AG genotypes in COPD group were significantly more frequent rather than in control group (p &lt;0.05). In case of allele, it was found that the T1G and T2G was higher in COPD group rather than in thecontrol group (p = 0.440 and 0.131, respectively). Conclusion: The results clearly conclude that there wassignificant association between T1 and T2 polymorphisms of ADAM33 gene and COPD in the Javanesepopulation of Lampung, Indonesia.

Genetic association of ADAM33 polymorphisms with childhood asthma in Chinese Han population: A case-control study.

To explore the association of a disintegrin and metalloprotease 33 (ADAM33) polymorphisms with childhood asthma susceptibility, we conducted this case-control study.In this case-control study, we selected 96 asthma children and 86 healthy children to conduct the genotyping of ADAM33 polymorphisms through polymerase chain reaction-direct sequencing (PCR-DS). Hardy-Weinberg equilibrium (HWE) status in the control group was detected adopting chi-square test. Frequency differences of genotypes, alleles, and haplotypes were compared by chi-square test between the case and control groups. Linkage disequilibrium (LD) between polymorphisms was checked using Haploview software. Association intensity of the polymorphisms with the disease risk was assessed by odds ratio (OR) and 95% confidence interval (95%CI).The frequency of rs678881 GA genotype was obviously higher in cases than in controls (P = .03) and the carriage of this genotype conferred higher risk of asthma among children than GG genotype (OR = 2.03, 95%CI = 1.05–3.91). However, neither rs2280089 nor rs2853209 polymorphism was significantly associated with the risk of childhood asthma. Strong LD was found among rs678881, rs2280089 and rs2853209, and haplotype GGT was distinctly associated with the risk of asthma in children (OR = 0.28, 95%CI = 0.13–0.57).ADAM33 rs678881 polymorphism is significantly correlated with increased susceptibility to asthma in Chinese Han children. Besides, haplotype GGT among the 3 polymorphisms was obviously associated with decreased risk of childhood asthma.

Association of ADAM33 gene polymorphisms with asthma in Mongolian and Han groups in Inner Mongolia.

Polymorphisms in the gene encoding for A disintegrin and metalloprotease 33 (ADAM33) are closely associated with the risk of bronchial asthma attacks in different populations. We collected blood samples from 248 asthma patients – 130 of the Han ethnic group and 118 of the Mongolian ethnic group – living in the Inner Mongolia region of China, and analyzed the single nuclear polymorphisms (SNPs) of the T1, T2 and V4 loci of the ADAM33 gene using PCR-RFLP (restriction fragment length polymorphism). In addition, we also tested 256 healthy controls (134 and 122 from the Han and Mongolian ethnic groups respectively) for the same SNPs. Three genotypes of the T1, T2 and V4 loci were predominantly detected: while polymorphisms in the T1 locus were significantly associated with asthma risk in both Mongolian and Han ethnicities (P < 0.05, ∗P < 0.05), that in the V4 locus were relevant only in the Mongolian patients (P < 0.05, ∗P > 0.05). In contrast, polymorphisms in the T2 locus showed no significant association with asthma risk in either ethnic group (P > 0.05, ∗P > 0.05).

Effects of IFN-γ on cell growth and the expression of ADAM33 gene in human embryonic lung Mrc-5 fibroblasts in vitro

ABSTRACTObjective: To investigate the effects of interferon-γ (IFN-γ) on the proliferation and viability of human embryonic lung Mrc-5 fibroblasts in vitro and the expression of the A Disintegrin and Metalloprotease 33 (ADAM33) gene and to explore the mechanism of airway remodeling. Methods: Mrc-5 fibroblasts were sensitized with Dermatophagoides farinae 1 (Derf1) in vitro to mimic in vivo conditions observed in bronchial asthma. An inverted fluorescence microscope was used to observe changes in cell morphology before and after treatment. The viability of Mrc-5 cells was tested using the Cell Counting kit-8 (CCK8). Expression of the ADAM33 gene and protein in Mrc-5 cells was assessed using qPCR and Western blotting, respectively. Results: Different concentrations of Derf1 increased cell growth and the expression of the ADAM33 gene in Mrc-5 cells, and these changes were most obvious in the 10 µg/ml group. In contrast, IFN-γ decreased cell growth and the expression of the ADAM33 gene in both Mrc-5 cells and Derf1-induced Mrc-5 cells, and these changes were most obvious in the 10 ng/ml group. The negative effects of 10 ng/ml IFN-γ were the most significant at 32 hours. Conclusions: Derf1-induced Mrc-5 cells successfully imitated the in vivo conditions observed in patients with asthma. IFN-γ inhibited the proliferation and viability of Mrc-5 cells, and Derf1-induced Mrc-5 cells were more sensitive to IFN-γ treatment. IFN-γ treatment significantly downregulated the expression of the ADAM33 gene in a concentration- and time-dependent manner. IFN-γ may participate in airway remodeling in asthma by regulating the expression of the ADAM33 gene.

