ADAM33 Single Nucleotide Polymorphisms Research Articles

Association between ADAM33 Single-Nucleotide Polymorphisms and Treatment Response to Inhaled Corticosteroids and a Long-Acting Beta-Agonist in Asthma.

ADAM33 has been linked to airway structural changes in patients with asthma, leading to airway hyperresponsiveness, narrowing, and ultimately poor treatment responsiveness. This study aimed to evaluate the genetic association of ADAM33 SNPs with asthma, disease severity, and treatment responsiveness to ICS+LABA in the South Indian population. In this case-control study (486 controls and 503 cases), we performed genotyping using MassArray for six SNPs of ADAM33, namely rs2280091, rs2787094, rs3918396, rs67044, rs2853209, and rs3918392. We studied the association with asthma and treatment responsiveness to ICS+LABA, using genotype, allele frequency distribution, and haplotype analysis. A significant clinical finding of the study was that certain patients in the disease severity group (moderate and mild) showed poor or no improvement after a three-month follow-up of regular ICS+LABA therapy. Of the studied ADAM33 SNPs, rs2853209 showed an association with asthma. The further analysis of asthma patients according to disease severity suggested an association between moderate disease and the minor allele "T" for rs2853209. The homozygous minor allele of SNP rs2787094 was found to be associated with poorer lung function and the least lung-function improvement after three months of ICS+LABA therapy. The haplotype analysis of six SNPs showed a significant association between the rs2853209 and rs3918396 blocks and asthma. ADAM33 gene polymorphism has clinical relevance in terms of disease association and response to treatment. SNP rs2853209 seemed most relevant to asthma, and SNP rs2787094 could be a genetic marker for predicting response to ICS+LABA therapy in the study population.

Genetic predisposition of RSV infection-related respiratory morbidity in preterm infants

The aim of this study was to assess whether prematurely born infants have a genetic predisposition to respiratory syncytial virus (RSV) infection-related respiratory morbidity. One hundred and forty-six infants born at less than 36 weeks of gestation were prospectively followed. Nasopharygeal aspirates were obtained on every occasion the infants had a lower respiratory tract infection (LRTI) regardless of need for admission. DNA was tested for 11 single-nucleotide polymorphisms (SNPs). Chronic respiratory morbidity was assessed using respiratory health-related questionnaires, parent-completed diary cards at a corrected age of 1 year and review of hospital notes. Lung function was measured at a post menstrual age (PMA) of 36 weeks and corrected age of 1 year. A SNP in ADAM33 was associated with an increased risk of developing RSV LRTIs, but not with significant differences in 36-week PMA lung function results. SNPs in several genes were associated with increased chronic respiratory morbidity (interleukin 10 (IL10), nitric oxide synthase 2A (NOS2A), surfactant protein C (SFTPC), matrix metalloproteinase 16 (MMP16) and vitamin D receptor (VDR)) and reduced lung function at 1 year (MMP16, NOS2A, SFTPC and VDR) in infants who had had RSV LRTIs. Our results suggest that prematurely born infants may have a genetic predisposition to RSV LRTIs and subsequent respiratory morbidity which is independent of premorbid lung function.

T1 and T2 ADAM33 single nucleotide polymorphisms and the risk of childhood asthma in a Saudi Arabian population: a pilot study.

BACKGROUND AND OBJECTIVESGenetic association studies have demonstrated that over 100 variants in target genes (including ADAM33) are associated with airway remodeling and hyper-responsiveness in different ethnic groups; however, this has never been evaluated in Arabic populations. The objective of this study was to determine whether ADAM33 polymorphisms that are associated with asthma in a population of asthmatic children from Saudi Arabia.DESIGN AND SETTINGA cross-sectional pilot study comparing the polymorphisms of normal subjects and asthmatic patients from Saudi Arabia over a period of 1 year.PATIENTS AND METHODSOne hundred and seven Saudi asthmatic children and 87 healthy Saudi children of 3–12 years old were assessed for allelic association of ADAM33 T1 (rs2280091), T2 (rs2280090), ST+4 (rs44707) and S1 (rs3918396) SNPs to asthma. Genotyping was done by real-time PCR, multiplex ARMS and PCR-RFLP.RESULTST1 and T2 SNP genotype frequencies in asthmatic children were significantly different compared to controls (P<.05), indicating allelic association with asthma. The T1 A/G and G/G and the T2 A/G and A/A genotypes (P=.0013 and P=.008, respectively) but not S1 and ST+4, increased the risk of asthma when using the best fit dominant model. Strong linkage disequilibrium between T1 (rs2280091) and T2 (rs2280090) was observed (r2=0.83; D′=0.95; P<.001). The haplotype G-A-A-C was significantly more frequent in asthmatics, thus supporting the association of T1 G-allele and T2 A-allele with increased predisposition to asthma (P=.007).CONCLUSIONST1 A/G and T2 G/A ADAM33 polymorphisms, but not S1 or ST+4, were significantly associated with asthma development in Saudi children, like those reported for white and Hispanic populations in the United States.

