抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

Inflammation and cancer

There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

/pdf/genome-wide-association-study-of-14-000-cases-of-seven-5ay7q0q3vy.pdf

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

/pdf/finding-the-missing-heritability-of-complex-diseases-3b6mbqztnq.pdf

Finding the missing heritability of complex diseases

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

/pdf/biological-insights-from-108-schizophrenia-associated-3rfvth8dm9.pdf

Biological insights from 108 schizophrenia-associated genetic loci

BACKGROUND: Inflammatory bowel disease (IBD) is postulated to result from a dysregulated mucosal immune response to host microflora in genetically susceptible individuals. Genetic studies identified several autophagy genes including ATG16L1 and IRGM to be associated with IBD. Autophagy describes a biological process that involves trafficking and handling of macro-molecules including bacteria. Studies show that autophagy plays an important role in the clearance of microbial pathogens. Alterations in the autophagic machinery such as in ATG16L1 and IRGM may result in the ineffective elimination of pathogens and the persistent activation of the inflammatory cascade in the intestine, which may contribute to the pathogenesis of IBD. This study examines the role of autophagy in the function of macrophages and dendritic cells. METHODS: We generated mice deficient in Atg16l1 in dendritic cells (Atg16l1f/f x CD11c-cre) and macrophages (Atg16l1f/f x LysM-cre). Bone marrow derived dendritic cells (BMDC) and bone marrow derived macrophages (BMDM) were isolated. Autophagy function was assessed with LC3 and P62 immunoblotting. Uptake of Salmonella enterica serovar Typhimurium carrying GFP was assessed by confocal microscopy and flow cytometry. Reactive oxygen (ROS) production and intracellular S. typhimurium killing in dendritic cells and macrophages were assessed. RESULTS: Atg16l1f/f x CD11c-cre and Atg16l1f/f x LysM-cre mice exhibit defective autophagy in dendritic cells and macrophages, respectively. There were no differences in S. typhimurium uptake in Atg16l1f/f x CD11c-cre dendritic cells and Atg16l1f/f x LysM-cre macrophages when compared to control Atg16l1f/f counterparts. Higher ROS production in response to S. typhimurium infection is observed in Atg16l1 deficient dendritic cells and macrophages as compared to WT macrophages or dendritic cells. Interestingly, although there was higher ROS production with Atg16l1 deficiency, we observe reduced S. typhimurium killing with Atg16l1 deficiency. CONCLUSIONS: Our data show that Atg16l1 is an essential component of the autophagic machinery and plays a role in the clearance of microbial organisms in dendritic cells and macrophages. The dichotomy between increased ROS production and reduction in intracellular bacteria killing suggests impaired trafficking of bacteria or its processed antigen to the appropriate autophagy vesicle(s) and is currently being investigated further.

P-221 Atg16l1 Deficiency Leads to Defects in Autophagy in Dendritic Cells and Macrophages

TNF-α and FAS antigen ligation stimulate apoptosis and IL-8 secretion in HT-29 cells by diverse mechanisms

592 - Gender-Stratified Analyses Identifies Sex-Specific IBD Associations

Alterations in expression and regulation of the chemokine receptor CXCR3 in LPL from normal compared to inflammatory bowel disease mucosa

Regional expression of thymus expressed chemokine (TECK) and its receptor CCR9 in the small bowel: Evidence for enhanced recirculation of CCR9+ lymphocytes in small bowel Crohn's disease

Stephan R. Targan

Papers

P-221 Atg16l1 Deficiency Leads to Defects in Autophagy in Dendritic Cells and Macrophages

TNF-α and FAS antigen ligation stimulate apoptosis and IL-8 secretion in HT-29 cells by diverse mechanisms

592 - Gender-Stratified Analyses Identifies Sex-Specific IBD Associations

Alterations in expression and regulation of the chemokine receptor CXCR3 in LPL from normal compared to inflammatory bowel disease mucosa

Regional expression of thymus expressed chemokine (TECK) and its receptor CCR9 in the small bowel: Evidence for enhanced recirculation of CCR9+ lymphocytes in small bowel Crohn's disease