ADAM33 gene polymorphisms identified to be associated with asthma in a Chinese Li population.

A disintegrin and metalloprotease 33 (ADAM33) is an asthma susceptibility gene that has been proven to be present in certain human populations. The Li population is a minority ethnic group, most of whom maintain a distinctive lifestyle on Hainan Island in southern China. To the best of our knowledge, no previous study has established whether ADAM33 polymorphisms are associated with asthma in the Li population. Therefore, the ADAM33 polymorphisms in a Li population were investigated in the present study. A total of 150 asthma patients and 100 healthy subjects were enrolled in the present study, and their DNA samples were evaluated to analyze eight single-nucleotide polymorphisms (SNPs) on the ADAM33 gene. Asthma patients were subcategorized into low and high severity groups, and their SNP data were compared with the data of the control subjects. Single-marker and haplotype association was analyzed to demonstrate the association between ADAM33 SNPs and asthma using multiple genetic statistic tests. The results indicated significant differences in allele frequencies at the SNPs rs44707/T2 (P=0.008), rs2787094/V4 (P=0.028) and rs2280089/T+1 (P=0.021) between asthma patients and control subjects. The SNP rs44707/T2 was also found to be associated with the high severity group (P=0.024), although SNPs rs2787094/V4 were associated with the low severity group (P=0.019). Two haplotypes, GGAGAGT and GAAGGGT, were significantly associated with asthma (P=0.003 and 0.008, respectively). To the best of our knowledge, this is the first time that SNP rs2280089/T+1 has been reported to be associated with asthma in an Asian population. These data confirm that ADAM33 polymorphisms are associated with asthma susceptibility in the Li population and confirm the uniqueness of the Li minority population within China.

ASSOCIATION OF A DISINTEGRIN AND METALLOPROTEASE 33 GENE POLYMORPHISMS AND THEIR HAPLOTYPES WITH ASTHMA IN THE NORTH‑INDIAN POPULATION

&lt;p&gt;&lt;strong&gt;AIMS, SETTINGS, AND DESIGN:&lt;/strong&gt; A disintegrin and metalloprotease 33 (ADAM33), was the first identified asthma‑susceptible gene by positional cloning. A case‑control study was performed. We investigated: (1) Association of ADAM33 gene polymorphisms (V2 C/T, T2 A/G, T1 A/G, Q‑1 A/G, BC+1 A/G and S1 A/G) with asthma and its severity. (2) The distribution of ADAM33 gene polymorphisms’ haplotypes in the studied population and their association with the risk of asthma. &lt;strong&gt;SUBJECTS AND METHODS:&lt;/strong&gt; Using polymerase chain reaction and restriction fragment length polymorphism, six polymorphic sites V2 (C/T), T2 (A/G), T1 (A/G), BC+1 (A/G), Q‑1 (A/G), and S1 (A/G) were genotyped in 390 controls and 386 cases of asthma to investigate their association with asthma. Among the recruited cases, 95 (24.6%) were mild intermittent, 235 (60.9%) were mild persistent and 56 (14.5%) were moderate persistent. &lt;strong&gt;STATISTICAL ANALYSIS USED:&lt;/strong&gt; The whole analysis was age‑ and gender‑adjusted. Logistic regression model was used to find out the contribution of genetic polymorphisms to the risk of disease. &lt;strong&gt;RESULTS AND CONCLUSION:&lt;/strong&gt; We found statistically significant association of single nucleotide polymorphisms (SNPs) T1, S1, and T2 with asthma; however, none of the SNPs were found to be associated with the severity of asthma. GTGGGG haplotype was associated with the risk of asthma (Odds ratio = 4.40; P &amp;lt; 0.0001). In conclusion, results suggest the importance of ADAM33 SNPs with asthma in the North‑Indian population.&lt;/p&gt;

Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life.

