Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling

Objective: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. Design: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p Results: We identified two novel coeliac disease risk regions: 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p= 1.3x10(-08), and rs842647 p= 5.26x10(-07)). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression. Conclusions: Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kappa B) inflammatory signalling pathway. For the first time, a role for primary heritable variation in this important biological pathway predisposing to coeliac disease has been identified. Currently, the HLA risk factors and the 10 established non-HLA risk factors explain similar to 40% of the heritability of coeliac disease

Extreme events and predictability of catastrophic failure in composite materials and in the Earth

Despite all attempts to isolate and predict extreme earthquakes, these nearly always occur without obvious warning in real time: fully deterministic earthquake prediction is very much a ‘black swan’. On the other hand engineering-scale samples of rocks and other composite materials often show clear precursors to dynamic failure under controlled conditions in the laboratory, and successful evacuations have occurred before several volcanic eruptions. This may be because extreme earthquakes are not statistically special, being an emergent property of the process of dynamic rupture. Nevertheless, probabilistic forecasting of event rate above a given size, based on the tendency of earthquakes to cluster in space and time, can have significant skill compared to say random failure, even in real-time mode. We address several questions in this debate, using examples from the Earth (earthquakes, volcanoes) and the laboratory, including the following. How can we identify ‘characteristic’ events, i.e. beyond the power law, in model selection (do dragon-kings exist)? How do we discriminate quantitatively between stationary and non-stationary hazard models (is a dragon likely to come soon)? Does the system size (the size of the dragon’s domain) matter? Are there localising signals of imminent catastrophic failure we may not be able to access (is the dragon effectively invisible on approach)? We focus on the effect of sampling effects and statistical uncertainty in the identification of extreme events and their predictability, and highlight the strong influence of scaling in space and time as an outstanding issue to be addressed by quantitative studies, experimentation and models

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn's disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Intralocus sexual conflict in humans: Physically and hormonally masculine individuals have more attractive brothers relative to sisters

Intralocus sexual conflict (IASC) occurs when sex-specific selection favors genes that increase fitness in one sex and decrease fitness in the other sex. The current study was designed to explore whether IASC occurs in humans. In a sample of siblings, we identified and measured sexually dimorphic traits and hormones within each sex that are related to fitness and are likely coded for by antagonistic genes: waist-to-hip ratio (WHR) and breast size in women, WHR and bicep size (an index of muscularity) in men, and estradiol (E) and testosterone (T) in both sexes. If these traits and hormones are coded for by genes under IASC, masculine or feminine expression of traits and hormones should differentially predict brothers' and sisters' fitness. Consistent with an IASC model, both men and women who were physically masculine for their sex reported higher mate value brothers relative to sisters. Similarly, in normal-weight individuals, E levels positively predicted the mate value of sisters relative to brothers and T levels positively predicted the mate value of brothers relative to sisters. We found no evidence that individuals with indicators of high genetic quality (i.e., physically masculine men and physically feminine women) share high mate value with all siblings, regardless of sibling sex. Results are novel and demonstrate for the first time that intralocus conflict in humans may influence the fitness of related individuals. © 2011 Elsevier Inc

Learning in small manufacturing firms: the case of investment decision-making behaviour

This article is concerned with investment decision-making processes in small manufacturing enterprises.The study, on which the article is based, used `insider accounts' as an innovative, qualitative methodology, involving in-depth, semi-structured interviews and direct observation, conducted longitudinally in eight case study companies. It is a research method which includes detailed accounts from the actors themselves, incorporating their actual motives and behaviour. Data from two case study firms is presented in the article to demonstrate different types of learning behaviour.The findings suggest that conceptualizing investment decision-making processes in small firms within the context of organizational learning holds promise as an explanatory framework for investment behaviour in small firms