SCOTT T contact WEISS

..It is anticipated that this will dramatically increase over the next 10 years as personalized medicine becomes more of a reality for asthma patients...

..Little is known about the role of most asthma susceptibility genes during human lung development. Genetic determinants for normal lung development are not only important early in life, but also for later lung function...

..However, little is known about the immunological effects of microbial stimulation on early immune responses and in association with maternal atopy...

..Signal transducer and activator of transcription 3 is a transcription factor latent in the cytoplasm; the gene (STAT3) is activated by a wide range of cytokines, and may play a role in lung development and asthma pathogenesis...

..Genetic variants at the vitamin D receptor (VDR) locus are associated with asthma and atopy. We hypothesized that polymorphisms in other genes of the vitamin D pathway are associated with asthma or atopy...

..Sequence variants in genes functioning in folate-mediated one-carbon metabolism are hypothesized to lead to changes in levels of homocysteine and DNA methylation, which, in turn, are associated with risk of cardiovascular disease...

..A modest number of prospective studies of the composition of the intestinal microbiota and eczema in early life have yielded conflicting results...

..The text descriptions in electronic medical records are a rich source of information. We have developed a Health Information Text Extraction (HITEx) tool and used it to extract key findings for a research study on airways disease...

..We hypothesized that the use of random forests classifiers to select SNPs would result in an improved predictive model of asthma exacerbations. We tested this hypothesis in a population of childhood asthmatics...

..We sought to find asthma-susceptibility variants by using probands from a single population in both family-based and case-control association designs...

..We have now demonstrated in this paper the use of SSARs in the context of longitudinal family data...

..0 and the Illumina HumanRef-8 v2 Expression Bead Chips, for comparability in a biological system in which changes may be subtle, namely fetal lung tissue as a function of gestational age...

..The FDA advisory on long-acting beta-agonists (LABAs) is not based on new data but on ongoing safety concerns about this class of medication. Not to be ignored are the potential safety risks of short-acting beta-agonists (SABAs)...

..It addresses methodological barriers that limit the available data and evaluates the adequacy of the data for risk assessment...

..These discoveries open new avenues for research in asthma and allergy, and highlight the power (and limitations) of positional cloning for the identification of asthma genes, and complex trait genes in general...

..For asthma genetics to begin to have an impact on clinical medicine we need to consider epistatic interaction...

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..The primary objective of this review is to discuss the prevalence, risk factors, and natural history of asthma and its relationship to chronic airflow obstruction...

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..001), and longer duration of asthma (r = -0.11, beta = -0.20, p < 0.002). These data provide evidence that the degree of airway responsiveness is linked to disease severity in children with mild to moderate asthma...

..This Pulmonary Perspective discusses what we are learning from genome-wide association studies, where the field of genetics and genomics is headed, and how this knowledge will ultimately be put to use in clinical medicine...

..Maternal vitamin D intake during pregnancy has been inversely associated with asthma symptoms in early childhood. However, no study has examined the relationship between measured vitamin D levels and markers of asthma severity in childhood...

..This study suggests that epithelium-specific ETS-2 and ETS-3 genes are unlikely to contain polymorphic loci that have a major impact on asthma susceptibility in our population...

..03). Although some evidence for replication was found for SFTPB and HMOX1, none of the previously published COPD genetic associations was convincingly replicated across both study designs...

..Polymorphisms in the gene for transforming growth factor-beta1 (TGFB1) have been associated with asthma, but not with airway responsiveness or disease exacerbations in subjects with asthma...

..008 and 0.043, respectively). Polymorphisms in IL10 are associated with asthma phenotypes in this cohort. Further studies of variation in the IL10 gene may help elucidate the mechanism of asthma development in children...

..Though it is unclear what gene or regulatory effect explains the association, the region warrants further investigation...

..The Met772-AC9 polymorphism represents one of most likely several multi-gene polymorphisms along the receptor-relaxation axis, which together may provide for a composite pharmacogenetic index for asthma therapy...

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..026 for c.+1031G>A). Consistent association in two independent samples and association with an intermediate phenotype provides strong support for TLR10 genetic variation contributing to asthma risk...

..Beta2-adrenergic receptor (B2AR) polymorphisms have been associated with a variety of asthma-related phenotypes, but association results have been inconsistent across different studies...

..The guidelines are illustrated by an application to an asthma study...