Asthma is a chronic inflammatory airways disease that usually begins in early life and involves gene-environment interactions. Although most asthma exhibits allergic inflammation, many allergic individuals do not have asthma. Here, we report how the asthma gene a disintegrin and metalloprotease 33 (ADAM33) acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble ADAM33 (sADAM33) is increased in asthmatic airways and plays a role in airway remodeling, independent of inflammation. Furthermore, remodeling and inflammation are both suppressed in Adam33-null mice after allergen challenge. When induced in utero or added ex vivo, sADAM33 causes structural remodeling of the airways, which enhances postnatal airway eosinophilia and bronchial hyperresponsiveness following subthreshold challenge with an aeroallergen. This substantial gene-environment interaction helps to explain the end-organ expression of allergic asthma in genetically susceptible individuals. Finally, we show that sADAM33-induced airway remodeling is reversible, highlighting the therapeutic potential of targeting ADAM33 in asthma.

Association of a disintegrin and metalloprotease 33 (ADAM33) gene polymorphisms with the risk of COPD: an updated meta-analysis of 2,644 cases and 4,804 controls

A series of observational studies have been made to investigate the association of the ADAM33 gene polymorphisms with the risk of COPD, but their results were conflicting. Therefore, we performed an updated meta-analysis to quantitatively summarize the associations of ADAM33 gene polymorphisms with the risk of COPD. Thirteen case-control studies referring to nine SNPs were identified: V4 (rs2787094), T+1 (rs2280089), T2 (rs2280090), T1 (rs2280091), S2 (rs528557), S1 (rs3918396), Q-1 (rs612709), F+1 (rs511898) and ST+5 (rs597980). 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 evaluate the association of ADAM33 polymorphism with the risk of COPD. The results indicated that significant associations were found for ADAM33 T1, T2, S1, Q-1, F+1 and ST+5 polymorphisms associated with the risk of COPD in different populations. However, no significant associations were found for V4, T+1 and S2 polymorphisms with the risk of COPD in all genetic models, even in the subgroup analysis by ethnicity. This meta-analysis provided evidence that the ADAM33 T1, T2, S1, Q-1, F+1 and ST+5 six locus polymorphisms association with the risk of COPD. Furthermore, T2, Q-1 and ST+5 indicated an association with the risk of COPD in the European populations, whereas T1, T2, S1, F+1 and Q-1 indicated an association with the risk of COPD in the Asian populations.

Association of a disintegrin and metalloprotease 33 gene polymorphisms with asthma.

Various studies reported a disintegrin and metalloprotease 33 (ADAM33) as an important susceptibility gene for asthma, which is frequently detected among certain populations. The aim of the present study was to investigate the association between single-nucleotide polymorphisms (SNPs) of the ADAM33 gene and asthma. Our case-control study included 183 patients (73 male and 110 female, mean age 42.93±13.48 years) who were admitted in the First Affiliated Hospital of Xinjiang Medical University between February, 2012 and May, 2013 and 155 healthy controls (66 male and 89 female, mean age 41.14±14.10 years). Allele-specific polymerase chain reaction technology and DNA testing training methods were applied to detect the T2 and ST+5 polymorphisms of the ADAM33 gene. The data were statistically analyzed to determine whether there exists an association between these genotypes and asthma-related morbidity. The genotypes and allele frequencies of the T2 and ST+5 SNPs of ADAM33 were not found to be significantly associated with asthma risk when compared between asthmatic patients and healthy controls (P>0.05). In addition, there was no association of the investigated SNPs with the severity of asthma. There was no significant difference in the forced vital capacity and the forced expiratory volume between patients with the ADAM33 T2 and ST+5 genotype. In conclusion, our results suggested that the T2 and ST+5 ADAM33 gene polymorphisms do not confer a significant risk of asthma or affect its severity in the population investigated.

Polymorphisms in a disintegrin and metalloprotease 33 gene and the risk of chronic obstructive pulmonary disease: A meta‐analysis

A number of polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) gene have been implicated in susceptibility to chronic obstructive pulmonary disease (COPD). However, results to date have been inconclusive. We conducted meta-analyses to investigate the associations between multiple polymorphisms in ADAM33 gene and COPD susceptibility. PubMed, Embase and Chinese databases (Wanfang and China National Knowledge Infrastructure) were searched for eligible case-control studies. We extracted data and used meta-analysis to calculate pooled odds ratios with 95% confidence intervals to evaluate the strength of associations. Twelve studies containing six ADAM33 polymorphisms (F+1, S1, S2, T1, V4 and Q-1) were identified, which involved 2630 cases and 4376 controls. ADAM33 S1 polymorphism showed stable and significant associations with COPD risks among the Chinese and smoking populations, and Q-1 polymorphism showed stable and significant associations with COPD risks among the overall populations. In subgroup analyses, T1 and Q-1 polymorphisms were significantly associated with COPD risks among the Chinese and smoking populations, and among the Chinese, Caucasians and smoking populations, respectively. However, none of the significant results was stable in sensitivity analyses. With respect to F+1, S2 or V4 polymorphism, there was no evidence of any significant association with COPD risks in either the overall or the subgroup analysis. The results of this meta-analysis indicate that ADAM33 S1 polymorphism is a risk factor for COPD among the Chinese and smoking populations, and that Q-1 polymorphism is a risk factor for COPD among the overall populations.

