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Background: Dermatological manifestations are frequent and often constitute a circumstance of HIV discovery in 70% of cases [1]. They are observed in 83% of patients with AIDS and at an early stage in 75% [2,3,4,5]. The objective of this study was to describe the epidemiological, clinical, therapeutic, and evolutionary aspects of skin manifestations during HIV infection in children. Materials and Methods: We conducted a cross-sectional, multicentric, descriptive study over a period of ten years in two dermatology departments and one pediatric department in Dakar, Senegal. We included all HIV-seropositive children aged 0–15 years with mucosal cutaneous manifestations. A dermatologist and a specialist in the medical care of HIV performed the diagnosis of cutaneous manifestations. Data entry and analysis were performed with the SPSS software, version 9.05. Results: We collected 206 cases of cutaneous manifestations in 454 children followed for HIV infection. The hospital frequency was 45.3%. The children were male in 115 cases (55.83%) and female in 91 cases (44.17%), giving a sex ratio of 1.26. The mean age of the patients was sixty months, with extremes of one month to fourteen years. A mycotic dermatosis origin was noted in 47.37%, ringworm in 22.37%, dermatophytosis in 8.58%, oral candidiasis in 6.58%, seborrheic dermatitis in 6.58%, and perleche in 3.29%. Bacterial skin diseases were represented by furunculosis in 1.97%, and impetigo in 7.24%. Viral dermatoses included molluscum contagiosum in 10.53%, shingles in 9.21%, warts in 9.87%, and chickenpox in 3.95%. As for parasitic dermatoses, scabies was noted in 8.55, followed by larva migrans in 0.66% and cutaneous leishmaniosis in 0.66%. Immuno-allergic dermatoses accounted for 25% and included prurigo in 94.3%, atopic dermatitis in 1.90%, and fixed pigmented erythema in 1.90%. Conclusion: Cutaneous manifestations are a common discovery during HIV infection in children. They are marked by a predominance of infectious dermatoses in sub-Saharan Africa. Key words: skin diseases; HIV; children; Dakar

Introduction: The general objective was to determine the epidemiological, clinical, paraclinical, therapeutic and evolutionary aspects of connectivitis in the dermatology department of the CHU Aristide Le Dantec. Patients and methods: This was a retrospective and descriptive study conducted in the Dermatology Department of the University Hospital Center (UHC) Aristide Le Dantec (HALD) of Dakar between January 2009 and December 2019. Their diagnoses were retained according to the international criteria validated in the course of connectivites Results: We identified 290 cases of connectivitis. Systemic scleroderma was the most frequent in 34.42% (n=94), followed by systemic lupus in 25.86% (n=75), mixed connectivities in 22,06% (n=64) and dermatomyositis in 19,32% (n=56). Cancer was associated with dermatomyositis in 11 cases and with systemic scleroderma in 3 cases. The mean age of our patients was 38.23 years. The sex ratio was 4.2 and the mean duration of evolution was 25 months. Dermatological manifestations were constant, found in all patients. In systemic lupus, they were dominated by discoid lupus lesions found in 40% and hypochromic spots (86%) in systemic scleroderma. In dermatomyositis, skin lesions were dominated by periorbital erythroedema (66.07%). Joint manifestations were found in 56.89% of cases (n= 165), muscular manifestations in 41.37% of cases (n= 120) and pleuropulmonary manifestations in 31.3% of cases (n=91). Neuropsychiatric manifestations were noted in 5.17% of cases (n=15). All our patients were treated with corticosteroid therapy and 12.06% of them had received immunosuppressive treatment, the most commonly used molecules being methotrexate (3.44%) and cyclophosphamide (8.27%). Hydroxychloroquine was prescribed in 59.31% of patients, while D-penicillamine was prescribed in 42.06% of patients, 100% of whom were treated for systemic scleroderma. The main complications encountered were infectious complications in 83 cases (28.6%). Visceral complications, a type of visceral insufficiency, were noted in 4.13% of cases. Conclusion: Our study demonstrates the frequency of connectivitis in the dermatology department. Its particularity was the predominance of systemic scleroderma over lupus which was classically the first connectivite in dermatology services. The delay in diagnosis noted is correlated with visceral attacks; hence the importance of a better knowledge of these affections for an early management.

Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is thought to develop in genetically predisposed individuals as a consequence of complex interactions between dysregulated inflammatory stimuli, immunological responses, and environmental factors. The pathogenesis of IBD has yet to be fully understood. The global increase in the incidence of IBD suggests a gap in the current understanding of the disease. The development of a new diagnostic tool for inflammatory bowel disease that is both less invasive and more cost-effective would allow for better management of this condition. MicroRNAs (miRNAs) are a class of noncoding RNAs with important roles as posttranscriptional regulators of gene expression, which has led to new insights into understanding IBD. Using techniques such as microarrays and real-time polymerase chain reactions, researchers have investigated the patterns in which patients with Crohn's disease and ulcerative colitis show alterations in the expression of miRNA in tissue, blood, and feces. These miRNAs are found to be differentially expressed in IBD and implicated in its pathogenesis through alterations in autophagy, intestinal barrier, and immune homeostasis. In this review, we discuss the miRNA expression profiles associated with IBD in tissue, peripheral blood, and feces and provide an overview of the miRNA mechanisms involved in IBD.We review the published studies on microRNA (miRNA) expression in inflammatory bowel disease, including miRNAs extracted from blood, tissue, and stool samples. We discuss the main mechanisms of miRNA involvement in inflammatory bowel disease and their potential use as biomarkers.

Background Adverse drug reactions (ADRs) are statistically characterized within randomized clinical trials and postmarketing pharmacovigilance, but their molecular mechanism remains unknown in most cases. This is true even for hepatic or skin toxicities, which are classically monitored during drug design. Aside from clinical trials, many elements of knowledge about drug ingredients are available in open-access knowledge graphs, such as their properties, interactions, or involvements in pathways. In addition, drug classifications that label drugs as either causative or not for several ADRs, have been established. Methods We propose in this paper to mine knowledge graphs for identifying biomolecular features that may enable automatically reproducing expert classifications that distinguish drugs causative or not for a given type of ADR. In an Explainable AI perspective, we explore simple classification techniques such as Decision Trees and Classification Rules because they provide human-readable models, which explain the classification itself, but may also provide elements of explanation for molecular mechanisms behind ADRs. In summary, (1) we mine a knowledge graph for features; (2) we train classifiers at distinguishing, on the basis of extracted features, drugs associated or not with two commonly monitored ADRs: drug-induced liver injuries (DILI) and severe cutaneous adverse reactions (SCAR); (3) we isolate features that are both efficient in reproducing expert classifications and interpretable by experts (i.e., Gene Ontology terms, drug targets, or pathway names); and (4) we manually evaluate in a mini-study how they may be explanatory. Results Extracted features reproduce with a good fidelity classifications of drugs causative or not for DILI and SCAR (Accuracy = 0.74 and 0.81, respectively). Experts fully agreed that 73% and 38% of the most discriminative features are possibly explanatory for DILI and SCAR, respectively; and partially agreed (2/3) for 90% and 77% of them. Conclusion Knowledge graphs provide sufficiently diverse features to enable simple and explainable models to distinguish between drugs that are causative or not for ADRs. In addition to explaining classifications, most discriminative features appear to be good candidates for investigating ADR mechanisms further. Supplementary Information The online version contains supplementary material available at 10.1186/s12911-021-01518-6.

Background: Nucleotide-binding oligomerization domain-containing two (NOD2/CARD15) gene polymorphisms are implicated in the pathogenesis of Crohn's disease (CD). Aim: To describe the allelic frequency of NOD2/CARD15 gene variants among Kuwaiti patients with CD and investigate potential genotype/phenotype associations. Methods: Adult Kuwaiti citizens with an established diagnosis of CD and healthy controls were enrolled from October 2018 to May 2020. Three common NOD2/CARD15 polymorphisms (R702W, G908R, and L1007fs) and P268S and IVS8 +158 polymorphisms were screened by polymerase chain reaction/restriction analysis length polymorphism (PCR/RFLP). Results: Ninety adult Kuwaiti patients with CD and 210 healthy subjects (as controls) were recruited. P268S, IVS8 +158, G908R, and R702W minor alleles were identified in 38.9%, 21.1%, 12.2%, and 4.4% of CD patients, respectively. NOD2/CARD15 polymorphisms coexisted in 35 healthy controls (16.7%) and 21 CD patients (23.3%). Individuals with either a single or multiple polymorphism were approximately two times more likely to have CD than those with no polymorphism. Patients with multiple polymorphisms had significantly more stricturing and penetrating disease. Conclusion: NOD2/CARD15 gene polymorphisms were significantly associated with an increased risk of disease and aggressive phenotypes among the Kuwaiti CD population.