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..aeruginosa acquisition...

..We aim to assess associations between genetic variants of CRHR2 and acute bronchodilator response in asthma...

..However, the existence of any genotype-dependent difference has not been tested in a prospective clinical trial...

..The allergenicity of dust mite exposure might be dependent on variants in the gene for IL-10 (IL10)...

..As iron and lead promote oxidative damage, and hemochromatosis (HFE) gene polymorphisms increase body iron burden, HFE variant alleles may modify the lead burden and cognitive decline relationship...

..Among asthmatic subjects, bronchodilator response (BDR) to inhaled beta(2)-adrenergic agonists is variable, and the significance of a consistent response over time is unknown...

..Increased allergen-induced IL-13 secretion is most strongly associated with early life increase of IgE...

..Genetic variants influencing lung function in children and adults may ultimately lead to the development of chronic obstructive pulmonary disease (COPD), particularly in high-risk groups...

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..Identification of a common AC9 variant that confers reduced enzyme activity reveals an additional polymorphism that should be considered in pharmacogenetic studies of beta-agonist therapy of asthma...

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..Increased cord blood IgE levels, in conjunction with a family history of atopy, are associated with the development of allergic diseases in children. However, little is known about predictors of cord blood IgE levels...

..Therefore, TLR2 and TLR4 stimuli differentially influence IL-13 and IFN-gamma secretion in neonates, adults, and mice, supporting a critical role for innate stimuli in the modulation of cytokine responses...

..6 x 10(-)(5)). PRKCA is a pleiotropic locus that is associated with both BMI and asthma and that has been identified via linkage analysis of BMI in a population ascertained on asthma...

..07), with adjustment for race and poverty. We conclude that cockroach and cat allergens may contribute to asthma morbidity in sensitized women...

..To the degree that these factors diminished plateau phase pulmonary function, they may be important predictors of chronic obstructive pulmonary disease in later life...

..Lastly, we utilize these tests to analyze a continuous lung function phenotype as a proxy for asthma in the Childhood Asthma Management Program. The methods are implemented in the free R package fbati...

..The implications of these findings for future development of allergy or asthma are, as yet, unknown...

..Few studies have examined the effects of in utero smoke exposure (IUS) on lung function in children with asthma, and there are no published data on the impact of IUS on treatment outcomes in children with asthma...

..Vitamin D status might play a role in preventing asthma exacerbations...

..The role of these mutations in the development of asthma is less clear, particularly in patients who do not have coincident atopic dermatitis...

..This result seems to provide further evidence that a severe bottleneck occurred during the founding of Europe and the conjectured "Out of Africa" event...

..Thus, the lung function response to zileuton is modulated by several of the loci that also influence montelukast response...

..Estimation of such networks has been a challenging problem when the genes considered greatly outnumber the samples, and the situation is exacerbated when one wishes to consider the impact of polymorphisms (SNPs) in genes...

..The effects of inhaled corticosteroid (ICS) preparations on bone health have been debated. Multiple analyses have been published examining the question, with mixed results...

..We then applied the approach to a genome-wide association scan to search for associations between single nucleotide polymorphisms and body mass index in the Childhood Asthma Management Program data...

..Although inhaled corticosteroids (ICSs) generally protect against severe exacerbations in asthma, they may result in elevated IgE levels, which are associated with exacerbations...

..Given the high acquisition cost of omalizumab, its role and cost-effectiveness in disease management require definition...

..Medicaid and the supplementary State Children's Health Insurance Plan data about health-care utilization for asthma were obtained for each child for the 12 months preceding completion of the screening survey...

..The purpose of this work was to examine the relation between cytokine secretions by cord blood mononuclear cells and acute lower respiratory illness in a birth cohort of 297 children...

..We hypothesized that levels of serum biomarkers would correlate with clinical course of CF as defined by pulmonary function testing (FEV1)...

..The objective of this study was to examine the relation between endotoxin exposure in early life and eczema in the first year of life in children with parental history of asthma or allergies...

..Few prospective data link early childhood adiposity with asthma-related symptoms...

..No SNP caused amino acid changes. Differences in pairwise linkage-disequilibrium (LD) patterns and in SNP and haplotype frequency distributions among the three populations may be of potential importance for disease association studies...

