Genetische Untersuchung entzündungsrelevanter Altersgene

Die Variation in der Lebensspanne wird beim Menschen bis zu 30% durch genetische Faktoren beinflusst, während ca. 70% dieser Variation auf Umweltbedingungen zurückzuführen ist. Bisher zeigen nur Einzelbasenvariationen (SNVs) in den Genen Apolipoprotein E (APOE) und Forkhead-Box-Protein O3A (FOXO3A) eine konsistente Assoziation mit Langlebigkeit beim Menschen in verschiedenen Populationen. Ziel der vorliegenden Studie war es daher, über Kandidatengenstudien und mittels ImmunochipTechnologie neue Suszeptibilitätsfaktoren und funktionell relevante Varianten in der deutschen Population zu identifizieren. Kandidatengenstudien wurden jeweils für die Superoxiddismutasen (SODs), das Cholesterinester-Transferprotein (CETP) und die FOXO3A-Genregion durchgeführt. Die SNV-Auswahl für die SODs und CETP erfolgte über einen umfassenden haplotype tagging Ansatz, während für die FOXO3A-Genregion drei verschiedene Sequenzierungs-Technologien (SOLiD, Illumina und Sanger) genutzt wurden, um potentielle funktionell relevante Varianten zu detektieren. In einem weiteren Ansatz sind mittels Immunochip-Technologie ca. 200.000 SNVs getestet worden. Der Immunochip umfasst genetische Varianten, die potentiell für immunvermittelte und altersbedingte Erkrankungen relevant sind. ...Up to 30% of variation in human lifespan is influenced by genetic factors, whereas 70% is attributed to environmental factors. However, thus far, only single nucleotide variants (SNVs) in the Apolipoprotein E and Forkhead box protein O3 (FOXO3A) genes have been consistently associated with human longevity in many populations. The aim of the current study was, therefore, to identify new susceptibility loci and functional relevant variants for human longevity in a German population by candidate gene studies and immunochip technology. Individual candidate gene studies were performed for the superoxide dismutases (SODs), the cholesterol ester transfer protein (CETP), and the FOXO3A gene regions. Selection of SNVs for SODs and CETP was conducted using a comprehensive haplotype tagging approach while for the FOXO3A gene region, three different sequencing technologies (SOLiD, Illumina, and Sanger) were applied to detect potentially functional relevant variants. In a parallel approach, about 200,000 SNVs were tested using immunochip technology. The immunochip contains genetic variants that are thought to be relevant for immune mediated and age-related diseases...

No association of alcohol use and the risk of ulcerative colitis or Crohn’s disease: data from a European Prospective cohort study (EPIC)

Background The role of long -term alcohol consumption for the risk of developing ulcerative colitis (UC) and Crohn’s disease (CD) is unclear. Aim s For the first time, t o prospectively assess the role of pre -disease alcohol consumption o n the risk of developing UC or CD. Methods Nested within the European Prospective Investigation into Cancer and Nutrition (EPIC - IBD ), incident UC and CD cases and ma tched controls where included. At recruitment, participants completed validated food frequency and lifestyle questionnaires. Alcohol consumption was classified as either: non -use, former, light ( ≤ 0.5 and 1 drink/week), below the recommended limits (BRL) ( ≤ 1 and 2 drinks/day), moderate ( ≤ 2.5 and 5 drinks/day) , or heavy use (>2.5 and >5 drinks/ day) for women and men, respectively ; and was expressed as consumption at enrolment and during lifetime. Conditional logistic regression was applied adjusting for smoking and education , taking light users as the 3 Abstract Background The role of long -term alcohol consumption for the risk of developing ulcerative colitis (UC) and Crohn’s disease (CD) is unclear. Aim s For the first time, t o prospectively assess the role of pre -disease alcohol consumption o n the risk of developing UC or CD. Methods Nested within the European Prospective Investigation into Cancer and Nutrition (EPIC - IBD ), incident UC and CD cases and ma tched controls where included. At recruitment, participants completed validated food frequency and lifestyle questionnaires. Alcohol consumption was classified as either: non -use, former, light ( ≤ 0.5 and 1 drink/week), below the recommended limits (BRL) ( ≤ 1 and 2 drinks/day), moderate ( ≤ 2.5 and 5 drinks/day) , or heavy use (>2.5 and >5 drinks/ day) for women and men, respectively ; and was expressed as consumption at enrolment and during lifetime. Conditional logistic regression was applied adjusting for smoking and education , taking light users as the reference. Results Out of 262,451 participants in 6 countries, 198 UC incident cases/792 controls and 84 CD cases/336 controls were included. At enrolment, 8%/27%/3 2%/2 3%/1 1% UC cases and 7%/2 9%/4 0%/19%/ 5% C D cases were: non -users, light, BRL, moderate and heavy users, respectively. The corresponding figures for lifetime non -use, former, light, BRL, moderate and heavy use were : 3%/5%/2 3%/44%/19%/6% and 5%/2%/25%/44%/23 %/1% for UC and CD cases , respectively. There were no associations between any categories of alcohol consumption and risk of UC or CD in the una djusted and adjusted odds ratios . Conclusion There was no evidence of association s between alcohol use and the odds of developing either UC or CD