International audience; Immoderate calorie intake coupled with a sedentary lifestyle are major determinants of health issues and inflammatory diseases in modern society.The balance between energy consumption and energy expenditure is critical for longevity. Excessive energy intake and adiposity cause systemicinflammation, whereas calorie restriction (CR) without malnutrition, exerts a potent anti-inflammatory effect. The objective of this review was toprovide an overview of different strategies used to reduce calorie intake, discuss physiological mechanisms by which CR might lead to improvedhealth outcomes, and summarize the present knowledge about inflammatory diseases. We discuss emerging data of observational studies andrandomized clinical trials on CR that have been shown to reduce inflammation and improve human health. Adv Nutr 2021;00:1–13.

International audience; Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract that encompass two main phenotypes, namely Crohn’s disease and ulcerative colitis. These conditions occur in genetically predisposed individuals in response to environmental factors. Epigenetics, acting by DNA methylation, post-translational histones modifications or by non-coding RNAs, could explain how the exposome (or all environmental influences over the life course, from conception to death) could influence the gene expression to contribute to intestinal inflammation. We performed a scoping search using Medline to identify all the elements of the exposome that may play a role in intestinal inflammation through epigenetic modifications, as well as the underlying mechanisms. The environmental factors epigenetically influencing the occurrence of intestinal inflammation are the maternal lifestyle (mainly diet, the occurrence of infection during pregnancy and smoking); breastfeeding; microbiota; diet (including a low-fiber diet, high-fat diet and deficiency in micronutrients); smoking habits, vitamin D and drugs (e.g., IBD treatments, antibiotics and probiotics). Influenced by both microbiota and diet, short-chain fatty acids are gut microbiota-derived metabolites resulting from the anaerobic fermentation of non-digestible dietary fibers, playing an epigenetically mediated role in the integrity of the epithelial barrier and in the defense against invading microorganisms. Although the impact of some environmental factors has been identified, the exposome-induced epimutations in IBD remain a largely underexplored field. How these environmental exposures induce epigenetic modifications (in terms of duration, frequency and the timing at which they occur) and how other environmental factors associated with IBD modulate epigenetics deserve to be further investigated.

Additional file 1. Table S1: Positive JRip rules learned from the DILI expert classification. Table S2: Positive JRip rules learned from the SCAR expert classification. Table S3: Features associated with DILI extracted from JRip rules, and presented to experts for evaluating their explanatory potential. Table S4: Features associated with SCAR extracted from JRip rules, and presented to experts for evaluating their explanatory potential.

Background Growing evidence reports an association between inflammatory markers, obesity and blood pressure (BP). Specifically, the intergenic single nucleotide polymorphism (SNP) rs7556897T > C (MAF = 0.34) located between SLC19A3 and the CCL20 was shown to be associated with chronic inflammatory diseases. In addition, CCL20 expression was found increased in pancreatic islets of obese rodents and human pancreatic β cells under the influence of inflammation. In this study, we hypothesized that SNP rs7556897 could affect BP levels, thus providing a link between inflammation, BP and obesity. Methods BP was measured under supine position with a manual sphygmomanometer; values reported were the means of three readings. We analyzed rs7556897 in 577 normal weight and 689 obese French children. Using real-time polymerase chain reaction (PCR), we quantified CCL20 and SLC19A3 expression in adipose tissue and peripheral blood mononuclear cells (PBMCs) of normal weight and overweight children. Results The rs7556897C allele was negatively associated with diastolic BP in normal weight children (β = −0.012 ± 0.004, p = 0.006) but positively associated in obese children (β = 2.178 ± 0.71, p = 0.002). A significant interaction between rs7556897T > C and the obesity status (obese or normal weight) was detected (β = 3.49, p = 9.79 × 10−5) for BP in a combined population analysis. CCL20 mRNA was only expressed in the adipose tissue of overweight children, and its expression levels were 10.7× higher in PBMCs of overweight children than normal weight children. Finally, CCL20 mRNA levels were positively associated with rs7556897T > C in PBMCs of 58 normal weight children (β = 0.43, p = 0.002). SLC19A3 was not expressed in PBMCs, and in adipose tissue, it showed same levels of expression in normal weight and overweight children. The gene expression results may highlight a specific involvement of CCL20 via communicating obesity/inflammation pathways that regulate BP. Conclusions Childhood obesity reverses the effect of rs7556897T > C on diastolic BP, possibly via the modulation of CCL20 expression levels.