..4; OR for two or more versus no courses of antibiotics, 0.9; 95% CI, 0.5 to 1.4). Our findings do not support the hypothesis that antibiotic use in early life is associated with the subsequent development of asthma and atopy in childhood...

..Studies have found that exposure to mice is highly prevalent among children with asthma living in urban areas...

..In smokers only, the maximum two point LOD score for mild airflow obstruction was 3.14. These observations provide suggestive evidence that there is a locus on chromosome 12p which contributes to susceptibility to early-onset COPD...

..It has been hypothesized that day care--related infections may explain the inverse relation between day care attendance in early life and asthma in childhood...

..This study has also identified several genomic regions that could contain loci regulating BDR in early-onset COPD families...

..Application of the proposed test to an asthma study illustrates the power of the approach...

..These results suggest that subjects with the E4 isoform of APOE may have advantages over those with the E2 or E3 isoforms with respect to early life neuronal/brain development...

..The practical importance of our testing strategy is illustrated by applications to the Childhood Asthma Management Program asthma data sets...

..However, a substantial proportion of patients with asthma do not have a favorable response to these drugs, and identifying genetic determinants of drug response may aid in tailoring treatment for individual patients...

..To examine the relationship between ethnicity and sensitization to allergens among children with asthma living in urban and suburban areas of Connecticut...

..Among elderly men, subjects with HFE variants had lower patella lead levels. These effects may be mediated by alterations in lead toxicokinetics via iron metabolic pathways regulated by the HFE gene product and body iron stores...

..Airway responsiveness is a prognostic marker for asthma symptoms in later life. Objectives: To evaluate characteristics responsible for persistence of airway responsiveness in children with asthma...

..Psychologic stress modifies immune function and cytokine production...

..Develop a new test for family-based association studies and continuous traits that incorporates power- enhancing techniques from two existing testing strategies...

..Fine mapping efforts for these loci are warranted...

..Identify clinical factors that modulate the risk of progression to COPD among asthma patients using data extracted from electronic medical records...

..To confirm these findings, we tested the hypothesis that serum cytokines are associated with longitudinal lung function decline...

..These findings suggest a more direct mechanism may be operating between stress and wheeze in early childhood. Stress may contribute significantly to the population burden of preventable childhood respiratory illness...

..We assess the potential of applying canonical correlation analysis to partitioned genomewide data as a method for discovering regulatory variants...

..We illustrate the approach by an application to a GWAS of attention deficit hyperactivity disorder parent-offspring trios and publicly available controls...

..To assess the feasibility of developing a Combined Clinical and Pharmacogenetic Predictive Test, comprised of multiple single nucleotide polymorphisms (SNPs) that is associated with poor bronchodilator response (BDR)...

..Animal models demonstrate that aberrant gene expression in utero can result in abnormal pulmonary phenotypes...

..We hypothesize that common IPO13 genetic variation influences the anti-inflammatory effects of inhaled corticosteroids for the treatment of asthma, as measured by change in methacholine airway hyperresponsiveness (AHR-PC20)...

..There was no association between wheezing and exposure to dog or dog allergen, and the father's allergy status had no effect on the relation between childhood wheezing and cat exposure...

..We examined whether bottle feeding in the bed or crib before sleep time in the first year of life is associated with wheezing in the first 5 years of life...

..These and other factors must be taken into account in the design and analysis of disease association studies...

..Functional relationships between FEV(1) percent predicted and asthma-related symptoms can be useful for inferring the effect on the symptoms of a population associated with overall improvements in lung function...

..Asthma is common in minority and disadvantaged populations, whereas atopic disorders other than asthma appear to be less prevalent. It is unclear whether the same holds true for objective markers of sensitization...

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..If successful, our research should directly benefit patient care by lowering morbidity and mortality and substantially decreasing health care costs. ..

..We have successfully taken 10/10 (100%) of our T-32 trainees in Genetics to successful K funding or its equivalent, and 6/6 (100%) of those eligible, to successful R01 funding in the past 10 years. (End of Abstract) ..

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..For the past 10 years, we've had a 96% retention of trainees in academic positions. (End of Abstract) ..

..The goal of this PPG is replicated genes for airways disease pointing the way to novel pathobiology and clinical prediction. ..

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..Thus, this proposal will greatly contribute to our understanding of the pathogenesis of a significant public health problem among Hispanic Americans: bronchial asthma. ..

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