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1. Retinal redetachment after silicone oil removal: a risk factor analysis

Author

Clément Gisquet, Ndeye Coumba Ndiaye, Chloé Dubroux, Karine Angioi-Duprez, Jean-Paul Berrod, and Jean-Baptiste Conart

Subjects
Rhegmatogenous retinal detachment, Silicone oil, Proliferative vitreoretinopathy, Ophthalmology, RE1-994
Abstract

Abstract Purpose To report the rate of retinal redetachment after silicone oil removal following rhegmatogenous retinal detachment surgery and to determine potential risk factors. Methods Retrospective observational case series of 161 eyes who underwent rhegmatogenous retinal detachment surgery and subsequent silicone oil removal. Pre- and intraoperative risk factors were evaluated using univariate and multivariate logistic regression. We also evaluated the effect of tamponade duration on anatomical outcomes. Results The median tamponade duration was 5.9 [4.3;7.6] months. Seventeen (10.6%) eyes underwent silicone oil removal within 3 months of surgery, with a median delay of 2.3 [2.0;2.8] months. The rate of retinal detachment after silicone oil removal was 14.9%. A history of previous unsuccessful surgery was the only significant risk factor for retinal redetachment after silicone oil removal (OR 4.8, 95%CI [1.5;19.0], p = 0.02). The use of 360° laser retinopexy and concomitant air or gas tamponade during silicone oil removal were not found to affect the redetachment rate. Eyes with silicone oil tamponade ≤ 3 months showed an increased, albeit not significant, risk of developing recurrent rhegmatogenous retinal detachment after silicone oil removal (35.3% versus 12.5%, p = 0.06). Conclusion A retinal redetachment occurred in 14.9% of eyes undergoing silicone oil removal following rhegmatogenous retinal detachment surgery. Previous failed surgery was associated with a 4.8-fold increased risk of developing recurrent rhegmatogenous retinal detachment after silicone oil removal. Eyes with silicone oil tamponade ≤ 3 months tended to have a higher redetachment rate. Trial registration number ID NCT05647928 (12th April 2022)

Published
2024
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2. NOD2/CARD15 polymorphisms (P268S, IVS8+158, G908R, L1007fs, R702W) among Kuwaiti patients with Crohn's disease: A case-control study

Author

Hassan Abdelnaby, Ndeye Coumba Ndiaye, Ferdinando D'Amico, Ahmed Mahmoud Fouad, Sameh Hassan, Alaa Elshafey, Wafaa Al Hashash, Mohammed Faisal, Yousef Alshamali, Talal Al-Taweel, and Laurent Peyrin-Biroulet

Subjects
crohn's, kuwait, nod2/card15, polymorphisms, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

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.

Published
2021
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3. Long-Term Overconsumption of Fat and Sugar Causes a Partially Reversible Pre-inflammatory Bowel Disease State

Author

Djésia Arnone, Marie Vallier, Sébastien Hergalant, Caroline Chabot, Ndeye Coumba Ndiaye, David Moulin, Anda-Maria Aignatoaei, Jean-Marc Alberto, Huguette Louis, Olivier Boulard, Camille Mayeur, Natacha Dreumont, Kenneth Peuker, Anne Strigli, Sebastian Zeissig, Franck Hansmannel, Matthias Chamaillard, Tunay Kökten, and Laurent Peyrin-Biroulet

Subjects
diet-induced, IBD-inflammatory bowel diseases, colitis, gut homeostasis, high-fat high-sucrose diet, Nutrition. Foods and food supply, TX341-641
Abstract

Nutrition appears to be an important environmental factor involved in the onset of inflammatory bowel diseases (IBD) through yet poorly understood biological mechanisms. Most studies focused on fat content in high caloric diets, while refined sugars represent up to 40% of caloric intake within industrialized countries and contribute to the growing epidemics of inflammatory diseases. Herein we aim to better understand the impact of a high-fat-high-sucrose diet on intestinal homeostasis in healthy conditions and the subsequent colitis risk. We investigated the early events and the potential reversibility of high caloric diet-induced damage in mice before experimental colitis. C57BL/6 mice were fed with a high-fat or high-fat high-sucrose or control diet before experimental colitis. In healthy mice, a high-fat high-sucrose diet induces a pre-IBD state characterized by gut microbiota dysbiosis with a total depletion of bacteria belonging to Barnesiella that is associated with subclinical endoscopic lesions. An overall down-regulation of the colonic transcriptome converged with broadly decreased immune cell populations in the mesenteric lymph nodes leading to the inability to respond to tissue injury. Such in-vivo effects on microbiome and transcriptome were partially restored when returning to normal chow. Long-term consumption of diet enriched in sucrose and fat predisposes mice to colitis. This enhanced risk is preceded by gut microbiota dysbiosis and transcriptional reprogramming of colonic genes related to IBD. Importantly, diet-induced transcriptome and microbiome disturbances are partially reversible after switching back to normal chow with persistent sequelae that may contribute to IBD predisposition in the general population.

Published
2021
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4. Impact of the Exposome on the Epigenome in Inflammatory Bowel Disease Patients and Animal Models

Author

Sophie Vieujean, Bénédicte Caron, Vincent Haghnejad, Jean-Yves Jouzeau, Patrick Netter, Anne-Charlotte Heba, Ndeye Coumba Ndiaye, David Moulin, Guillermo Barreto, Silvio Danese, and Laurent Peyrin-Biroulet

Subjects
inflammatory bowel disease, epigenetics, exposome, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

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.

Published
2022
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5. Un danger de la chirurgie thyroidienne: le nerf larynge inferieur non recurrent: cas clinique

Author

Moustapha Ndiaye, Mame Sanou Diouf, Abdallah Witti, Mame Coumba Sarr, Ndeye Coumba Ndiaye, Abdou Sy, Malick Ndiaye, and Abdourahmane Tall

Subjects
nerf laryngé récurrent, non récurrent, chirurgie thyroïdienne, Medicine
Abstract

Les lésions du nerf laryngé inférieur représentent les complications les plus dévastatrices de la chirurgie thyroïdienne. L´identification du nerf laryngé inférieur est d´autant plus difficile que son trajet est atypique. Nous rapportons un cas de nerf laryngé inférieur droit non récurrent découvert à l´occasion d´une thyroïdectomie.

Published
2020
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6. Learning from biomedical linked data to suggest valid pharmacogenes

Author

Kevin Dalleau, Yassine Marzougui, Sébastien Da Silva, Patrice Ringot, Ndeye Coumba Ndiaye, and Adrien Coulet

Subjects
Linked data, Pharmacogenomics, Data mining, Knowledge discovery from databases, Machine learning, Valid pharmacogenes, Computer applications to medicine. Medical informatics, R858-859.7
Abstract

Abstract 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.

Published
2017
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7. TREM-1 SNP rs2234246 regulates TREM-1 protein and mRNA levels and is associated with plasma levels of L-selectin.

Author

Alex-Ander Aldasoro Arguinano, Sébastien Dadé, Maria Stathopoulou, Marc Derive, Ndeye Coumba Ndiaye, Ting Xie, Christine Masson, Sébastien Gibot, and Sophie Visvikis-Siest

Subjects
Medicine, Science
Abstract

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.