Background Lymphoma is a dreaded complication of inflammatory bowel diseases [IBD]. Knowledge about lymphoma in patients with IBD is limited to epidemiological data and the description of risk factors. We performed a systematic review to describe the clinical characteristics and prognosis of lymphoma in patients with IBD. Methods Electronic databases were searched up to June 1, 2020. All published clinical characteristics of lymphoma occurring in patients with IBD were collected. Results Eleven studies were included. A total of 589 lymphomas were described in patients with IBD. As seen in de novo lymphoma, non-Hodgkin’s lymphoma [NHL] was the most common histological subtype [83.9%]. Diffuse large B-cell lymphoma [DLBCL] and follicular lymphoma were the most well-represented NHL in patients with IBD [30% and 13% respectively]. Two main differences were observed in comparison with de novo lymphoma: primary intestinal lymphoma [PIL] represented a large proportion of lymphoma in patients with IBD [22–75%] whereas mucosa-associated lymphoid tissue [MALT] lymphoma was under-represented. Epstein–Barr virus [EBV]-positive status was observed in a large proportion of tumours [44–75%]. Survival data of lymphoma in patients with IBD were similar to those of de novo lymphoma. Discussion This systematic review first highlights that PIL [especially DLBCL subtype] is significantly more frequent in patients with IBD and represents the most common entity. Conversely, MALT lymphoma is extremely rare in the IBD population. However, the overall quality of the evidence is low. Further studies are required to better define lymphoma characteristics in patients with IBD.

International audience; BACKGROUND:We have investigated the association between 4 cis- and trans-genetic variants (rs6921438, rs4416670, rs6993770 and rs10738760) of the vascular endothelial growth factor (VEGF) gene and metabolic syndrome (MetS) and its individual components in an Iranian population.MATERIAL & METHOD:Three hundred and thirty-six subjects were enrolled and MetS was defined according to the International-Diabetes-Federation (IDF) criteria. Genotyping was carried out in all the individuals for 4 VEGF genetic variants using an assay based on a combination of multiplex polymerase chain reaction and biochip array hybridization.RESULTS:As may be expected, patients with MetS had significantly higher levels of serum high-sensitivity C-reactive protein, waist circumference, hip circumference, body mass index, fat percentage, systolic blood pressure, diastolic blood pressure and triglyceride, whereas the high-density lipoprotein cholesterol levels were significantly lower, compared to the control group (P < 0.05). We also found that 1 of the VEGF- level associated genetic variants, rs6993770, was associated with the presence of MetS; the less common T allele at this locus was associated with an increased risk for MetS. This association remained significant after adjustment for confounding factors (P = 0.007). Individuals with MetS carrying the AT + TT genotypes had markedly higher levels of fasting blood glucose, triglyceride and systolic blood pressure (P < 0.05).CONCLUSIONS:We have found an association between the rs6993770 polymorphism and MetS. This gene variant was also associated with serum VEGF concentrations. There was also an association between this variant and the individual components of the MetS, including triglyceride, fasting blood glucose and systolic blood pressure.Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Introduction L’importance des manifestations dermatologiques dans le diagnostic des deficits immunitaires primitifs a ete deja rapportee par certaines etudes mais exceptionnellement en Afrique subsaharienne. Le but de cette etude est de decrire les manifestations dermatologiques au cours des deficits immunitaires primitifs sur peau noire. Materiel et methodes Il s’agit d’une etude de cohorte ouverte portant sur des enfants presentant des manifestations dermatologiques suspectes de deficit immunitaire primitif a l’hopital d’Enfant Albert Royer de Dakar. Le diagnostic de deficit immunitaire primitif est basee sur la classification phenotypique de l’union internationale des societes d’immunologistes. Resultats Vingt huit patients ont ete suivi dont 18 filles et 10 garcons. L’âge moyen etait de 7 ans (extreme = 4 mois et 18 ans). L’âge de debut des symptomes etait inferieur a 3 ans dans 17 cas, entre 3 et 10 ans dans 6 cas, superieur a 10 ans dans 5 cas. La medecine traditionnelle etait le premier recours therapeutique dans 26 cas. Les manifestations dermatologiques etaient : condylomes ano-genitaux (n = 9) ; maladie de Kaposi (n = 2), epidermodysplasie verruciforme (n = 2), varicelle maligne (n = 1), molluscum contagiosum tumoral dissemine (n = 1) ; Candidose bucco-oesophagienne (n = 1) ; mycetome fongique cervico-facial (n = 1) ; becegite disseminee (n = 1) ; tuberculose scrofuloderme (n = 1) ; lupus aigu (n = 3) ; vitiligo extensif (n = 1) ; syndrome PAA ou Pyoderma-Acne-Arthrite (n = 1) ; erythrodermie (n = 1) ; acrodermatite enteropathique (n = 2) ; lymphome cutane (n = 1). Les manifestations extradermatologiques etaient : sepsis (n = 4) ; arthrite (n = 4) ; diarrhee (n = 3) ; pneumopathie infectieuse (n = 2) ; pericardite (n = 1) ; calcifications cardiaques (n = 1) ; crises convulsives (n = 1), thyroidite auto-immune (n = 1) ; alteration de l’etat general (n = 7). Cinq cas ont beneficie d’exploration pour le typage immunologique du deficit. Cette exploration a revele : 1 deficit d’expression de la classe CMHII, 1 syndrome d’hyper Ig E, 1 deficit primitif en complement C2 et 2 deficits congenitaux en zinc. Apres 3 ans de suivi regulier de la cohorte, nous avons eu 4 perdus de vue, 3 deces dont 2 par sepsis et 1 par metastase de neoplasie, 1 cas d’aggravation de molluscum contagiosum tumoral et 7 cas de recidive de condylome. Discussion Ces resultats montrent le deficit d’exploration des deficits immunitaires primitifs dans notre contexte d’exercice et la diversite des manifestations dermatologiques revelatrices. Cependant, tous les cas qui beneficie d’un typage immunologique ont ete confirme, suggerant une tres grande sensibilite des manifestations dermatologiques pour le diagnostic des deficits immunitaires primitifs. Ce constat devra etre confirme par d’autres etudes.

