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 ...

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Innate Immune Recognition

By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations.

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An integrated map of genetic variation from 1,092 human genomes

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.

Intestinal hypomotility is a common late complication in infants with acute diarrhoeal disease in pakistan. Among the infants admitted to our gastrointestinal unit with a history of acute diarrhoea, 35% developed abdominal distension and 12% developed the full clinical picture of paralytic ileus. The infants with ileus were treated with decompression and total parenteral nutrition; in this group the mortality rate was 25%. We compared 30 infants who developed ileus (group A) with an age-matched control group of infants (group B) who were admitted because of acute diarrhoea but did not develope ileus. The use of antimotility drugs was significantly more frequent in group A. Serum-K was not different in in group A (3.92 +/- 0.22 mmol/l) and group B (4.32 +/- 0.18 mmol/1). However, there were more patients who had serum-K below 3 mmol/l in group A (8/30) than in group B (5/30). We conclude that the use of antimotility drugs predisposes to the development of ileus in infants with acute diarrhoea. Hypokalemia may contribute to ileus in a few cases but is generally not a prerequisite.

Paralytic Ileus, a Serious Complication in Acute Diarrhoeal Disease among Infants in Developing Countries

Objective The aim of the study was to evaluate the outcome and to identify predictors for survival and enteral autonomy in neonatal intestinal failure (IF). Methods A retrospective observational study in a Swedish tertiary centre of children born between 1995 and 2016 with neonatal IF, defined as dependency on parenteral nutrition (PN) ≥60 days, starting with PN before the age of 44 gestational weeks. Data were extracted from medical records and predictors for survival and enteral autonomy were identified by the Cox regression model. Time to death and weaning off PN analysis were performed with Kaplan-Meier curves including log rank test. Results In total, 105 children were included. Median gestational age was 28 weeks (22-42), 50% were born extremely preterm ( 50% and birth 2009 to 2016 were predictors for survival. Enteral autonomy was achieved in 87%, with positive prediction by small bowel length of >25% of expected for gestational age and remaining ileocecal valve. Conclusions Preterm neonates with IF, at high risk of IF-associated morbidity, showed a high overall survival rate. Small-bowel length and being born 2009 to 2016 were predictors for survival and remaining ICV and small-bowel length were predictors for enteral autonomy.

Improved Outcome of Intestinal Failure in Preterm Infants.

The oral absorption of pc V in different preparations, given at various times before and after a meal, was investigated in children with upper respiratory infections. The best absorption with respect to peak concentration was observed when potassium pc V (Calciopen) was given after at least two hours of fasting with no food intake within the following hour. Shorter periods of fasting (1, 1/2, 0 hrs) before drug intake resulted in significantly lower plasma concentrations. When drug intake was followed by a meal, the absorption was also decreased to some extent. When pc V was given in an oil suspension (Fenoxypen), or in a small volume (Roscopenin) together with a meal, the peak concentration was significantly lower than when pc V was given in an aqueous solution with a larger volume (Calciopen).

The effect of food on the oral absorption of penicillin V preparations in children.

Aim: To evaluate the practice of diagnosing coeliac disease with only one small-bowel mucosal biopsy in a selected group of children with suspected coeliac disease.



Methods: A retrospective review of medical records and a follow-up interview of 102 children (65 girls, 37 boys) at diagnosis of coeliac disease. The inclusion criteria were age >18 months, increased levels of serum antitissue transglutaminase IgA antibodies and pathologic small-bowel mucosal biopsy. Anthropometric data were calculated for children 1.5–11 years of age.



Results: The levels of serum antitissue transglutaminase IgA antibodies were either normal (92%) or slightly elevated (8%) in all children after 1 year on a gluten-free diet. The height-for-age Z score increased in 52 of 61 (85%) children, (median 0.26 SD, range −0.45 to 1.83 SD) and the weight-for-age Z score increased in 50 of 61 (82%) children (median 0.42 SD, range −0.77 to 2.24 SD). Sixty of 61 (98%) children showed normal or catch-up growth. Regression of symptoms after 1 year on a gluten-free diet was reported for 71 of 72 (98%) children.



Conclusion: We propose that a control biopsy is not necessary for the diagnosis of coeliac disease in these children.

Omitting control biopsy in paediatric coeliac disease: a follow-up study.

Net sodium and fluid absorption in the colon is higher in young than in adult rats. The mechanism behind the high absorption in young rats is not well understood. In this study, we investigated the structural and functional properties of the proximal and the distal colon in 20- and 40-day-old rats. The surface area of the mucosa along the luminal surface of the gut in relation to the mucosal volume (surface density) was determined by morphometry. Net sodium and water absorption was determined by in vivo perfusion experiments. The surface density of the mucosa was greater in the proximal than in the distal colon in both 20- and 40-day-old rats. No developmental change in the surface density of the mucosa occurred between 20 and 40 days of age, however, in either the proximal or distal colon. Net sodium and fluid absorption per unit of weight were higher in both segments in 20- than in 40-day-old rats, and higher in the distal than in the proximal colon in 40-day-old rats. We conclude that other factors than the absorptive area are responsible for the decrease in the net colonic sodium and fluid absorption observed during late postnatal development and for the differences in sodium net absorption between the proximal and distal colon in 40-day-old rats.

Yigael Finkel

Papers

Paralytic Ileus, a Serious Complication in Acute Diarrhoeal Disease among Infants in Developing Countries

Improved Outcome of Intestinal Failure in Preterm Infants.

The effect of food on the oral absorption of penicillin V preparations in children.

Omitting control biopsy in paediatric coeliac disease: a follow-up study.

Morphometric and functional studies of proximal and distal colon in young and adult rats.