Faecal calprotectin: factors affecting levels and its potential role as a surrogate marker for risk of development of Crohn's Disease.

BACKGROUND: Faecal calprotectin (FC) is one of the most widely used non-invasive tests for the diagnosis and assessment of Crohn's disease (CD) activity. Despite this, factors other than disease activity which affect levels have not been extensively reviewed. This is of importance when using FC in the diagnostic setting but also may be of utility in studying the aetiology of disease. OBJECTIVES: Our review outlines environmental risk factors that affect FC levels influencing diagnostic accuracy and how these may be associated with risk of developing CD. FC as a surrogate marker could be used to validate risk factors established in case control studies where prospective studies are not feasible. Proof of this concept is provided by our identification of obesity as being associated with elevated FC, our subsequent confirmation of obesity as risk factor for CD and the subsequent verification in prospective studies, as well as associations of lack of physical activity and dietary fibre intake with elevated FC levels and their subsequent confirmation as risk factors in prospective studies. CONCLUSION: We believe that FC is likely to prove a useful surrogate marker for risk of developing CD. This review has given a theoretical basis for considering the epidemiological determinants of CD which to date has been missing

Sexually dimorphic characteristics of the small intestine and colon of prepubescent C57BL/6 mice

Background There is increasing appreciation for sexually dimorphic effects, but the molecular mechanisms underlying these effects are only partially understood. In the present study, we explored transcriptomics and epigenetic differences in the small intestine and colon of prepubescent male and female mice. In addition, the microbiota composition of the colonic luminal content has been examined. Methods At postnatal day 14, male and female C57BL/6 mice were sacrificed and the small intestine, colon and content of luminal colon were isolated. Gene expression of both segments of the intestine was analysed by microarray analysis. DNA methylation of the promoter regions of selected sexually dimorphic genes was examined by pyrosequencing. Composition of the microbiota was explored by deep sequencing. Results Sexually dimorphic genes were observed in both segments of the intestine of 2-week-old mouse pups, with a stronger effect in the small intestine. Amongst the total of 349 genes displaying a sexually dimorphic effect in the small intestine and/or colon, several candidates exhibited a previously established function in the intestine (i.e. Nts, Nucb2, Alox5ap and Retnlγ). In addition, differential expression of genes linked to intestinal bowel disease (i.e. Ccr3, Ccl11 and Tnfr) and colorectal cancer development (i.e. Wt1 and Mmp25) was observed between males and females. Amongst the genes displaying significant sexually dimorphic expression, nine genes were histone-modifying enzymes, suggesting that epigenetic mechanisms might be a potential underlying regulatory mechanism. However, our results reveal no significant changes in DNA methylation of analysed CpGs within the selected differentially expressed genes. With respect to the bacterial community composition in the colon, a dominant effect of litter origin was found but no significant sex effect was detected. However, a sex effect on the dominance of specific taxa was observed. Conclusions This study reveals molecular dissimilarities between males and females in the small intestine and colon of prepubescent mice, which might underlie differences in physiological functioning and in disease predisposition in the two sexes