Genetic Analyses of Heme Oxygenase 1 (HMOX1) in Different Forms of Pancreatitis

Contains fulltext : 107993.pdf (publisher's version ) (Open Access)BACKGROUND: Heme oxygenase 1 (HMOX1) is the rate limiting enzyme in heme degradation and a key regulator of inflammatory processes. In animal models the course of pancreatitis was ameliorated by up-regulation of HMOX1 expression. Additionally, carbon monoxide released during heme breakdown inhibited proliferation of pancreatic stellate cells and might thereby prevent the development of chronic pancreatitis (CP). Transcription of HMOX1 in humans is influenced by a GT-repeat located in the promoter. As such, HMOX1 variants might be of importance in the pathogenesis of pancreatitis. METHODS: The GT-repeat and SNP rs2071746 were investigated with fluorescence labelled primers and by melting curve analysis in 285 patients with acute pancreatitis, 208 patients with alcoholic CP, 207 patients with idiopathic/hereditary CP, 147 patients with alcoholic liver cirrhosis, and in 289 controls, respectively. GT-repeat analysis was extended to a total of 446 alcoholic CP patients. In addition, we performed DNA sequencing in 145 patients with alcoholic CP, 138 patients with idiopathic/hereditary CP, 147 patients with alcoholic liver cirrhosis, and 151 controls. Exon 3 screening was extended to additional patients and controls. RESULTS: S- and L-alleles of the GT-repeat, genotypes and alleles of SNP rs2071746 and non-synonymous variants detected by sequencing were found with similar frequencies in all groups. CONCLUSIONS: Although functional data implicate a potential influence of HMOX1 variants on the pathogenesis of pancreatitis, we did not find any association. As rare non-synonymous HMOX1 variants were found in patients and controls, it is rather unlikely that they will have functional consequences essential for pancreatitis development

A Common Variant of PNPLA3 (p.I148M) Is Not Associated with Alcoholic Chronic Pancreatitis

Contains fulltext : 110441.pdf (publisher's version ) (Open Access)BACKGROUND: Chronic pancreatitis (CP) is an inflammatory disease that in some patients leads to exocrine and endocrine dysfunction. In industrialized countries the most common aetiology is chronic alcohol abuse. Descriptions of associated genetic alterations in alcoholic CP are rare. However, a common PNPLA3 variant (p.I148M) is associated with the development of alcoholic liver cirrhosis (ALC). Since, alcoholic CP and ALC share the same aetiology PNPLA3 variant (p.I148M) possibly influences the development of alcoholic CP. METHODS: Using melting curve analysis we genotyped the variant in 1510 patients with pancreatitis or liver disease (961 German and Dutch alcoholic CP patients, 414 German patients with idiopathic or hereditary CP, and 135 patients with ALC). In addition, we included in total 2781 healthy controls in the study. RESULTS: The previously published overrepresentation of GG-genotype was replicated in our cohort of ALC (p-value <0.0001, OR 2.3, 95% CI 1.6-3.3). Distributions of genotype and allele frequencies of the p.I148M variant were comparable in patients with alcoholic CP, idiopathic and hereditary CP and in healthy controls. CONCLUSIONS: The absence of an association of PNPLA3 p.I148M with alcoholic CP seems not to point to a common pathway in the development of alcoholic CP and alcoholic liver cirrhosis

Der Mediensport Olympia - ein globales Integrationsritual?

Die Olympischen Spiele wirken als ein Integrationsritus in einer sich globalisierenden Welt. Der Sport überwindet die Länder-, Kultur- und Rassengrenzen und vereint die Öffentlichkeit mithilfe der Medien. Diese inszenieren die Sportarten gemäß ihrer Wirkungslogik, und verändern somit den Sport selbst. Trotz Skandalen nimmt die Bedeutung der Spiele stetig zu, sie erreichen mit der Eröffnungsfeier das weltweit größte (Fernseh-)Publikum. Diese Feier ist ein globaler sakraler Ritus. Besonders das Fernsehen lässt alle um Ritus teilhaben. Der Sport als soziales Handeln vermittelt einen Glauben an Fortschritt durch Leistung, und die Zuschauer können mithilfe der Medien auch teilnehmen. In Zeiten des Wandels wird der Ritus wichtig für die Gemeinschaft.The Olympic Games appear to be a rite of integration in a world of increasing globalization. Sport overcomes national, cultural und racial boundaries, und unites the public with the help of the media. The media (re)produce the different sports according to the functional logic of their medial presentation und therefore change the sports itself: Economy has replaced morality as the highest precept. Despite certain scandals, the Games become more und more significant. The opening ceremony reaches the largest (TV-)audience worldwide. This ceremony is a global religious rite which could have never been accomplished without the media. It is especially television that enables everyone to be a part of the rite. Sport as social action educates a belief in Progress through achievement, and the audience can participate with the help of the media. In times of constant changes, this rite becomes highly important to the community

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Legislative Documents

Also, variously referred to as: Senate bills; Senate documents; Senate legislative documents; legislative documents; and General Court documents

Feasible and Successful: Genome-Wide Interaction Analysis Involving All 1.9 × 10&lt;sup&gt;11&lt;/sup&gt; Pair-Wise Interaction Tests

The Genome-Wide Association Study (GWAS) is the study design of choice for detecting common genetic risk factors for multifactorial diseases. The performance of full Genome-Wide Interaction Analyses (GWIA) has always been considered computationally challenging. Two-stage strategies to reduce the amount of numerical analysis require the detection of single marker effects or prior pathophysiological hypotheses before the analysis of interaction. This prevents the detection of pure epistatic effects. Our case-control study in idiopathic generalized epilepsy demonstrates that a full GWIA is feasible through use of data compression, specific data representation, interleaved data organization, and parallelization of the analysis on a multi-processor system. Following extensive quality control of the genotypes, our final list of top interaction hits contains only pairs of interacting SNPs with negligible marginal effects. The TOP HIT interaction was between a SNP-pair intragenic to gene &lt;i&gt;DNER&lt;/i&gt; (chr 2) and gene &lt;i&gt;CTNNA3&lt;/i&gt; (chr 10). Both of these genes are functionally involved in neuronal migration, synaptogenesis, and the formation of neuronal circuits. Our results therefore indicate a possible interaction between these two genes in epileptogenesis. Results from GWAS are beginning to reveal a ‘missing heritability’ in complex traits and diseases. Systematic, hypothesis-free analysis of epistatic interaction (GWIA) may help to close this increasingly recognized gap in heritability.</jats:p