Published
2017
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8. A common variant highly associated with plasma VEGFA levels also contributes to the variation of both LDL-C and HDL-C[S]

Author

Maria G. Stathopoulou, Amélie Bonnefond, Ndeye Coumba Ndiaye, Mohsen Azimi-Nezhad, Said El Shamieh, Abdelsalam Saleh, Marc Rancier, Gerard Siest, John Lamont, Peter Fitzgerald, and Sophie Visvikis-Siest

Subjects
vascular endothelial growth factor A polymorphism, lipid metabolism, cardiovascular disease, high density lipoprotein-C, low density lipoprotein-C, epistatic interaction, Biochemistry, QD415-436
Abstract

Vascular endothelial growth factor A (VEGFA) is among the most-significant stimulators of angiogenesis. Its effect on cardiovascular diseases and on the variation of related risk factors such as lipid parameters is considered important, although as yet unclear. Recently, we identified four common variants (rs6921438, rs4416670, rs6993770, and rs10738760) that explain up to 50% of the heritability of plasma VEGFA levels. In the present study, we aimed at assessing the contribution of these variants to the variation of blood lipid levels (including apoE, triglycerides, total cholesterol, low- and high-density lipoprotein cholesterol levels (LDL-C and HDL-C)] in healthy subjects. The effect of these single-nucleotide polymorphisms (SNPs) on lipid levels was assessed using linear regression in discovery and replication samples (n = 1,006 and n = 1,145; respectively), followed by a meta-analysis. Their gene×gene and gene×environment interactions were also assessed. SNP rs6921438 was associated with HDL-C (β=−0.08 mmol/l, Poverall= 1.2 × 10−7) and LDL-C (β= 0.13 mmol/l, Poverall= 1.5 × 10−4). We also identified a significant association between the interaction rs4416670×hypertension and apoE variation (Poverall= 1.7 × 10−5). Therefore, our present study shows a common genetic regulation between VEGFA and cholesterol homeostasis molecules. The SNP rs6921438 is in linkage disequilibrium with variants located in an enhancer- and promoter-associated histone mark region and could have a regulatory effect in the expression of surrounding genes, including VEGFA.

Published
2013
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9. Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies.

Author

Seung Hoan Choi, Daniela Ruggiero, Rossella Sorice, Ci Song, Teresa Nutile, Albert Vernon Smith, Maria Pina Concas, Michela Traglia, Caterina Barbieri, Ndeye Coumba Ndiaye, Maria G Stathopoulou, Vasiliki Lagou, Giovanni Battista Maestrale, Cinzia Sala, Stephanie Debette, Peter Kovacs, Lars Lind, John Lamont, Peter Fitzgerald, Anke Tönjes, Vilmundur Gudnason, Daniela Toniolo, Mario Pirastu, Celine Bellenguez, Ramachandran S Vasan, Erik Ingelsson, Anne-Louise Leutenegger, Andrew D Johnson, Anita L DeStefano, Sophie Visvikis-Siest, Sudha Seshadri, and Marina Ciullo

Subjects
Genetics, QH426-470
Abstract

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 = 6.79 x 10(-13)), rs74506613 (JMJD1C, P = 1.17 x 10(-19)), rs4782371 (ZFPM1, P = 1.59 x 10(-9)) and rs2639990 (ZADH2, P = 1.72 x 10(-8)), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52 x 10(-18); rs7043199, VLDLR-AS1, P = 5.12 x 10(-14)) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39 x 10(-1467); rs1740073, C6orf223, P = 2.34 x 10(-17); rs6993770, ZFPM2, P = 2.44 x 10(-60); rs2375981, KCNV2, P = 1.48 x 10(-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.

Published
2016
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10. What is the contribution of two genetic variants regulating VEGF levels to type 2 diabetes risk and to microvascular complications?

Author

Amélie Bonnefond, Pierre-Jean Saulnier, Maria G Stathopoulou, Niels Grarup, Ndeye Coumba Ndiaye, Ronan Roussel, Mohsen Azimi Nezhad, Aurélie Dechaume, Olivier Lantieri, Serge Hercberg, Torsten Lauritzen, Beverley Balkau, Julia S El-Sayed Moustafa, Torben Hansen, Oluf Pedersen, Philippe Froguel, Guillaume Charpentier, Michel Marre, Samy Hadjadj, and Sophie Visvikis-Siest

Subjects
Medicine, Science
Abstract

Vascular endothelial growth factor (VEGF) is a key chemokine involved in tissue growth and organ repair processes, particularly angiogenesis. Elevated circulating VEGF levels are believed to play a role in type 2 diabetes (T2D) microvascular complications, especially diabetic retinopathy. Recently, a genome-wide association study identified two common single nucleotide polymorphisms (SNPs; rs6921438 and rs10738760) explaining nearly half of the variance in circulating VEGF levels. Considering the putative contribution of VEGF to T2D and its complications, we aimed to assess the effect of these VEGF-related SNPs on the risk of T2D, nephropathy and retinopathy, as well as on variation in related traits.SNPs were genotyped in several case-control studies: French and Danish T2D studies (N(cases) = 6,920-N(controls) = 3,875 and N(cases) = 3,561-N(controls) = 2,623; respectively), two French studies one for diabetic nephropathy (N(cases) = 1,242-N(controls) = 860) and the other for diabetic retinopathy (N(cases) = 1,336-N(controls) = 1,231). The effects of each SNP on quantitative traits were analyzed in a French general population-based cohort (N = 4,760) and two French T2D studies (N = 3,480). SNP associations were assessed using logistic or linear regressions.In the French population, we found an association between the G-allele of rs6921438, shown to increase circulating VEGF levels, and increased T2D risk (OR = 1.15; P = 3.7×10(-5)). Furthermore, the same allele was associated with higher glycated hemoglobin levels (β = 0.02%; P = 9.2×10(-3)). However, these findings were not confirmed in the Danes. Conversely, the SNP rs10738760 was not associated with T2D in the French or Danish populations. Despite having adequate statistical power, we did not find any significant effects of rs6921438 or rs10738760 on diabetic microvascular complications or the variation in related traits in T2D patients.In spite of their impact on the variance in circulating VEGF, we did not find any association between SNPs rs6921438 and rs10738760, and the risk of T2D, diabetic nephropathy or retinopathy. The link between VEGF and T2D and its complications might be indirect and more complex than expected.

Published
2013
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11. Functional epistatic interaction between rs6046G>A in F7 and rs5355C>T in SELE modifies systolic blood pressure levels.