International audience; Telomeres are repetitive DNA sequences located at the ends of linear chromosomes that preserve the integrity and stability of the genome. Telomere dysfunctions due to short telomeres or altered telomere structures can ultimately lead to replicative cellular senescence and chromosomal instability, both mechanisms being hallmarks of ageing. Chronic inflammation, oxidative stress and finally telomere length (TL) dynamics have been shown to be involved in various age-related non-communicable diseases (NCDs). Immune-mediated inflammatory diseases (IMIDs), including affections such as inflammatory bowel disease, psoriasis, rheumatoid arthritis, spondyloarthritis and uveitis belong to this group of age-related NCDs. Although in recent years, we have witnessed the emergence of studies in the literature linking these IMIDs to TL dynamics, the causality between these diseases and telomere attrition is still unclear and controversial. In this review, we provide an overview of available studies on telomere dynamics and discuss the utility of TL measurements in immune-mediated inflammatory diseases.

Interleukin 6 receptor (IL-6R), mediating IL-6's biological functions, plays an important role in different diseases such as diabetes, obesity and cardio-vascular diseases. In this study, we investigated the effects of two single nucleotide polymorphisms (SNPs), within the IL-6R loci, previously associated with C-reactive protein (CRP) and coronary heart diseases risk, and with controversial effects on lipids traits: SNP rs4845625 and SNP rs4537545. The results showed that both investigated SNPs were antagonistically related with CRP levels; the minor rs4845625*T allele was associated with increased CRP levels (P-value = 0.011), while the minor rs4537545* T allele was associated with decreased CRP levels (P-value = 0.009). Interestingly, the minor rs4845625* T allele was significantly associated with higher low-density lipoprotein cholesterol (LDL-C) and ApoB levels (P = 0.007 and P = 0.009 respectively). Haplotype analysis showed that the TC haplotype, having the minor rs4845625* T allele, was related simultaneously with increased levels of CRP, LDL-C and ApoB levels, thus could be considered as a risk factor. Our investigation detects for the first time an independent effect of rs4845625 on LDL-C and ApoB traits, explaining an important range of those traits variability (3.49 and 5.57% respectively). Our findings might be of high clinical significance in pharmacogenomics studies of tocilizumab for which IL-6R is target.

Pharmacogenomics (PGx) studies how individual gene variations impact drug response phenotypes, which makes PGx-related knowledge a key component towards precision medicine. A significant part of the state-of-the-art knowledge in PGx is accumulated in scientific publications, where it is hardly reusable by humans or software. Natural language processing techniques have been developed to guide experts who curate this amount of knowledge. But existing works are limited by the absence of a high quality annotated corpus focusing on PGx domain. In particular, this absence restricts the use of supervised machine learning. This article introduces PGxCorpus, a manually annotated corpus, designed to fill this gap and to enable the automatic extraction of PGx relationships from text. It comprises 945 sentences from 911 PubMed abstracts, annotated with PGx entities of interest (mainly gene variations, genes, drugs and phenotypes), and relationships between those. In this article, we present the corpus itself, its construction and a baseline experiment that illustrates how it may be leveraged to synthesize and summarize PGx knowledge., Measurement(s)gene_variant • response to drug • textual entity • chemical entity • haplotype • gene • Pharmacogenomics • Pharmacogenetics • abbreviation textual entity • Pharmacokinetics • Pharmacodynamics • phenotypeTechnology Type(s)digital curationSample Characteristic - OrganismHomo sapiens Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.11323724