Genetic polymorphisms and asthma: findings from a case-control study in the Madeira island population.

BackgroundAsthma is a complex disease influenced by multiple genetic and environmental factors. While Madeira has the highest prevalence of asthma in Portugal (14.6%), the effect of both genetic and environmental factors in this population has never been assessed. We categorized 98 asthma patients according to the Global Initiative for Asthma (GINA) guidelines, established their sensitization profile, and measured their forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) indexes. Selected single nucleotide polymorphisms (SNPs) were analysed as potential markers for asthma susceptibility and severity in the interleukin 4 (IL4), interleukin 13 (IL13), beta-2-adrenergic receptor (ADRB2), a disintegrin and metalloprotease 33 (ADAM33), gasdermin-like (GSDML) and the signal transducer and activator of transcription 6 (STAT6) genes comparatively to a population reference set.ResultsAlthough mites are the major source of allergic sensitization, no significant difference was found amongst asthma severity categories. IL4-590*CT/TT and IL4-RP2*253183/183183 were found to predict the risk (2-fold) and severity (3 to 4-fold) of asthma and were associated with a lower FEV1 index. ADRB2-c.16*AG is a risk factor (3.5-fold), while genotype GSDML-236*TT was protective (4-fold) for moderate-severe asthma. ADAM33-V4*C was associated to asthma and mild asthma by the transmission disequilibrium test (TDT). Finally, ADAM33-V4*CC and STAT6-21*TT were associated with higher sensitization (mean wheal size ≥10 mm) to house dust (1.4-fold) and storage mite (7.8-fold).ConclusionIn Madeira, IL4-590C/T, IL4-RP2 253/183, GSDML-236C/T and ADAM33-V4C/G SNPs are important risk factors for asthma susceptibility and severity, with implications for asthma healthcare management.Electronic supplementary materialThe online version of this article (doi:10.1186/0717-6287-47-40) contains supplementary material, which is available to authorized users.

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.

Effect of a disintegrin and metalloprotease 33 (ADAM33) gene polymorphisms and smoking in COPD

BackgroundCOPD is characterized by air flow limitation that is not fully reversed and associated with an influx of neutrophils, macrophages and CD8 T lymphocytes in the airways. The disease is characterized by airflow limitation and is associated with an abnormal inflammatory response of the lungs in response to noxious particles or gases and associated with systemic manifestation. MethodsSixty consecutive patients with COPD and 40 normal healthy individuals were included. All cases and controls were subjected to detection of 2 polymorphic loci (S1 AND Q1) of ADAM33 by PCR-RFLP technique. ResultsThe percentage of S1 and Q1 AA genotype and A allele were significantly increased in control than in COPD patients while there was significant increase in S1 and Q1 GG genotype and G allele in COPD patients than in control (p<0.001). No significant difference was found between smoker and non-smoker among the two studied groups in genotype and alleles distribution of ADAM33 SNPs S1 and Q1 p>0.05, whereas there was significant increase in ADAM33 S1 G allele and Q1 G allele in smoker and non-smoker in COPD patients as compared to their corresponding fellows in control group (p<0.05). As regard to Pulmonary function test there was significant decrease in % of FEV1 in COPD patients as compared to control group for both smokers and non-smokers (p<0.001). Within both control and COPD groups smokers had significant decrease in FEV1 % as compared to non-smokers (p<0.001). There was a significant decrease in FEV1 % among all genotypes in smoker as compared to non-smoker COPD patients (p<0.001), the most prominent decrease was found in smoker GG genotype for both ADAM33 S1 and Q1 in COPD patients. ConclusionIn conclusion, we found that polymorphisms in the SNPs (Q1 and S1) of ADAM33 gene are associated with COPD in the general population. In addition, smoker patients with GG genotype in (S1 and Q1) ADAM33 will have more pronounced decline in the pulmonary function test (FEV1).