Author

Said El Shamieh, Ndeye Coumba Ndiaye, Maria G Stathopoulou, Helena A Murray, Christine Masson, John V Lamont, Peter Fitzgerald, Athanase Benetos, and Sophie Visvikis-Siest

Subjects
Medicine, Science
Abstract

BackgroundAlthough numerous genetic studies have been performed, only 0.9% of blood pressure phenotypic variance has been elucidated. This phenomenon could be partially due to epistatic interactions. Our aim was to identify epistatic interaction(s) associated with blood pressure levels in a pre-planned two-phase approach.Methods and resultsIn a discovery cohort composed of 3,600 French individuals, we found rs6046A allele in F7 associated with decreased blood pressure levels (P≤3.7×10(-3)) and rs5355T allele in SELE associated with decreased diastolic blood pressure levels (P = 5×10(-3)). Both variants interacted in order to influence blood pressure levels (P≤0.048). This interaction was replicated with systolic blood pressure in 4,620 additional European individuals (P = 0.03). Similarly, in this replication cohort, rs6046A was associated with decreased blood pressure levels (P≤8.5×10(-4)). Furthermore, in peripheral blood mononuclear cells of a subsample of 90 supposed healthy individuals, we found rs6046A positively associated with NAMPT mRNA levels (P≤9.1×10(-5)), suggesting an eventual involvement of NAMPT expression in blood pressure regulation. Confirming this hypothesis, further transcriptomic analyses showed that increased NAMPT mRNA levels were positively correlated with ICAM1, SELL, FPR1, DEFA1-3, and LL-37 genes expression (P≤5×10(-3)). The last two mRNA levels were positively associated with systolic blood pressure levels (P≤0.01) and explained 4% of its phenotypic variation.ConclusionThese findings reveal the importance of epistatic interactions in blood pressure genetics and give new insights for the role of inflammation in its complex regulation.

Published
2012
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12. A genome-wide association study identifies rs2000999 as a strong genetic determinant of circulating haptoglobin levels.

Author

Philippe Froguel, Ndeye Coumba Ndiaye, Amélie Bonnefond, Nabila Bouatia-Naji, Aurélie Dechaume, Gérard Siest, Bernard Herbeth, Mario Falchi, Leonardo Bottolo, Rosa-Maria Guéant-Rodriguez, Cécile Lecoeur, Michel R Langlois, Yann Labrune, Aimo Ruokonen, Said El Shamieh, Maria G Stathopoulou, Anita Morandi, Claudio Maffeis, David Meyre, Joris R Delanghe, Peter Jacobson, Lars Sjöström, Lena M S Carlsson, Andrew Walley, Paul Elliott, Marjo-Riita Jarvelin, George V Dedoussis, and Sophie Visvikis-Siest

Subjects
Medicine, Science
Abstract

Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far.We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (P(overall) = 8.1 × 10(-59)), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23 ± 0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P(total cholesterol) = 0.002 and P(LDL) = 0.0008).Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.

Published
2012
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15. Deep Dive Into MicroRNAs in Inflammatory Bowel Disease

Author

Jaber Alfaifi, Adeline Germain, Anne-Charlotte Heba, Djésia Arnone, Laura Gailly, Ndeye Coumba Ndiaye, Emilie Viennois, Bénédicte Caron, Laurent Peyrin-Biroulet, and Natacha Dreumont

Subjects
Gastroenterology, Immunology and Allergy
Abstract

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.

Published
2022

16. Investigating ADR mechanisms with Explainable AI: a feasibility study with knowledge graph mining

Author

Emmanuel Bresso, Pierre Monnin, Cédric Bousquet, François-Elie Calvier, Ndeye-Coumba Ndiaye, Nadine Petitpain, Malika Smaïl-Tabbone, Adrien Coulet, Computational Algorithms for Protein Structures and Interactions (CAPSID), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Knowledge representation, reasonning (ORPAILLEUR), Department of Natural Language Processing & Knowledge Discovery (LORIA - NLPKD), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Orange Labs [Belfort] (Orange Labs), France Télécom, Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Régional de PharmacoVigilance de Lorraine (CRPV Lorraine), Health data- and model- driven Knowledge Acquisition (HeKA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), ANR-15-CE23-0028,PractiKPharma,Confrontation entre connaissances de l'état de l'art et connaissances extraites de dossiers patients en pharmacogénomique(2015), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Natural Language Processing & Knowledge Discovery (LORIA - NLPKD), Orange Labs, ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), CRHU Nancy, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Monnin, Pierre, Interactions humain-machine, objets connectés, contenus numériques, données massives et connaissance - Confrontation entre connaissances de l'état de l'art et connaissances extraites de dossiers patients en pharmacogénomique - - PractiKPharma2015 - ANR-15-CE23-0028 - AAPG2015 - VALID, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École pratique des hautes études (EPHE), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Coulet, Adrien, and Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID

Subjects
[INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], Knowledge graph, [INFO.INFO-DB]Computer Science [cs]/Databases [cs.DB], Drug-Related Side Effects and Adverse Reactions, Explanation, Computer applications to medicine. Medical informatics, R858-859.7, Adverse drug reaction, Mechanism of action, Pattern Recognition, Automated, Molecular mechanism, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Pharmacovigilance, Artificial Intelligence, Machine learning, Explainable AI, Adverse Drug Reaction Reporting Systems, Feasibility Studies, Humans, [INFO.INFO-DB] Computer Science [cs]/Databases [cs.DB], Drug mechanism of action, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Data mining, Research Article, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract

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.

Published
2022

17. NOD2/CARD15 polymorphisms (P268S, IVS8+158, G908R, L1007fs, R702W) among Kuwaiti patients with Crohn's disease: A case-control study

Author

Mohammed Faisal, Wafaa Al Hashash, Yousef Alshamali, Laurent Peyrin-Biroulet, Ferdinando D'Amico, Alaa Elshafey, Hassan Abdelnaby, Talal Al-Taweel, Ahmed Fouad, Sameh Hassan, and Ndeye Coumba Ndiaye

Subjects
medicine.medical_specialty, nod2/card15, Population, RC799-869, Gastroenterology, Polymorphism (computer science), Internal medicine, Genotype, medicine, crohn's, Allele, education, Allele frequency, Crohn's disease, education.field_of_study, business.industry, Case-control study, Diseases of the digestive system. Gastroenterology, medicine.disease, digestive system diseases, Original Article, Restriction fragment length polymorphism, business, polymorphisms, kuwait
Abstract

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.

Published
2021

18. Calorie Restriction as a New Treatment of Inflammatory Diseases

Author

Tunay Kökten, Laurent Peyrin-Biroulet, Anne-Charlotte Heba, Didier Quilliot, Franck Hansmannel, Natacha Dreumont, Ndeye Coumba Ndiaye, Djésia Arnone, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Endocrinologie - Diabète - Nutrition [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Hépato-gastro-entérologie [CHRU Nancy], TK was funded by grants from the Association François Aupetit (AFA) and by the French Investments for the Future Programme (PIA) project Lorraine Université d’Excellence (reference ANR-15-IDEX-04-LUE)., DA was funded by a grant from the 'Fondation pour la Recherche Médicale'(reference ECO20170637494)., IMPACT GEENAGE, and ANR-15-IDEX-0004,LUE,Isite LUE(2015)

Subjects
0301 basic medicine, autophagy, fasting, [SDV]Life Sciences [q-bio], Longevity, Calorie restriction, Medicine (miscellaneous), 030209 endocrinology & metabolism, Review, Systemic inflammation, Bioinformatics, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Humans, Medicine, Obesity, Social determinants of health, Adiposity, Sedentary lifestyle, metabolic switch, Nutrition and Dietetics, gut microbiota, business.industry, medicine.disease, 3. Good health, inflammatory disease, Malnutrition, 030104 developmental biology, endoplasmic reticulum stress, Observational study, caloric restriction, medicine.symptom, Energy Intake, business, Food Science
Abstract

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.

