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.

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

▪ Abstract The innate immune system is a universal and ancient form of host defense against infection. Innate immune recognition relies on a limited number of germline-encoded receptors. These receptors evolved to recognize conserved products of microbial metabolism produced by microbial pathogens, but not by the host. Recognition of these molecular structures allows the immune system to distinguish infectious nonself from noninfectious self. Toll-like receptors play a major role in pathogen recognition and initiation of inflammatory and immune responses. Stimulation of Toll-like receptors by microbial products leads to the activation of signaling pathways that result in the induction of antimicrobial genes and inflammatory cytokines. In addition, stimulation of Toll-like receptors triggers dendritic cell maturation and results in the induction of costimulatory molecules and increased antigen-presenting capacity. Thus, microbial recognition by Toll-like receptors helps to direct adaptive immune responses ...

/pdf/innate-immune-recognition-3eedeqyq83.pdf

Innate Immune Recognition

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

The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.

The International HapMap Project

The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms. In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway. In mammals there are at least 10 members of the Toll-like receptor (TLR) family that recognize specific components conserved among microorganisms. Activation of the TLRs leads not only to the induction of inflammatory responses but also to the development of antigen-specific adaptive immunity. The TLR-induced inflammatory response is dependent on a common signaling pathway that is mediated by the adaptor molecule MyD88. However, there is evidence for additional pathways that mediate TLR ligand-specific biological responses.

Toll-like receptors.

6-Thioguanine levels versus white blood cell counts in guiding 6-mercaptopurine and azathioprine therapy

There are conflicting data assessing the impact of isolated post‐operative anastomotic inflammation on future disease progression. The aim of this study was to determine the relative risk of severe disease progression in post‐operative Crohn’s disease (CD) patients with isolated anastomotic disease.

Mild neoterminal ileal post‐operative recurrence of Crohn’s disease conveys higher risk for severe endoscopic disease progression than isolated anastomotic lesions

SUMMARY Background: Recent studies have suggested that mercaptopurine metabolism is influenced by drug formulation (mercaptopurine vs. azathioprine) and concomitant use of 5-aminosalicylic acid medications. Aim: To determine the influence of dose, formulation and 5-aminosalicylic acid use on mercaptopurine metabolism. Methods: Metabolites from 131 inflammatory bowel disease patients were analysed. Logistic regression was used to analyse correlations between dose and metabolite levels. Multivariate analysis was used to determine the effects of drug formulation and 5-aminosalicylic acid use. Results: A positive correlation was detected between dose and 6-tioguanine nucleotides levels for azathioprine/Imuran formulation (P ¼ 0.005) but not for mercaptopurine formulation. Adjusted mean 6-tioguanine nucleotides levels were similar for both formulations. Adjusted mean 6-methylmercaptopurine levels were higher for mercaptopurine formulation than for azathioprine formulation (1950 vs. 1056, P ¼ 0.04). 5-aminosalicylic acid use: 6-tioguanine nucleotides levels did not differ based on concomitant 5-aminosalicylic acid use. However, 5-aminosalicylic acid use did result in higher adjusted mean 6-methylmercaptopurine levels: 2078 on 5-aminosalicylic acid vs. 991 off 5-aminosalicylic acid (P ¼ 0.004). Conclusions: (i) Azathioprine may have metabolic benefits by achieving a correlation of dose with 6-tioguanine nucleotides levels and by leading to lower mean 6-methylmercaptopurine levels. (ii) 5-aminosalicylic acid use does not significantly impact 6-tioguanine levels and may lead to higher 6-methylmercaptopurine levels.

Azathioprine formulation optimizes metabolite profile in inflammatory bowel disease.

Ciprofloxacin is more effective in treating acute pouchitis than metronidazole: A randomized clinical trial

Sa2018 - Radiomic Texture Analysis Shows Differential Expression within Visceral Adipose Tissue Regions on MRI Reflecting Severity of Pediatric Crohn's Disease

Jean-Paul Achkar

Papers

6-Thioguanine levels versus white blood cell counts in guiding 6-mercaptopurine and azathioprine therapy

Mild neoterminal ileal post‐operative recurrence of Crohn’s disease conveys higher risk for severe endoscopic disease progression than isolated anastomotic lesions

Azathioprine formulation optimizes metabolite profile in inflammatory bowel disease.

Ciprofloxacin is more effective in treating acute pouchitis than metronidazole: A randomized clinical trial

Sa2018 - Radiomic Texture Analysis Shows Differential Expression within Visceral Adipose Tissue Regions on MRI Reflecting Severity of Pediatric Crohn's Disease