Interactions between genes and environmental factors in asthma and atopy: new developments

Asthma and associated phenotypes are complex traits most probably caused by an interaction of multiple disease susceptibility genes and environmental factors. Major achievements have occurred in identifying chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma, atopic dermatitis, IgE levels and response to asthma therapy. The aims of this review are to explain the methodology of genetic studies of multifactorial diseases, to summarize chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma and associated traits, to list genetic alterations that may alter response to asthma therapy, and to outline genetic factors that may render individuals more susceptible to asthma and atopy due to environmental changes

Association and Linkage of Atopic Dermatitis with Chromosome 13q12–14 and 5q31–33 Markers

Atopic dermatitis is a chronic inflammatory skin disease that affects 10–20% of the population. Linkage of atopy, asthma, allergic rhinitis, and total serum IgE levels to several different chromosomal regions have been described extensively, but little is known about the genetic control of atopic dermatitis. We tested for the association and linkage between atopic dermatitis and five chromosomal regions: 5q31–33, 6p21.3, 12q15–24.1, 13q12–31, and 14q11.2/14q32.1–32.3. Marker analysis was performed in two Caucasian populations: (i) 192 unrelated German children with atopic dermatitis and 59 non-atopic children from a German birth cohort study (MAS'90), parental DNA was tested in 77 of 192 children with atopic dermatitis; (ii) 40 Swedish families with at least one family member with atopic dermatitis selected from the International Study of Asthma and Allergy in Children. Evidence for linkage and allelic association for atopic dermatitis was observed for markers on chromosome 13q12–14 and 5q31–33

Streulichtarme holografische Blaze-Gitter für den EUV-Bereich

Die physikalisch-optischen Randbedingungen beim Einsatz von Beugungsgittern im Wellenlängen-Bereich um 13,5nm bedingen einen großen Einfallswinkel. Die gebeugte Strahlung hinter einem solchen Grazing-Incidence-Gitter wird dabei an einer wesentlich größeren Fläche umgelenkt, als dies bei üblichen Anwendungen in einem Wellenlängenbereich der Fall wäre, in dem sich Schichtmaterialien mit hohem Reflexionsgrad verwenden ließen. Deshalb wirken sich Abweichungen von der Ebenheit bzw. Sollform des Gittersubstrats wesentlich stärker aus. Durch das sehr große Verhältnis von Gitterperiode zu Wellenlänge ist die Form der Blaze-Facetten der dominierend effizienzbestimmende Faktor. Sehr ungünstig sind in diesem Zusammenhang schlecht definierte Blaze-Facetten sowie auch Oberflächendefekte und Rauigkeit. Wir zeigen, dass die Herstellung dieser anspruchsvollen Gitter basierend auf einem holografischen Mastering in Photoresist in Kombination mit einem RIBE-Transfer-Prozess zu geeigneten Blaze-Strukturen führt. Projekt-Partner: Zeiss: Holografie; IOM: Reaktives Ionenstrahlätzen; PTB: Messungen bei Arbeitswellenlänge unter Nutzung von Synchrotron-Strahlung am Speicherring BESSY; TUI: wissenschaftliche Grundlagen zur Holografi

CD14 C-159T and Toll-Like Receptor 4 Asp299Gly Polymorphisms in Surviving Meningococcal Disease Patients

BACKGROUND: Carriage of Neisseria meningitidis occurs approximately in 10% of the population, onset of invasive meningococcal disease (IMD) cannot be predicted and differs between ages. It remains unclear, which host factors determine invasion of the bloodstream by the bacteria. Innate immunity has a very important role in the first recognition of invading pathogens. The functional single nucleotide polymorphisms (SNPs) CD14 C-159T and toll-like receptor 4 (TLR4) Asp299Gly have been associated with the risk of gram-negative infections. However, their role in development of IMD still remains unclear. Our aim was to investigate the influence of CD14 C-159T and TLR4 Asp299Gly polymorphisms on the risk of IMD. METHODOLOGY/PRINCIPAL FINDINGS: It was a retrospective case control study. Surviving Austrian meningococcal disease patients were enrolled by sending buccal swabs for DNA analysis. 185 cases with a proven meningococcal infection and 770 healthy controls were enrolled. In surviving meningococcal disease patients DNA analysis of CD14 C-159T and TLR 4 Asp299Gly polymorphisms was performed, as they are part of the innate immune response to bacterial determinants. CD14 C-159T and TLR4 Asp299Gly SNPs were not significantly associated with the presence of IMD when compared to healthy controls. The odds ratio for CD14 C-159T SNP was 1.14 (95% confidence interval (CI) 0.91-1.43; p = 0.266). In TLR4 Asp 299 Gly SNP the odds ratio was 0.78 (CI 0.47-1.43; p = 0.359). CONCLUSION/SIGNIFICANCE: We could not observe a significant influence of CD14 C-159T and TLR4 Asp299Gly polymorphisms on the risk of developing IMD in surviving meningococcal disease patients. To our knowledge, this is the first study investigating the influence of the CD14 C-159T SNP on the susceptibility to IMD