Published
2021

19. Additional file 1 of Investigating ADR mechanisms with Explainable AI: a feasibility study with knowledge graph mining

Author

Bresso, Emmanuel, Monnin, Pierre, Bousquet, Cédric, François-Elie Calvier, Ndeye-Coumba Ndiaye, Petitpain, Nadine, Smaïl-Tabbone, Malika, and Coulet, Adrien

Abstract

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.

Published
2021
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20. Obesity status modifies the association between rs7556897T>C in the intergenic region SLC19A3-CCL20 and blood pressure in French children

Author

Maria G. Stathopoulou, George V. Dedoussis, Pia Chedid, Philippe Froguel, Sophie Visvikis-Siest, Said El Shamieh, Ndeye Coumba Ndiaye, Ali Salami, Payman Shahabi, Amélie Bonnefond, Cécile Lecoeur, Sébastien Dadé, David Meyre, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Beirut Arab University [Beyrouth, Liban] (BAU), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), McMaster University [Hamilton, Ontario], Harokopio University of Athens, Imperial College London, and Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M))

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Population, Gene Expression, Adipose tissue, Blood Pressure, Single-nucleotide polymorphism, Inflammation, 030204 cardiovascular system & hematology, Overweight, Polymorphism, Single Nucleotide, White People, Childhood obesity, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Obesity, Child, education, ComputingMilieux_MISCELLANEOUS, education.field_of_study, Chemokine CCL20, business.industry, Biochemistry (medical), Membrane Transport Proteins, General Medicine, medicine.disease, 030104 developmental biology, Endocrinology, Blood pressure, Adipose Tissue, Leukocytes, Mononuclear, DNA, Intergenic, Female, France, medicine.symptom, business
Abstract

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.

Published
2020

21. Characteristics of Lymphoma in Patients with Inflammatory Bowel Disease: A Systematic Review

Author

Tunay Kökten, Pierre Feugier, Ndeye Coumba Ndiaye, Silvio Danese, Catherine Thieblemont, Laurent Beaugerie, Rémi Houlgatte, Laurent Peyrin-Biroulet, Djésia Arnone, Julien Broséus, Marie Muller, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Hématologie [CHRU Nancy], Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Humanitas Clinical and Research Center [Rozzano, Milan, Italy]

Subjects
medicine.medical_specialty, Lymphoma, [SDV]Life Sciences [q-bio], Population, Follicular lymphoma, Lymphoproliferative disorders, Gastroenterology, Inflammatory bowel disease, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Internal medicine, medicine, Humans, education, ComputingMilieux_MISCELLANEOUS, education.field_of_study, business.industry, MALT lymphoma, General Medicine, medicine.disease, Inflammatory Bowel Diseases, Prognosis, digestive system diseases, 3. Good health, Lymphatic system, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Complication, business
Abstract

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.

Published
2020

22. PGxCorpus, a manually annotated corpus for pharmacogenomics

Author

Kevin Dalleau, Joël Legrand, Adrien Coulet, Nadine Petitpain, Malika Smaïl-Tabbone, Romain Gogdemir, Yannick Toussaint, William Digan, Cédric Bousquet, Marie-Dominique Devignes, Patrice Ringot, Ndeye-Coumba Ndiaye, Chia-Ju Lee, Natural Language Processing : representations, inference and semantics (SYNALP), Department of Natural Language Processing & Knowledge Discovery (LORIA - NLPKD), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Knowledge representation, reasonning (ORPAILLEUR), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Natural Language Processing & Knowledge Discovery (LORIA - NLPKD), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Computational Algorithms for Protein Structures and Interactions (CAPSID), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Department of Biomedical Informatics and Medical Education, University of Washington, University of Washington [Seattle], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Régional de PharmacoVigilance de Lorraine (CRPV Lorraine), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), ANR-15-CE23-0028, Agence Nationale de la Recherche, 15-IDEX-0004, Université de Lorraine, Snowball Inria Associate Team, GRID5000, ANR-15-CE23-0028,PractiKPharma,Confrontation entre connaissances de l'état de l'art et connaissances extraites de dossiers patients en pharmacogénomique(2015), Coulet, Adrien, Interactions humain-machine, objets connectés, contenus numériques, données massives et connaissance - Confrontation entre connaissances de l'état de l'art et connaissances extraites de dossiers patients en pharmacogénomique - - PractiKPharma2015 - ANR-15-CE23-0028 - AAPG2015 - VALID, CRHU Nancy, and Service Informatique de Soutien à la Recherche (SISR)

Subjects
Data Descriptor, Computer science, [INFO.INFO-TT] Computer Science [cs]/Document and Text Processing, computer.software_genre, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], 0302 clinical medicine, Resource (project management), Drug response, 030212 general & internal medicine, lcsh:Science, Data Curation, ComputingMilieux_MISCELLANEOUS, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, 3. Good health, Computer Science Applications, [INFO.INFO-TT]Computer Science [cs]/Document and Text Processing, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Supervised Machine Learning, Statistics, Probability and Uncertainty, Natural language processing, Information Systems, [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], Statistics and Probability, PubMed, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Library and Information Sciences, Domain (software engineering), Education, 03 medical and health sciences, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Component (UML), Genetics, Humans, 030304 developmental biology, business.industry, Health care, Significant part, Precision medicine, ComputingMethodologies_PATTERNRECOGNITION, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Pharmacogenetics, Pharmacogenomics, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, lcsh:Q, Artificial intelligence, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, computer
Abstract

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

Published
2020
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23. The Relationship Between Vascular Endothelial Growth Factor Cis- and Trans-Acting Genetic Variants and Metabolic Syndrome

Author

Majid Ghayour-Mobarhan, John Victor Lamont, Bernard Herbeth, Abdoreza Varasteh, Abdollah Bahrami, Peter Fitzgerald, Marc Rancier, Amélie Bonnefond, Helena Murray, Hassan Mehrad-Majd, Amir Avan, Sophie Visvikis-Siest, Maria G. Stathopoulou, Seyed Reza Mirhafez, Ndeye Coumba Ndiaye, Mohsen Azimi-Nezhad, Gordon A. Ferns, Mashhad University of Medical Sciences, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Randox Laboratories, Brighton and Sussex Medical School (BSMS), (Grant No. 910823) from Mashhad University of Medical Sciences (MUMS) Research Council, Université de Lorraine, Nancy, and Center for Preventive Medicine of Vandoeuvre-lès-Nancy (France)

Subjects
Male, Vascular Endothelial Growth Factor A, 0301 basic medicine, [SDV]Life Sciences [q-bio], Blood Pressure, Iran, 030204 cardiovascular system & hematology, Body Mass Index, chemistry.chemical_compound, 0302 clinical medicine, Gene Frequency, Polymorphism (computer science), 2. Zero hunger, Anthropometry, General Medicine, Middle Aged, Metabolic syndrome, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Vascular endothelial growth factor, Phenotype, Female, Transcriptional Activation, medicine.medical_specialty, Waist, Genotype, Systole, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Diabetes Complications, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Diabetes Mellitus, medicine, Humans, Genetic Predisposition to Disease, Alleles, Triglycerides, Aged, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic polymorphism, Triglyceride, business.industry, medicine.disease, Single nucleotide polymorphism, 030104 developmental biology, Endocrinology, Blood pressure, chemistry, business, Body mass index, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

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.