The 5th Biologie Prospective Santorini Conference explored the themes of systems biology, nutrigenomics and pharmacogenomics, all of which are related to personalized health, personalized therapy and personalized medicine. The conference started with a satellite meeting on genome-wide scan studies where the need for simplified models, the quality of the phenotypes and the input of epigenetics were dominant remarks. All of the omics approaches were then applied during the 3 days’ sessions to multifactorial diseases (e.g., diabetes, atherosclerosis, cancer and inflammation) and often focused on gene–gene and gene–environment interactions. Afterwards, a fundamental session on drug metabolism, theranostics and pharmacogenetics and their practical aspects showed that the translation to clinical practice is finally happening although much slower than expected.

International audience

International audience; Background and Aims: Triggering receptor expressed on myeloid cells-1 [TREM-1] is known to amplify inflammation in several diseases. Autophagy and endoplasmic reticulum [ER] stress, which activate the unfolded protein response [UPR], are closely linked and defects in these pathways contribute to the pathogenesis of inflammatory bowel disease [IBD]. Both autophagy and UPR are deeply involved in host-microbiota interactions for the clearance of intracellular pathogens, thus contributing to dysbiosis. We investigated whether inhibition of TREM-1 would prevent aberrant inflammation by modulating autophagy and ER stress and preventing dysbiosis.Methods: An experimental mouse model of colitis was established by dextran sulphate sodium treatment. TREM-1 was inhibited, either pharmacologically by LR12 peptide or genetically with Trem-1 knock-out [KO] mice. Colon tissues and faecal pellets of control and colitic mice were used. Levels of macroautophagy, chaperone-mediated autophagy [CMA], and UPR proteins were evaluated by western blotting. The composition of the intestinal microbiota was assessed by MiSeq sequencing in both LR12-treated and KO animals.Results: We confirmed that inhibition of TREM-1 attenuates the severity of colitis clinically, endoscopically and histologically. We observed an increase in macroautophagy [ATG1/ULK-1, ATG13, ATG5, ATG16L1, and MAP1LC3-I/II] and in CMA [HSPA8 and HSP90AA1], whereas there was a decrease in the UPR [PERK, IRE-1α, and ATF-6α] protein expression levels in TREM-1 inhibited colitic mice. TREM-1 inhibition prevented dysbiosis.Conclusions: TREM-1 may represent a novel drug target for the treatment of IBD, by modulating autophagy activity and ER stress.

High levels of TREM-1 are associated with cardiovascular and inflammatory diseases risks and the most recent studies have showed that TREM-1 deletion or blockade is associated with up to 60% reduction of the development of atherosclerosis. So far, it is unknown whether the levels of TREM-1 protein are genetically regulated. Moreover, TREM family receptors have been suggested to regulate the cellular adhesion process. The goal of this study was to investigate whether polymorphisms within TREM-1 are regulating the variants of serum TREM-1 levels and the expression levels of their mRNA. Furthermore, we aimed to point out associations between polymorphisms on TREM-1 and blood levels of selectins. Among the 10 SNPs studied, the minor allele T of rs2234246, was associated with increased sTREM-1 in the discovery population (p-value = 0.003), explaining 33% of its variance, and with increased levels of mRNA (p-value = 0.007). The same allele was associated with increased soluble L-selectin levels (p-value = 0.011). The higher levels of sTREM-1 and L-selectin were confirmed in the replication population (p-value = 0.0007 and p-value = 0.018 respectively). We demonstrated for the first time one SNP on TREM-1, affecting its expression levels. These novel results, support the hypothesis that TREM-1 affects monocytes extravasation and accumulation processes leading to atherogenesis and atherosclerotic plaque progression, possibly through increased inflammation and subsequent higher expression of sL-selectin.