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

Multiple A disintegrin and metalloprotease 33 (ADAM33) single nucleotide polymorphisms (SNPs) have been shown to be associated with asthma, but results have been inconsistent. To examine the association between ADAM33 SNPs rs2787094, rs628977, rs2280089, rs2280090, rs2280091, rs2853209, rs528557 and rs612709 and asthma in young adult Japanese women, and to perform haplotype analyses and assess interactions between SNPs and smoking. A total of 89 cases who met the criteria of the European Community Respiratory Health Survey (ECRHS) for asthma were included in the study. Control subjects were 1281 women without asthma, as per ECRHS criteria, who had not been diagnosed with asthma by a doctor. Adjustment was made for age, region of residence, presence of older siblings, smoking and education. Under a co-dominant model, the AA genotype of the rs612709 SNP was significantly positively associated with asthma compared with the GG genotype: the adjusted OR was 4.27 (95%CI 1.49-12.25). A significant positive relationship was found between the CCGGAAGA haplotype and asthma. Interactions between SNPs rs628977 and rs528557 and smoking were marginally significant (P = 0.09 and 0.095, respectively). ADAM33 SNP rs612709 and the CCGGAAGA haplotype may be associated with asthma. Smoking may modify the associations between SNPs rs628977 and rs528557 and asthma.

ADAM33 as a Psoriasis Susceptibility Gene in the Han Population of Northeastern China

Background: A disintegrin and metalloprotease 33 (ADAM33) has recently been suspected to be associated with psoriasis. Objective:To study the association between ADAM33 and psoriasis in the northeastern Chinese Han population. Methods: We genotyped six common single nucleotide polymorphisms from ADAM33 in 400 psoriasis cases and 398 controls using the Multiplex SNaPSHOT method. Results: We observed an increased risk of psoriasis to be associated with the rs2787094CC CG, rs528557CC CG genotypes (p < 0.05) and 3 haplotypes (H1, H3, and H5; p < 0.05). We also found that the rs512625AA rs612709AA GA genotypes and haplotype H8 may be protective against psoriasis (p < 0.05). Among these genotypes, rs2787094CC exhibited the strongest association with psoriasis (OR = 2.537,being the highest OR, p = 0.0014). Conclusions: ADAM33 polymorphisms are associated with psoriasis in the northeastern Chinese Han population.

Airway epithelial cells from asthmatic children differentially express proremodeling factors

The airway epithelium can express factors that drive subepithelial airway remodeling. TGF-β2, vascular epithelial growth factor (VEGF), a disintegrin and metalloprotease 33 (ADAM33), and periostin are hypothesized to be involved in subepithelial remodeling and are overexpressed in adult asthmatic airways. Epidemiologic data suggest that lung function deficits in asthmatic patients are acquired in childhood. We sought to determine whether airway epithelial cells (AECs) from asthmatic children differentially express TGF-β2, VEGF, ADAM33, or periostin compared with cells from atopic nonasthmatic and healthy children intrinsically or in response to IL-4/IL-13 stimulation. Bronchial and nasal epithelial cells were obtained from brushings from well-characterized asthmatic (n= 16), atopic nonasthmatic (n= 9), and healthy (n= 15) children after achievement of anesthesia for elective procedures. After differentiation at an air-liquid interface (ALI) for 3 weeks, conditioned media were sampled and RNA was extracted from unstimulated and IL-4/IL-13-stimulated cultures. TGF-β2 and VEGF levels were measured with ELISA. ADAM33 and periostin expression was assessed by using real-time PCR. TGF-β2 and VEGF production was significantly greater in bronchial and nasal ALI cultures from asthmatic children than in cultures from atopic nonasthmatic and healthy children. TGF-β2 levels increased significantly in asthmatic cultures after IL-4/IL-13 stimulation. Within-subject correlation between nasal and bronchial ALI production of TGF-β2 (r= 0.64, P= .001) and VEGF (r= 0.73, P< .001) was good. Periostin expression was 3.7-fold higher in bronchial cells (P< .001) and 3.9-fold higher in nasal cells (P< .004) from asthmatic children than in cells from atopic nonasthmatic or healthy children. ADAM33 was not differentially expressed by AECs from asthmatic patients compared with that from cells from atopic nonasthmatic or healthy children. AECs from asthmatic children differentially express TGF-β2, VEGF, and periostin compared with cells from atopic nonasthmatic and healthy children. Nasal epithelial cells might be a suitable surrogate for bronchial cells that could facilitate investigation of the airway epithelium in future longitudinal pediatric studies.