Published
2018

24. Telomeres: New players in immune-mediated inflammatory diseases?

Author

Laurent Peyrin-Biroulet, Anne-Charlotte Heba, Simon Toupance, Ndeye Coumba Ndiaye, Anthanase Benetos, Djésia Arnone, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHRU-Nancy, Pôle 'Maladies du Vieillissement, Gérontologie et Soins Palliatif, Doctoral Fellowship from 'Reseau Lorrain des Maladies inflammatoires chroniques intestinales' MICILOR and Association des chefs de service from CHRU de Nancy to ACH. Research award 2020 from 'Societe Francophone de Nutrition Clinique et Métabolisme' SFNCM [GRANT_NUMBER: SFNCM2020] to DA. This work was supported by the French PIA project « Lorraine Université d’Excellence », reference ANR-15-IDEX-04-LUE and the Investments for the Future program under grant agreement No. ANR-15-RHU-0004., IMPACT GEENAGE, ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), and ANR-15-IDEX-0004,LUE,Isite LUE(2015)

Subjects
Immune-mediated inflammatory diseases, [SDV]Life Sciences [q-bio], Immunology, Inflammation, Biology, Bioinformatics, medicine.disease_cause, Inflammatory bowel disease, Arthritis, Rheumatoid, Uveitis, 03 medical and health sciences, 0302 clinical medicine, Chromosome instability, Psoriasis, Spondylarthritis, medicine, Humans, Immunology and Allergy, 030304 developmental biology, 0303 health sciences, Telomere, Inflammatory Bowel Diseases, medicine.disease, Dynamics, 3. Good health, Rheumatoid arthritis, medicine.symptom, 030217 neurology & neurosurgery, Oxidative stress
Abstract

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.

Published
2021

25. IL6R haplotype rs4845625*T/rs4537545*C is a risk factor for simultaneously high CRP, LDL and ApoB levels

Author

B Alizadeh, Ndeye Coumba Ndiaye, Maria G. Stathopoulou, Sophie Visvikis-Siest, A A Arguinano, S Dadé, Elnaz Naderi, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), University Medical Center Groningen [Groningen] (UMCG), Service de Médecine Interne et Médecine Générale [CHRU Nancy], and Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Apolipoprotein B, [SDV]Life Sciences [q-bio], Immunology, Single-nucleotide polymorphism, VARIANTS, Polymorphism, Single Nucleotide, 03 medical and health sciences, INFLAMMATION, Internal medicine, Diabetes mellitus, Genetics, medicine, Humans, SNP, CORONARY-HEART-DISEASE, Allele, INTERLEUKIN-6 RECEPTOR GENE, TOCILIZUMAB, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Apolipoproteins B, METABOLIC SYNDROME, biology, Haplotype, C-reactive protein, Cholesterol, LDL, Middle Aged, medicine.disease, Receptors, Interleukin-6, C-REACTIVE PROTEIN, POLYMORPHISM, 3. Good health, 030104 developmental biology, Endocrinology, Haplotypes, DENSITY-LIPOPROTEIN CHOLESTEROL, biology.protein, Female, Metabolic syndrome, ASSOCIATION ANALYSES
Abstract

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.

Published
2017

26. Functional genomics towards personalized healthcare and systems medicine

Author

Said El Shamieh, Ndeye Coumba Ndiaye, Daniel Lambert, Denyse Bagrel, Mohsen Azimi Nezhad, Sophie Visvikis-Siest, Gérard Siest, and Payman Shahabi

Subjects
Pharmacology, medicine.medical_specialty, business.industry, Systems biology, MEDLINE, General Medicine, Bioinformatics, Omics, Systems medicine, Nutrigenomics, Pharmacogenomics, Molecular Medicine, Medicine, Medical physics, Personalized medicine, business, Pharmacogenetics
Abstract

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.

Published
2018

27. Zinc-Alpha-2-Glycoprotein in Inflammatory Bowel Disease

Author

Seiamak Bahram, Cécile Macquin, Laurent Peyrin-Biroulet, David Moulin, Véronique Rolli, Tunay Kökten, Ndeye-Coumba Ndiaye, Jean-Yves Jouzeau, Julie Hablot, Philippe Georgel, Patrick Netter, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunorhumathologie moléculaire, and Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, medicine.medical_specialty, Mice Knockout, [SDV]Life Sciences [q-bio], Zn-Alpha-2-Glycoprotein, Inflammatory bowel disease, Gastroenterology, Seminal Plasma Proteins/genetics, 03 medical and health sciences, Mice, Internal medicine, medicine, Immunology and Allergy, Animals, Humans, Colitis, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, business.industry, Animal, Zinc-Alpha-2-Glycoprotein, Case-control study, Seminal Plasma Proteins, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Seminal Plasma Proteins/blood, Disease Models, Animal, 030104 developmental biology, Ulcerative/blood, Case-Control Studies, Disease Models, Colitis, Ulcerative, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience

Published
2018

28. TREM-1 Inhibition Restores Impaired Autophagy Activity and Reduces Colitis in Mice

Author

Silvia D'Alessio, Hélène Busby-Venner, Julie Hablot, Laurent Peyrin-Biroulet, David Moulin, Céline Monot, Silvio Danese, Franck Hansmannel, Tunay Kökten, Benjamin Garnier, Jean-Yves Jouzeau, Sébastien Gibot, Ndeye-Coumba Ndiaye, Sylviane Muller, Patricia Lepage, Jean-Louis Guéant, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Faculté de Médecine [Nancy], Université de Lorraine (UL), Service de Réanimation Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Humanitas Clinical and Research Institute, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Département d’Anatomie et Cytologie Pathologiques [CHRU Nancy], Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Service d'Hépato-gastro-entérologie [CHRU Nancy], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), and MOULIN, David

Subjects
0301 basic medicine, DNA, Bacterial, Male, autophagy, TREM-1, Atg1, ATG5, 03 medical and health sciences, Feces, Mice, inflammatory bowel disease, Medicine, Animals, Colitis, Animal models of IBD, endoscopy, ATG16L1, innovative therapy, Mice, Knockout, business.industry, Autophagy, Dextran Sulfate, Gastroenterology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, General Medicine, dysbiosis, Autophagy-related protein 13, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Triggering Receptor Expressed on Myeloid Cells-1, 3. Good health, Gastrointestinal Microbiome, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, inflammation, peptide-based therapy, Cancer research, Unfolded protein response, Unfolded Protein Response, LR12 peptide, endoplasmic reticulum stress, business, Peptides, Dysbiosis
Abstract

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.