An arrhythmogenic metabolite in atrial fibrillation

Abstract Background Long-chain acyl-carnitines (ACs) are potential arrhythmogenic metabolites. Their role in atrial fibrillation (AF) remains incompletely understood. Using a systems medicine approach, we assessed the contribution of C18:1AC to AF by analysing its in vitro effects on cardiac electrophysiology and metabolism, and translated our findings into the human setting. Methods and results Human iPSC-derived engineered heart tissue was exposed to C18:1AC. A biphasic effect on contractile force was observed: short exposure enhanced contractile force, but elicited spontaneous contractions and impaired Ca2+ handling. Continuous exposure provoked an impairment of contractile force. In human atrial mitochondria from AF individuals, C18:1AC inhibited respiration. In a population-based cohort as well as a cohort of patients, high C18:1AC serum concentrations were associated with the incidence and prevalence of AF. Conclusion Our data provide evidence for an arrhythmogenic potential of the metabolite C18:1AC. The metabolite interferes with mitochondrial metabolism, thereby contributing to contractile dysfunction and shows predictive potential as novel circulating biomarker for risk of AF

Spatially valid data of atmospheric deposition of heavy metals and nitrogen derived by moss surveys for pollution risk assessments of ecosystems

For analysing element input into ecosystems and associated risks due to atmospheric deposition, element concentrations in moss provide complementary and time-integrated data at high spatial resolution every 5 years since 1990. The paper reviews (1) minimum sample sizes needed for reliable, statistical estimation of mean values at four different spatial scales (European and national level as well as landscape-specific level covering Europe and single countries); (2) trends of heavy metal (HM) and nitrogen (N) concentrations in moss in Europe (1990–2010); (3) correlations between concentrations of HM in moss and soil specimens collected across Norway (1990–2010); and (4) canopy drip-induced site-specific variation of N concentration in moss sampled in seven European countries (1990–2013). While the minimum sample sizes on the European and national level were achieved without exception, for some ecological land classes and elements, the coverage with sampling sites should be improved. The decline in emission and subsequent atmospheric deposition of HM across Europe has resulted in decreasing HM concentrations in moss between 1990 and 2010. In contrast, hardly any changes were observed for N in moss between 2005, when N was included into the survey for the first time, and 2010. In Norway, both, the moss and the soil survey data sets, were correlated, indicating a decrease of HM concentrations in moss and soil. At the site level, the average N deposition inside of forests was almost three times higher than the average N deposition outside of forests

Modelling and mapping heavy metal and nitrogen concentrations in moss in 2010 throughout Europe by applying Random Forests models

Objective: This study explores the statistical relations between the concentration of nine heavy metals(HM) (arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), nickel (Ni), lead (Pb),vanadium (V), zinc (Zn)), and nitrogen (N) in moss and potential explanatory variables (predictors)which were then used for mapping spatial patterns across Europe. Based on moss specimens collected in 2010 throughout Europe, the statistical relation between a set of potential predictors (such as the atmospheric deposition calculated by use of two chemical transport models (CTM), distance from emission sources, density of different land uses, population density, elevation, precipitation, clay content of soils) and concentrations of HMs and nitrogen (N) in moss (response variables) were evaluated by the use of Random Forests (RF) and Classification and Regression Trees (CART). Four spatial scales were regarded: Europe as a whole, ecological land classes covering Europe, single countries participating in the European Moss Survey (EMS), and moss species at sampling sites. Spatial patterns were estimated by applying a series of RF models on data on potential predictors covering Europe. Statistical values and resulting maps were used to investigate to what extent the models are specific for countries, units of the Ecological Land Classification of Europe (ELCE), and moss species. Results: Land use, atmospheric deposition and distance to technical emission sources mainly influence the element concentration in moss. The explanatory power of calculated RF models varies according to elements measured in moss specimens, country, ecological land class, and moss species. Measured and predicted medians of element concentrations agree fairly well while minima and maxima show considerable differences. The European maps derived from the RF models provide smoothed surfaces of element concentrations (As, Cd, Cr, Cu, N, Ni, Pb, Hg, V, Zn), each explained by a multivariate RF model and verified by CART, and thereby more information than the dot maps depicting the spatial patterns of measured values. Conclusions: RF is an eligible method identifying and ranking boundary conditions of element concentrations in moss and related mapping including the influence of the environmental factors

Genetische und epidemiologische Risikofaktoren für allergische Erkrankungen

Asthma, hay fever and atopic dermatitis are complex diseases. Presumably, genetic factors that protected from infectious agents in the past do promote allergic disease in the absence of infectious agents. Linkage and candidate gene studies identified common as well as disease specific genetic determinants of atopic diseases. However, a large number of chromosomal regions and candidate genes were related to asthma and associated traits. International collaborations and meta analyses appear to be mandatory to identify the major genes for asthma and atopy. Also, gene-gene and gene-environment interaction analyses are of great importance to identify genetic risk factors for allergic diseases. Birth cohorts are particularly valuable since exposure to various environmental agents have been documented since early childhood. This work summarizes genetic and epidemiologic studies of the German Multicenter Allergy Study (MAS) that contributed significantly to our understanding of the development of asthma and allergy in childhood. This work summarizes candidate and linkage studies performed in the MAS-cohort and outlines early risk factors for allergic diseases in childhood that were observed in MAS-participants