Background:TheABOgene has been widely studied and associated with many different diseases such as myocardial infarction and diabetes. Pleiotropic effects of theABOlocus have been demonstrated. Indeed it affects different phenotypes such as E- and P-selectins, triglycerides and total cholesterol. The goal of this work was to study the SNP rs644234 located in theABOgene with different phenotypes related with diseases where theABOgene has been involved.Methods:We analyzed the SNP rs644234 located in theABOgene, by performing association studies with different lipid phenotypes as well as with the soluble E-selectin levels in 348 adults from the STANISLAS Family Study.Results:The major rs644234*T allele was associated with increased levels of soluble E-selectin (p=8.7×10−12). According to the lipid phenotypes, the major rs644234*T allele was associated with decreased levels of apolipoproteins E (ApoE) (p=0.001) and low-density lipoprotein cholesterol (LDL-C) (p=0.032) but was associated with increased levels of high-density lipoprotein cholesterol (HDL-C) (p=0.013). The association of the HDL-C was especially significant in the male individuals (p=0.001).Conclusions:We confirmed thatABOis a major locus for serum soluble E-selectin levels variability, and we also correlated this gene with different lipid phenotypes. Furthermore, we demonstrated that this pleiotropic effect is independent. This is the first time that a correlation has been made between the ABOgene and the ApoE levels. According to these results, the major allele of this polymorphism may have a protective effect when it comes to cardiovascular related diseases, and more specifically when it comes to the lipid phenotypes.

The second international European Society of Pharmacogenomics and Theranostics (ESPT) conference was organized in Lisbon, Portugal, and attracted 250 participants from 37 different countries. The participants could listen to 50 oral presentations, participate in five lunch symposia and were able to view 83 posters and an exhibition. The first part of this Conference Scene will focus on the pharmacogenomics and biomarkers used in medical oncology, and in particular solid tumors. In addition, this article covers the two keynote conference introductory lectures by Ann K Daly and Magnus Ingelman-Sundberg. The second part of this article will discuss the clinical implementation of pharmacogenomic tests; the role of transports and pharmacogenomics; how stem cells and other new tools are helping the development of pharmacogenomics and drug discovery; and an update on the clinical translation of pharmacogenomics to personalized medicine. Part two of this Conference Scene will be featured in the next issue of Pharmacogenomics.

Second International ESPT Meeting Lisbon, Portugal, 26–28 September 2013 The second European Society of Pharmacogenomics and Theranostics (ESPT) conference was organized in Lisbon, Portugal, and attracted 250 participants from 37 different countries. The participants could listen to 50 oral presentations, participate in five lunch symposia and were able to view 83 posters and an exhibition. Part 1 of this Conference Scene was presented in the previous issue of Pharmacogenomics. This second part will focus on: clinical implementation of pharmacogenomics tests; transporters and pharmacogenomics; stem cells and other new tools for pharmacogenomics and drug discovery; from system pharmacogenomics to personalized medicine; and, finally, we will discuss the Posters and Awards that were presented at the conference.

Noonan syndrome is a genetic autosomal dominant disorder characterized by facial dysmorphy, short stature, delayed puberty and congenital heart defects. The first gene implicated in this syndrome is PTPN11, encoding protein tyrosine phosphatase SHP-2. Several studies worldwide have identified missense mutations in this gene in patients with Noonan syndrome. Our objective focused on mutations screening of PTPN11 on a Senegalese population with Noonan syndrome. Six patients clinically diagnosed with Noonan syndrome were included in this study. DNA was extracted from whole blood by phenol chloroform. Mutation screening was performed by bidirectional sequencing of amplified polymerase chain reaction (PCR) products of PTPN11 exons frequently mutated in Noonan syndrome. This study identified in two patients, a c.923AEƒC mutation in exon 8, predicting Asn308Thr (N308T) on SHP-2 protein. This is the first time that this mutation is described in Noonan syndrome in Africa, while codon 308 was reported as a hot spot mutation site in other populations. Frequently reported amino acid substitutions were Asn308Asp and Asn308Ser. All these mutations affected the protein tyrosine phosphatase domain (PTP) of SHP-2 protein exerting a gain of function which would likely explain observed phenotypes in patients. Key words: Mutation, N308T, protein tyrosine phosphatise (PTP), SHP-2 protein, Noonan syndrome, Senegal.

After a 1-day advanced course on systems biology, the main themes of this 3-day colloquium were developed: from systems biology to systems medicine with special applications to cancer; pharmacogenomics in drug discovery and clinical application; and epigenomics and genome-wide association studies in cardiovascular diseases. In two roundtable discussions on pharmacogenomics and genome-wide association studies, the progress and the difficulties in the implementation of omics technologies in clinical practice were discussed. Three workshops were also organized on technical tools linked to the meeting themes.