Published
2018

29. Pleiotropy of ABO gene: correlation of rs644234 with E-selectin and lipid levels

Author

Christine Masson, Ndeye Coumba Ndiaye, Alex-Ander Aldasoro Arguinano, Sophie Visvikis-Siest, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)

Subjects
0301 basic medicine, Apolipoprotein E, Adult, Male, medicine.medical_specialty, Genotype, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Locus (genetics), 030204 cardiovascular system & hematology, Biology, Apolipoproteins E, ABO Blood-Group System, 03 medical and health sciences, 0302 clinical medicine, soluble E-selectin, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, ABO blood group system, medicine, SNP, Humans, Allele, apolipoproteins E (ApoE), Gene, ComputingMilieux_MISCELLANEOUS, Genetic association, Polymorphism, Genetic, Biochemistry (medical), General Medicine, Lipids, cardiovascular diseases, 030104 developmental biology, Endocrinology, Phenotype, high-density lipoprotein cholesterol (HDL-C), lipids (amino acids, peptides, and proteins), Female, E-Selectin, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

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.

Published
2017

30. Learning from biomedical linked data to suggest valid pharmacogenes

Author

Adrien Coulet, Kevin Dalleau, Patrice Ringot, Sébastien Da Silva, Ndeye Coumba Ndiaye, Yassine Marzougui, Knowledge representation, reasonning (ORPAILLEUR), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Natural Language Processing & Knowledge Discovery (LORIA - NLPKD), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Ecole Nationale Supérieure des Mines de Nancy (ENSMN), Institut Mines-Télécom [Paris] (IMT)-Université de Lorraine (UL), Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), ANR PractiKPharma project, grant ANR-15-CE23-0028, funded by the French National Research Agency (http://practikpharma.loria.fr/) and *Snowflake, an Inria associate team (http://snowflake.loria.fr/), Snowflake Inria Associate Team, Inria@SiliconValley, Snowball Inria Associate Team, ANR-15-CE23-0028,PractiKPharma,Confrontation entre connaissances de l'état de l'art et connaissances extraites de dossiers patients en pharmacogénomique(2015), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Coulet, Adrien, and Interactions humain-machine, objets connectés, contenus numériques, données massives et connaissance - Confrontation entre connaissances de l'état de l'art et connaissances extraites de dossiers patients en pharmacogénomique - - PractiKPharma2015 - ANR-15-CE23-0028 - AAPG2015 - VALID

Subjects
0301 basic medicine, Graph kernel, Computer science, Knowledge discovery from databases, computer.software_genre, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], 0302 clinical medicine, False positive paradox, [INFO.INFO-DB] Computer Science [cs]/Databases [cs.DB], [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Valid pharmacogenes, Linked data, Computer Science Applications, Random forest, Identification (information), Phenotype, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030220 oncology & carcinogenesis, lcsh:R858-859.7, Information Systems, [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], Computer Networks and Communications, Health Informatics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, lcsh:Computer applications to medicine. Medical informatics, Machine learning, Set (abstract data type), 03 medical and health sciences, [INFO.INFO-LG]Computer Science [cs]/Machine Learning [cs.LG], Computer Graphics, Selection (linguistics), Data mining, Semantic Web, Linkage (software), [INFO.INFO-DB]Computer Science [cs]/Databases [cs.DB], business.industry, Research, Computational Biology, [INFO.INFO-LG] Computer Science [cs]/Machine Learning [cs.LG], 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Pharmacogenetics, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Artificial intelligence, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, Pharmacogenomics, computer
Abstract

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.

Published
2017

31. Conference Scene: Pharmacogenomics: from cell to clinic (Part 2)

Author

Peter Meier Abt, Maria G. Stathopoulou, Gérard Siest, Rui Medeiros, David Gurwitz, Ramón Cacabelos, Carolino Monteiro, Helder Mota-Filipe, Ron H.N. van Schaik, Jao Queiroz, Bohuslav Melichar, Ndeye Coumba Ndiaye, and Sophie Visvikis-Siest

Subjects
Pharmacology, Medical education, Portugal, business.industry, Stem Cells, MEDLINE, Pharmacogenetics, Pharmacogenomics, Drug Discovery, Genetics, Humans, Molecular Medicine, Personalized medicine, Precision Medicine, business, Psychology
Abstract

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.

Published
2014

32. Conference Scene: Systems biology and personalized health science and translation

Author

Gérard Siest, Thibaut Godjo, Abdel Salam Saleh, Ndeye Coumba Ndiaye, Laetitia Albertini, Payman Shahabi, Said El Shamieh, Sophie Visvikis-Siest, and Maria G. Stathopoulou

Subjects
Pharmacology, Engineering, business.industry, Systems biology, Personalized health, Computational biology, Systems medicine, Clinical Practice, Pharmacogenomics, Genetics, Molecular Medicine, Engineering ethics, Personalized medicine, business, Omics technologies
Abstract

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.

Published
2013

33. Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies

Author

Ndeye Coumba Ndiaye, Vilmundur Gudnason, Daniela Ruggiero, Maria Pina Concas, Andrew D. Johnson, Seung Hoan Choi, Caterina Barbieri, Albert V. Smith, Teresa Nutile, Giovanni Battista Maestrale, Sophie Visvikis-Siest, Maria G. Stathopoulou, Rossella Sorice, Stéphanie Debette, Marina Ciullo, Anne-Louise Leutenegger, Cinzia Sala, Vasiliki Lagou, John Victor Lamont, Ramachandran S. Vasan, Erik Ingelsson, Peter Fitzgerald, Sudha Seshadri, Céline Bellenguez, Daniela Toniolo, Ci Song, Peter Kovacs, Anita L. DeStefano, Mario Pirastu, Anke Tönjes, Michela Traglia, Lars Lind, Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche (CNR), Uppsala Universitet [Uppsala], Karolinska Institutet [Stockholm], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], IRCCS San Raffaele Scientific Institute [Milan, Italie], Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Faculté de Pharmacie [Nancy], Université de Lorraine (UL), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Leipzig [Leipzig], Randox Laboratories, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), UL, IGEPCV, Choi, Seung Hoan, Ruggiero, Daniela, Sorice, Rossella, Song, Ci, Nutile, Teresa, Vernon Smith, Albert, Concas, Maria Pina, Traglia, Michela, Barbieri, Caterina, Ndiaye, Ndeye Coumba, Stathopoulou, Maria G., Lagou, Vasiliki, Maestrale, Giovanni Battista, Sala, Cinzia, Debette, Stephanie, Kovacs, Peter, Lind, Lar, Lamont, John, Fitzgerald, Peter, Tönjes, Anke, Gudnason, Vilmundur, Toniolo, Daniela, Pirastu, Mario, Bellenguez, Celine, Vasan, Ramachandran S., Ingelsson, Erik, Leutenegger, Anne-Louise, Johnson, Andrew D., Destefano, Anita L., Visvikis-Siest, Sophie, Seshadri, Sudha, Ciullo, Marina, and University of Oxford [Oxford]