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.

Association of STAT6 and ADAM33 single nucleotide polymorphisms with asthma bronchiale and IgE level and its possible epigenetic background

ADAM33 and STAT6 belong to the candidate genes that have been commonly associated with asthma, bronchial hyperresponsiveness or IgE levels. Our objective was to assess the association of 11 SNPs of the ADAM33 and 6 of the STAT6 and their haplotypes with IgE levels and asthma. We also evaluated the possible role of parental origin of haplotypes on IgE levels. We enrolled 109 children with asthma and 45 healthy controls. Genotyping was performed by TaqMan probes and confirmed by sequencing. Haplotype construction was based on the knowledge of parental genotypes and also inferred by using the EM algorithm and Bayes' theorem. None of the SNPs were associated with elevated IgE level or asthma. We found that the most frequent STAT6 haplotype ATTCAA (built from rs324012, rs324011, rs841718, rs3024974, rs3024974, rs4559 SNPs, respectively) was associated with elevated total IgE levels (P=0.01) and this haplotype was predominantly transmitted paternally (P<0.001). We compared our results with those of studies performed on German and Australian Caucasian populations and found that rs324011, rs3024974 and rs4559 SNPs in STAT6 should have a major effect on IgE levels. Therefore, we suggest the TCA haplotype alone (built from rs324011, rs3024974 and rs4559 SNPs, respectively) in STAT6 is associated with total IgE elevation. The influence of paternal origin of the STAT6 haplotype on IgE levels is surprising but the exact role of possible paternal imprinting in STAT6 regulation should be investigated and confirmed in future studies.

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

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 (FEV(1)) 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. 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. Six ADAM33 single-nucleotide polymorphisms (SNPs) were genotyped. Rint was measured at age 4 and 8 years, FEV(1) and BHR at age 8 years; asthma was based on questionnaire data at age 8. 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 FEV(1)% predicted. 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.

Adam33 polymorphisms are associated with COPD and lung function in long-term tobacco smokers

BackgroundVariation in ADAM33 has been shown to be important in the development of asthma and altered lung function. This relationship however, has not been investigated in the population susceptible to COPD; long term tobacco smokers. We evaluated the association between polymorphisms in ADAM33 gene with COPD and lung function in long term tobacco smokers.MethodsCaucasian subjects, at least 50 year old, who smoked ≥ 20 pack-years (n = 880) were genotyped for 25 single nucleotide polymorphisms (SNPs) in ADAM33. COPD was defined as an FEV1/FVC ratio < 70% and percent-predicted (pp)FEV1 < 75% (n = 287). The control group had an FEV1/FVC ratio ≥ 70% and ppFEV1 ≥ 80% (n = 311) despite ≥ 20 pack years of smoking. Logistic and linear regressions were used for the analysis. Age, sex, and smoking status were considered as potential confounders.ResultsFive SNPs in ADAM33 were associated with COPD (Q-1, intronic: p < 0.003; S1, Ile → Val: p < 0.003; S2, Gly → Gly: p < 0.04; V-1 intronic: p < 0.002; V4, in 3' untranslated region: p < 0.007). Q-1, S1 and V-1 were also associated with ppFEV1, FEV1/FVC ratio and ppFEF25–75 (p values 0.001 – 0.02). S2 was associated with FEV1/FVC ratio (p < 0.05). The association between S1 and residual volume revealed a trend toward significance (p value < 0.07). Linkage disequilibrium and haplotype analyses suggested that S1 had the strongest degree of association with COPD and pulmonary function abnormalities.ConclusionFive SNPs in ADAM33 were associated with COPD and lung function in long-term smokers. Functional studies will be needed to evaluate the biologic significance of these polymorphisms in the pathogenesis of COPD.