Background A standard task in pharmacogenomics research is identifying genes that may be involved in drug response variability, i.e., pharmacogenes. Because genomic experiments tended to generate many false positives, computational approaches based on the use of background knowledge have been proposed. Until now, only molecular networks or the biomedical literature were used, whereas many other resources are available. Method We propose here to consume a diverse and larger set of resources using linked data related either to genes, drugs or diseases. One of the advantages of linked data is that they are built on a standard framework that facilitates the joint use of various sources, and thus facilitates considering features of various origins. We propose a selection and linkage of data sources relevant to pharmacogenomics, including for example DisGeNET and Clinvar. We use machine learning to identify and prioritize pharmacogenes that are the most probably valid, considering the selected linked data. This identification relies on the classification of gene–drug pairs as either pharmacogenomically associated or not and was experimented with two machine learning methods –random forest and graph kernel–, which results are compared in this article. Results We assembled a set of linked data relative to pharmacogenomics, of 2,610,793 triples, coming from six distinct resources. Learning from these data, random forest enables identifying valid pharmacogenes with a F-measure of 0.73, on a 10 folds cross-validation, whereas graph kernel achieves a F-measure of 0.81. A list of top candidates proposed by both approaches is provided and their obtention is discussed. Electronic supplementary material The online version of this article (doi:10.1186/s13326-017-0125-1) contains supplementary material, which is available to authorized users.

Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79x10-13), rs74506613 (JMJD1C, P = 1.17x10-19), rs4782371 (ZFPM1, P = 1.59x10-9) and rs2639990 (ZADH2, P = 1.72x10-8), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52x10-18; rs7043199, VLDLR-AS1, P = 5.12x10-14) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39x10-1467; rs1740073, C6orf223, P = 2.34x10-17; rs6993770, ZFPM2, P = 2.44x10-60; rs2375981, KCNV2, P = 1.48x10-100). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases., Author Summary Vascular Endothelial Growth Factor (VEGF) is a protein with a fundamental role in development of vascular system. The protein, produced by many types of cells, is released in the blood. High levels of VEGF have been observed in different pathological conditions especially in cancer, cardiovascular, and inflammatory diseases. Therefore, identifying the genetic factors influencing VEGF levels is important for predicting and treating such pathologies. The number of genetic variants associated with VEGF levels has been limited. To identify new loci, we have performed a Genome Wide Association Study meta-analysis on a sample of more than 16,000 individuals from 10 cohorts, using a high-density genetic map. This analysis revealed 10 variants associated with VEGF circulating levels, 6 of these being novel associations. The 10 variants cumulatively explain more than 50% of the variability of VEGF serum levels. Our analyses have identified genes known to be involved in angiogenesis related diseases and genes implicated in platelet metabolism, suggesting the importance of links between this process and VEGF regulation. Overall, these data have improved our understanding of the genetic variation underlying circulating VEGF levels. This in turn could guide our response to the challenge posed by various VEGF-related pathologies.

The aim of this study was to investigate the difference in the prevalence of metabolic syndrome and its components between an Iranian and a French population.The prevalence of metabolic syndrome, defined according to the Adult Treatment Panel III (ATP III), and of related abnormalities, was estimated in 1,386 French and 1,194 Iranian adults.The prevalence of metabolic syndrome was significantly higher in Iranian women (55.0%), followed by Iranian men (30.1%), than in French men (13.7%) and French women (6.6%). Iranian women were characterized by high rates of abdominal obesity (65.0%), hypertension (52.1%), hypertriglyceridemia (43.1%), and low high-density lipoprotein cholesterol (HDL-C; 92.7%). Iranian men were characterized by high rates of hypertension (48.9%), hypertriglyceridemia (42.8%), and low HDL-C (81.8%). French men had high rates of hypertension (44.7%) and mild rates of hypertriglyceridemia (28.6%) and hyperglycemia (23.9%). There was a relationship between waist circumference and the lipid components of metabolic syndrome in both countries.The main finding of this study is the high prevalence of low HDL-C concentrations in the Iranian population, especially in Iranian women, compared with French women. Explanation of this observation could help in establishing prevention strategies.

Genome-Wide Association Studies (GWAS) on cardiovascular diseases and related quantitative traits revealed numerous genetic variants, which however have been partially replicated, probably due to the heterogeneity of the clinical phenotypes and the populations studied. Even if novel biological pathways have been identified through these studies, there is still a long way until the validation of causal variants and their use in clinical practice as factors for prevention, risk assessment and as targets for the development of new medications. GWAS methodologies should, in the following years, integrate gene–gene and gene–environment interaction analyses in a global research strategy and also involve subsequent transcriptomic and proteomic investigations. The GWAS era is very promising but it is just at the beginning.