Subjects
0301 basic medicine, Vascular Endothelial Growth Factor A, Cell signaling, Medicin och hälsovetenskap, Cancer Research, Physiology, Angiogenesis, Gene Expression, Genome-wide association study, Signal transduction, Medical and Health Sciences, Database and Informatics Methods, chemistry.chemical_compound, Mathematical and Statistical Techniques, 0302 clinical medicine, Animal Cells, Medicine and Health Sciences, Chromosomes, Human, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, Ecology, Chromosome Biology, Genomics, Hematology, Single Nucleotide, VEGF signaling, Genomic Databases, VEGF, Phenotype, Body Fluids, 3. Good health, Vascular endothelial growth factor, Blood, 030220 oncology & carcinogenesis, Physical Sciences, Anatomy, Cellular Types, Statistics (Mathematics), Research Article, Human, Platelets, lcsh:QH426-470, Evolution, European Continental Ancestry Group, Single-nucleotide polymorphism, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Research and Analysis Methods, Genome Complexity, Chromosome, Polymorphism, Single Nucleotide, Chromosomes, White People, 03 medical and health sciences, Behavior and Systematics, Genetic, Genome-Wide Association Studies, Humans, Statistical Methods, 1000 Genomes Project, Polymorphism, Gene, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Genome-Wide Association Study, Genetic Loci, Blood Cells, Biology and Life Sciences, Computational Biology, Human Genetics, Cell Biology, Genome Analysis, Ecology, Evolution, Behavior and Systematic, Introns, lcsh:Genetics, Biological Databases, 030104 developmental biology, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Expression quantitative trait loci, Mathematics, Meta-Analysis
Abstract

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.

Published
2016

34. High Prevalence of Metabolic Syndrome in Iran in Comparison with France: What Are the Components That Explain This?

Author

Sébastien Dadé, Sophie Visvikis-Siest, Habibollah Esmaily, Mohsen Azimi-Nezhad, Gérard Siest, Ndeye Coumba Ndiaye, S.J. Hosseini, Bernard Herbeth, and Majid Ghayour-Mobarhan

Subjects
Adult, Blood Glucose, Cross-Cultural Comparison, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Population, Blood Pressure, Iran, Body Mass Index, Sex Factors, Internal medicine, Prevalence, otorhinolaryngologic diseases, Internal Medicine, Humans, Medicine, education, Abdominal obesity, Lipoprotein cholesterol, Hypertriglyceridemia, Metabolic Syndrome, High rate, Analysis of Variance, education.field_of_study, Chi-Square Distribution, High prevalence, business.industry, Cholesterol, HDL, nutritional and metabolic diseases, Middle Aged, medicine.disease, Endocrinology, Hyperglycemia, Obesity, Abdominal, Hypertension, population characteristics, Female, France, Waist Circumference, medicine.symptom, Metabolic syndrome, Factor Analysis, Statistical, business, Biomarkers, geographic locations
Abstract

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.

Published
2012

35. Cardiovascular diseases and genome-wide association studies

Author

Mohsen Azimi Nehzad, Maria G. Stathopoulou, Ndeye Coumba Ndiaye, Sophie Visvikis-Siest, and Said El Shamieh

Subjects
Genetics, Biochemistry (medical), Clinical Biochemistry, Haplotype, Single-nucleotide polymorphism, Genome-wide association study, General Medicine, Quantitative trait locus, Biology, Biochemistry, Genome, Phenotype, Cardiovascular Diseases, Genetic variation, Humans, Allele, Genome-Wide Association Study, Genetic association
Abstract

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.

Published
2011

36. Identification of cis - and trans -Acting Genetic Variants Explaining Up to Half the Variation in Circulating Vascular Endothelial Growth Factor Levels

Author

Ci Song, Anita L. DeStefano, John Victor Lamont, Ndeye-Coumba Ndiaye, Radwan Safa, Seung Hoan Choi, Ramachandran S. Vasan, Michèle Pfister, Jean-Brice Marteau, Lisa M. Sullivan, Mohammad Azimi Nezhad, Qiong Yang, Stéphanie Debette, Vanessa Xanthakis, Erik Ingelsson, Peter Fitzgerald, Sudha Seshadri, Douglas B. Sawyer, Holly M. Smith, Ming-Huen Chen, Sophie Visvikis-Siest, Lars Lind, and Gérard Siest

Subjects
Physiology, Angiogenesis, Single-nucleotide polymorphism, Genome-wide association study, Biology, Bioinformatics, Vascular endothelial growth factor, chemistry.chemical_compound, Vascular endothelial growth factor A, Framingham Heart Study, chemistry, Genetic variation, Cardiology and Cardiovascular Medicine, Prospective cohort study
Abstract

Rationale: Vascular endothelial growth factor (VEGF) affects angiogenesis, atherosclerosis, and cancer. Although the heritability of circulating VEGF levels is high, little is known about its genetic underpinnings. Objective: Our aim was to identify genetic variants associated with circulating VEGF levels, using an unbiased genome-wide approach, and to explore their functional significance with gene expression and pathway analysis. Methods and Results: We undertook a genome-wide association study of serum VEGF levels in 3527 participants of the Framingham Heart Study, with preplanned replication in 1727 participants from 2 independent samples, the STANISLAS Family Study and the Prospective Investigation of the Vasculature in Uppsala Seniors study. One hundred forty single nucleotide polymorphism (SNPs) reached genome-wide significance ( P −8 ). We found evidence of replication for the most significant associations in both replication datasets. In a conditional genome-wide association study, 4 SNPs mapping to 3 chromosomal regions were independently associated with circulating VEGF levels: rs6921438 and rs4416670 (6p21.1, P =6.11×10 −506 and P =1.47×10 −12 ), rs6993770 (8q23.1, P =2.50×10 −16 ), and rs10738760 (9p24.2, P =1.96×10 −34 ). A genetic score including these 4 SNPs explained 48% of the heritability of serum VEGF levels. Six of the SNPs that reached genome-wide significance in the genome-wide association study were significantly associated with VEGF messenger RNA levels in peripheral blood mononuclear cells. Ingenuity pathway analyses showed found plausible biological links between VEGF and 2 novel genes in these loci ( ZFPM2 and VLDLR ). Conclusions: Genetic variants explaining up to half the heritability of serum VEGF levels were identified. These new insights provide important clues to the pathways regulating circulating VEGF levels.

Published
2011

37. Association of Genetic Loci With Glucose Levels in Childhood and Adolescence

Author

Nicholas J. Timpson, George Dedoussis, Beate St Pourcain, Inga Prokopenko, Neelam Hassanali, Stephen J. Sharp, Anders Grøntved, Panos Deloukas, Lawrence J. Beilin, Soren Brage, Naveed Sattar, David M. Evans, Sophie Visvikis-Siest, Ioanna Ntalla, George Davey Smith, Debbie A Lawlor, Philippe Froguel, Stephen J. Lye, Nicholas J. Wareham, Nabila Bouatia-Naji, Adam Barker, Ulf Ekelund, Nicole M. Warrington, Claudia Langenberg, Ruth J. F. Loos, Mark I. McCarthy, Cécile Lecoeur, Trevor A. Mori, Susan M. Ring, Lyle J. Palmer, Craig E. Pennell, John P. Newnham, Ndeye Coumba Ndiaye, and Stavroula Kanoni

Subjects
Blood Glucose, Male, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, Genome-wide association study, Single-nucleotide polymorphism, Biology, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Germinal Center Kinases, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Genetics, Humans, Child, 030304 developmental biology, Genetic association, Glucose Transporter Type 2, Homeodomain Proteins, 0303 health sciences, Framingham Risk Score, Insulin, Tumor Suppressor Proteins, Fasting, medicine.disease, 3. Good health, Cryptochromes, DNA-Binding Proteins, Repressor Proteins, Endocrinology, Genetic Loci, Meta-analysis, biology.protein, Glucose-6-Phosphatase, Trans-Activators, Female, Glucose 6-phosphatase, Adenylyl Cyclases, Genome-Wide Association Study, Transcription Factors
Abstract

OBJECTIVE To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents. RESEARCH DESIGN AND METHODS A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9–16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose. RESULTS Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced β-cell function, as indicated by homeostasis model assessment of β-cell function. Analysis using a weighted risk score showed an increase [β (95% CI)] in fasting glucose level of 0.026 mmol/L (0.021–0.031) for each unit increase in the score. CONCLUSIONS Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards.