Analysis of polymorphisms in 16 genes in type 1 diabetes that have been associated with other immune-mediated diseases

BackgroundThe identification of the HLA class II, insulin (INS), CTLA-4 and PTPN22 genes as determinants of type 1 diabetes (T1D) susceptibility indicates that fine tuning of the immune system is centrally involved in disease development. Some genes have been shown to affect several immune-mediated diseases. Therefore, we tested the hypothesis that alleles of susceptibility genes previously associated with other immune-mediated diseases might perturb immune homeostasis, and hence also associate with predisposition to T1D.MethodsWe resequenced and genotyped tag single nucleotide polymorphisms (SNPs) from two genes, CRP and FCER1B, and genotyped 27 disease-associated polymorphisms from thirteen gene regions, namely FCRL3, CFH, SLC9A3R1, PADI4, RUNX1, SPINK5, IL1RN, IL1RA, CARD15, IBD5-locus (including SLC22A4), LAG3, ADAM33 and NFKB1. These genes have been associated previously with susceptibility to a range of immune-mediated diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Graves' disease (GD), psoriasis, psoriatic arthritis (PA), atopy, asthma, Crohn disease and multiple sclerosis (MS). Our T1D collections are divided into three sample subsets, consisting of set 1 families (up to 754 families), set 2 families (up to 743 families), and a case-control collection (ranging from 1,500 to 4,400 cases and 1,500 to 4,600 controls). Each SNP was genotyped in one or more of these subsets. Our study typically had approximately 80% statistical power for a minor allele frequency (MAF) >5% and odds ratios (OR) of 1.5 with the type 1 error rate, α = 0.05.ResultsWe found no evidence of association with T1D at most of the loci studied 0.02 <P < 1.0. Only a SNP in ADAM33, rs2787094, was any evidence of association obtained, P = 0.0004 in set 1 families (relative risk (RR) = 0.78), but further support was not observed in the 4,326 cases and 4,610 controls, P = 0.57 (OR = 1.02).ConclusionPolymorphisms in a variety of genes previously associated with immune-mediated disease susceptibility and/or having effects on gene function and the immune system, are unlikely to be affecting T1D susceptibility in a major way, even though some of the genes tested encode proteins of immune pathways that are believed to be central to the development of T1D. We cannot, however, rule out effect sizes smaller than OR 1.5.

Identifying SNPs predictive of phenotype using random forests

There has been a great interest and a few successes in the identification of complex disease susceptibility genes in recent years. Association studies, where a large number of single-nucleotide polymorphisms (SNPs) are typed in a sample of cases and controls to determine which genes are associated with a specific disease, provide a powerful approach for complex disease gene mapping. Genes of interest in those studies may contain large numbers of SNPs that classical statistical methods cannot handle simultaneously without requiring prohibitively large sample sizes. By contrast, high-dimensional nonparametric methods thrive on large numbers of predictors. This work explores the application of one such method, random forests, to the problem of identifying SNPs predictive of the phenotype in the case-control study design. A random forest is a collection of classification trees grown on bootstrap samples of observations, using a random subset of predictors to define the best split at each node. The observations left out of the bootstrap samples are used to estimate prediction error. The importance of a predictor is quantified by the increase in misclassification occurring when the values of the predictor are randomly permuted. We extend the concept of importance to pairs of predictors, to capture joint effects, and we explore the behavior of importance measures over a range of two-locus disease models in the presence of a varying number of SNPs unassociated with the phenotype. We illustrate the application of random forests with a data set of asthma cases and unaffected controls genotyped at 42 SNPs in ADAM33, a previously identified asthma susceptibility gene. SNPs and SNP pairs highly associated with asthma tend to have the highest importance index value, but predictive importance and association do not always coincide.

ADAM33 polymorphisms and phenotype associations in childhood asthma

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. To examine whether ADAM33 is associated with asthma in a North American population of childhood asthmatic patients. 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. 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. 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.