Regulation of a disintegrin and metalloprotease-33 expression by transforming growth factor-β.

The asthma susceptibility gene, a disintegrin and metalloprotease-33 (ADAM33), is selectively expressed in mesenchymal cells, and the activity of soluble ADAM33 has been linked to angiogenesis and airway remodeling. Transforming growth factor (TGF)-β is a profibrogenic growth factor, the expression of which is increased in asthma, and recent studies show that it enhances shedding of soluble ADAM33. In this study, we hypothesized that TGF-β also affects ADAM33 expression in bronchial fibroblasts in asthma. Primary fibroblasts were grown from bronchial biopsies from donors with and those without asthma, and treated with TGF-β(2) to induce myofibroblast differentiation. ADAM33 expression was assessed using quantitative RT-PCR and Western blotting. To examine the mechanisms whereby TGF-β(2) affected ADAM33 expression, quantitative methylation-sensitive PCR, chromatin immunoprecipitation, and nuclear accessibility assays were conducted on the ADAM33 promoter. We found that TGF-β(2) caused a time- and concentration-dependent reduction in ADAM33 mRNA expression in normal and asthmatic fibroblasts, affecting levels of splice variants similarly. TGF-β(2) also induced ADAM33 protein turnover and appearance of a cell-associated C-terminal fragment. TGF-β(2) down-regulated ADAM33 mRNA expression by causing chromatin condensation around the ADAM33 promoter with deacetylation of histone H3, demethylation of H3 on lysine-4, and hypermethylation of H3 on lysine-9. However, the methylation status of the ADAM33 promoter did not change. Together, these data suggest that TGF-β(2) suppresses expression of ADAM33 mRNA in normal or asthmatic fibroblasts. This occurs by altering chromatin structure, rather than by gene silencing through DNA methylation as in epithelial cells. This may provide a mechanism for fine regulation of levels of ADAM33 expression in fibroblasts, and may self-limit TGF-β(2)-induced ectodomain shedding of ADAM33.

Inhibition of 1,25-(OH)2D3 on passively sensitized human airway smooth muscle cells

To investigate the effects of 1,25-(OH)(2)D(3) on the proliferation of passively sensitized human airway smooth muscle cells (HASMCs) and their expressions of MMP-9 and a disintegrin and metalloprotease 33(ADAM33). HASMCs were passively sensitized with 10% serum from asthmatic patients. MTT colorimetry assay was used to examine the effect of 1,25-(OH)(2)D(3) on cell proliferation at different concentrations (10(-10) mol/L, 10(-9) mol/L, 10(-8) mol/L, 10(-7) mol/L).By this way, its optimal inhibitory concentration was determined. And then the effects of 1,25-(OH)(2)D(3) at the optimal concentration on cell proliferation was examined by the same MTT assay and cell cycle analysis by flow cytometry. The expressions of MMP-9 and ADAM33 in HASMCs were studied by real-time quantitative RT-PCR and Western blotting analysis. (1) Inhibition of cell proliferation by 1,25-(OH)(2)D(3) was barely detectable at 10(-10) mol/L. But with the increasing concentration ranging from 10(-9) mol/L to 10(-7) mol/L, 1,25-(OH)(2)D(3) markedly inhibited the cell proliferation concentration-dependently and reached the maximum effect at the concentration of 10(-7) mol/L. Accordingly, 10(-7) mol/L was chosen as the optimal concentration of 1,25-(OH)(2)D(3) for the following study. (2) At the concentration of 10(-7) mol/L, 1,25-(OH)(2)D(3) inhibited the cell proliferation of passively sensitized HASMCs in a time-dependent manner and hampered the G(1)/S transition. (3) 1,25-(OH)(2)D(3) pretreatment attenuated the MMP-9 and ADAM33 protein levels in passively sensitized HASMCs by (63.4 ± 3.6)% and (50.9 ± 2.9)%, respectively (P < 0.01). (4) 1,25-(OH)(2)D(3) significantly inhibited the MMP-9 and ADAM33 mRNA levels in passively sensitized HASMCs by (52.2 ± 2.5)% and (67.8 ± 3.2)%, respectively (P < 0.01). 1,25-(OH)(2)D(3) has a direct inhibitory effect on passively sensitized HASMCs in vitro, including the inhibition of cell proliferation and the expressions of MMP-9 and ADAM33, which maybe associated with the beneficial role of 1,25-(OH)(2)D(3) in the prevention and therapy of asthmatic airway remodeling.