We performed a systematic, large-scale analysis of human protein complexes comprising gene products implicated in many different categories of human disease to create a phenome-interactome network. This was done by integrating quality-controlled interactions of human proteins with a validated, computationally derived phenotype similarity score, permitting identification of previously unknown complexes likely to be associated with disease. Using a phenomic ranking of protein complexes linked to human disease, we developed a Bayesian predictor that in 298 of 669 linkage intervals correctly ranks the known disease-causing protein as the top candidate, and in 870 intervals with no identified disease-causing gene, provides novel candidates implicated in disorders such as retinitis pigmentosa, epithelial ovarian cancer, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer disease, type 2 diabetes and coronary heart disease. Our publicly available draft of protein complexes associated with pathology comprises 506 complexes, which reveal functional relationships between disease-promoting genes that will inform future experimentation.

Alternative premessenger RNA splicing enables genes to generate more than one gene product. Splicing events that occur within protein coding regions have the potential to alter the biological function of the expressed protein and even to create new protein functions. Alternative splicing has been suggested as one explanation for the discrepancy between the number of human genes and functional complexity. Here, we carry out a detailed study of the alternatively spliced gene products annotated in the ENCODE pilot project. We find that alternative splicing in human genes is more frequent than has commonly been suggested, and we demonstrate that many of the potential alternative gene products will have markedly different structure and function from their constitutively spliced counterparts. For the vast majority of these alternative isoforms, little evidence exists to suggest they have a role as functional proteins, and it seems unlikely that the spectrum of conventional enzymatic or structural functions can be substantially extended through alternative splicing.function ͉ human ͉ isoforms ͉ splice ͉ structure A lternative mRNA splicing, the generation of a diverse range of mature RNAs, has considerable potential to expand the cellular protein repertoire (1-3), and recent studies have estimated that 40-80% of multiexon human genes can produce differently spliced mRNAs (4, 5). The importance of alternative splicing in processes such as development (6) has long been recognized, and proteins coded by alternatively spliced transcripts have been implicated in a number of cellular pathways (7-9). The extent of alternative splicing in eukaryotic genomes has lead to suggestions that alternative splicing is key to understanding how human complexity can be encoded by so few genes (10).The pilot project of the Encyclopedia of DNA Elements (ENCODE) (11), which aims to identify all the functional elements in the human genome, has undertaken a comprehensive analysis of 44 selected regions that make up 1% of the human genome. One valuable element of the project has been the detailing of a reference set of manually annotated splice variants by the GENCODE consortium (12). The annotation by the GENCODE consortium is an extension of the manually curated annotation by the Havana team at The Sanger Institute.Although a full understanding of the functional implications of alternative splicing is still a long way off, the GENCODE set has provided us with the material to make an in-depth assessment of a systematically collected reference set of splice variants. ResultsAlternative Splicing Frequency. The GENCODE set is made up of 2,608 annotated transcripts for 487 distinct loci. A total of 1,097 transcripts from 434 loci are predicted to be protein coding. There are on average 2.53 protein coding variants per locus; 182 loci have only one variant, whereas one locus, RP1-309K20.2 (CPNE1) has 17 coding variants.A total of 57.8% of the loci are annotated with alternatively spliced transcripts, although there are differences between target re...

The aim of the Ostomy Life Study was to get a better understanding of the challenges that people living with a stoma face in their everyday livee. With more than 4000 participants from 11 countries, the study provides a wealth of information covering all age groups, stoma types, stoma products and a variety of cultures. The result shows that the majority of ostomates have issues related to leakage and ballooning which, among other things, have a negative effect on sleep, or lead to unplanned appliance changes for approximately 40% of the respondents. Two-piece users are concerned specifically about coupling failure and the associated consequences. The results can be used to provide guidance in everyday stoma care and in development of new products.

BackgroundPeople suffering from neurogenic bowel dysfunction (NBD) and an ineffective bowel regimen often suffer from fecal incontinence (FI) and related symptoms, which have a huge impact on their quality of life. In these situations, transanal irrigation (TAI) has been shown to reduce these symptoms and improve quality of life.AimTo investigate the long-term cost-effectiveness of initiating TAI in patients with NBD who have failed standard bowel care (SBC).MethodsA deterministic Markov decision model was developed to project the lifetime health economic outcomes, including quality-adjusted life years (QALYs), episodes of FI, urinary tract infections (UTIs), and stoma surgery when initiating TAI relative to continuing SBC. A data set consisting of 227 patients with NBD due to spinal cord injury (SCI), multiple sclerosis, spina bifida and cauda equina syndrome was used in the analysis. In the model a 30-year old individual with SCI was used as a base-case. A probabilistic sensitivity analysis was applied to evaluate the robustness of the model.ResultsThe model predicts that a 30-year old SCI patient with a life expectancy of 37 years initiating TAI will experience a 36% reduction in FI episodes, a 29% reduction in UTIs, a 35% reduction in likelihood of stoma surgery and a 0.4 improvement in QALYs, compared with patients continuing SBC. A lifetime cost-saving of £21,768 per patient was estimated for TAI versus continuing SBC alone.ConclusionTAI is a cost-saving treatment strategy reducing risk of stoma surgery, UTIs, episodes of FI and improving QALYs for NBD patients who have failed SBC.

Type 1 diabetes (T1D) is a complex disease characterized by the loss of insulin-secreting β-cells. Although the disease has a strong genetic component, and several loci are known to increase T1D susceptibility risk, only few causal genes have currently been identified. To identify disease-causing genes in T1D, we performed an in silico "phenome-interactome analysis" on a genome-wide linkage scan dataset. This method prioritizes candidates according to their physical interactions at the protein level with other proteins involved in diabetes. A total of 11 genes were predicted to be likely disease genes in T1D, including the INS gene. An unexpected topscoring candidate gene was huntingtin-interacting protein (HIP)-14/ZDHHC17. Immunohistochemical analysis of pancreatic sections demonstrated that HIP14 is almost exclusively expressed in insulinpositive cells in islets of Langerhans. RNAi knockdown experiments established that HIP14 is an antiapoptotic protein required for β-cell survival and glucose-stimulated insulin secretion. Proinflammatory cytokines (IL-1β and IFN-γ) that mediate β-cell dysfunction in T1D down-regulated HIP14 expression in insulin-secreting INS-1 cells and in isolated rat and human islets. Overexpression of HIP14 was associated with a decrease in IL-1β-induced NF-κB activity and protection against IL-1β-mediated apoptosis. Our study demonstrates that the current network biology approach is a valid method to identify genes of importance for T1D and may therefore embody the basis for more rational and targeted therapeutic approaches.autoimmunity | huntington's disease | protein network | bioinformatics | programmed cell death