Published
2011

38. Parental precocious influences on offspring cardiovascular risk markers: an exploratory study in the STANISLAS Cohort

Author

Sébastien Dadé, Gilles Chatellier, Isabelle Colombet, Jean-Brice Marteau, Eliane Albuisson, Gérard Siest, Sophie Visvikis-Siest, and Ndeye Coumba Ndiaye

Subjects
Pharmacology, Pediatrics, medicine.medical_specialty, education.field_of_study, Waist, business.industry, Offspring, Population, Exploratory research, General Medicine, Disease, Blood pressure, Cohort, Molecular Medicine, Medicine, Risk factor, business, education, Demography
Abstract

Familial history of cardiovascular disease is acknowledged as a risk indicator in offspring. The aim of this study was to assess whether the cardiovascular risk factors in parents predicted the risk of their children developing cardiovascular disease in a French population: the STANISLAS Cohort, in which Caucasian biparental families with at least two siblings were followed for 5 years. Silent risk factors (blood pressure, lipid traits, glycemia, BMI and waist circumference) of children were compared according to their parents’ risk status in a subsample of 693 families. All of these traits, with the exception of glucose, were significantly higher in children who had parents at a high risk than in children with parents at a low risk at the first health examination, and these results were confirmed again 5 years later at the second health examination. Thus, silent cardio–metabolic risk factors can be screened in children according to the risk status of their parents for early prevention. The influence of parents’ variants on their offspring underlined the need to initiate familial prevention strategies, with a particular follow-up of young individuals between childhood and adolescence.

Published
2009

39. Functional genomics towards personalized healthcare

Author

Jean-Brice Marteau, Daniel Lambert, Christine Masson, Gérard Siest, Ndeye Coumba Ndiaye, Sophie Visvikis-Siest, and Hamanou Benachour

Subjects
Pharmacology, World Wide Web, business.industry, MEDLINE, Molecular Medicine, Medicine, General Medicine, Personalized medicine, business, Functional genomics
Published
2009

41. Dairy product consumption, calcium intakes, and metabolic syndrome–related factors over 5 years in the STANISLAS study

Author

Ndeye Coumba Ndiaye, Gérard Siest, Sophie Visvikis-Siest, Anastasia Samara, Bernard Herbeth, Stéphanie Billod, Frédéric Fumeron, Génétique cardiovasculaire (GC), Université Henri Poincaré - Nancy 1 (UHP), Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Déterminants génétiques du diabète de type 2 et de ses complications vasculaires ((U 695)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)

Subjects
Adult, Blood Glucose, Male, 5-y Changes, Waist, 030309 nutrition & dietetics, Endocrinology, Diabetes and Metabolism, chemistry.chemical_element, 030209 endocrinology & metabolism, Calcium, Calcium intake, Body Mass Index, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Sex Factors, Medicine, Animals, Humans, Food science, Adiposity, 2. Zero hunger, 0303 health sciences, Nutrition and Dietetics, business.industry, Cholesterol, Cholesterol, HDL, Middle Aged, medicine.disease, Yogurt, Metabolic syndrome, Diet, Calcium, Dietary, Blood pressure, Milk, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cohort, Female, Waist Circumference, business, Body mass index, Cohort study, Dairy products
Abstract

Objective We assessed the associations of total dairy products; milk, yogurt, and cottage cheese; cheese; and calcium with 5-y changes in components of the metabolic syndrome. Methods Two hundred eighty-eight men and 300 women 28 to 60 y of age from the suivi temporaire annuel non invasif de la sante des lorrains assures sociaux (STANISLAS) cohort completed at baseline a 3-d dietary record. Statistics were performed using multivariate regression analysis. Results In men, no relation was found between the four dietary indices and components of the metabolic syndrome measured at baseline. Conversely, the consumption of milk, yogurt, and cottage cheese at entry was inversely associated with 5-y changes in glucose levels ( P ≤ 0.05, P ≤ 0.01 for sex interaction) and positively with 5-y changes in high-density lipoprotein cholesterol ( P ≤ 0.05). Higher calcium intakes were significantly related to a lower 5-y increase of the body mass index (BMI) and waist circumference in men ( P ≤ 0.01, P ≤ 0.05 for sex interaction). In addition, changes in diastolic blood pressure were inversely associated with the consumption of milk, yogurt, and cottage cheese only in men with a normal BMI ( P ≤ 0.05 for BMI interaction). In women, unlike men, associations were shown for some components measured at baseline: total dairy positively related to BMI and waist circumference; total dairy, milk, yogurt, and cottage cheese, and calcium were positively related to triacylglycerols and negatively to high-density lipoprotein cholesterol. However, no significant association was found for any 5-y-changes. Conclusion In men only, a higher consumption of dairy products was associated with positive changes in the metabolic profile in a 5-y period; a higher calcium consumption was associated with a lower 5-y increase of the BMI and waist circumference.

Published
2013

42. Associations of vascular endothelial growth factor (VEGF) with adhesion and inflammation molecules in a healthy population

Author

Abdelsalam Saleh, Marc Rancier, Sophie Visvikis-Siest, Peter Fitzgerald, Mohsen Azimi-Nezhad, Maria G. Stathopoulou, Ndeye Coumba Ndiaye, Amélie Bonnefond, John Victor Lamont, Génétique cardiovasculaire (GC), Université Henri Poincaré - Nancy 1 (UHP), Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), and Randox Laboratories

Subjects
Adult, Male, Vascular Endothelial Growth Factor A, Immunology, Inflammation, Biochemistry, Peripheral blood mononuclear cell, Polymorphism, Single Nucleotide, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, E-selectin, Gene expression, medicine, Immunology and Allergy, Humans, Protein Isoforms, Interleukin 6, Molecular Biology, 030304 developmental biology, 0303 health sciences, Messenger RNA, biology, Cell adhesion molecule, Interleukin-6, Epistasis, Genetic, Hematology, 3. Good health, Vascular endothelial growth factor, chemistry, Gene Expression Regulation, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Health, 030220 oncology & carcinogenesis, biology.protein, Female, medicine.symptom, E-Selectin, Cell Adhesion Molecules
Abstract

International audience; Vascular endothelial growth factor (VEGF) is implicated in numerous pathologies through complex relationships with cellular adhesion molecules (CAMs) and inflammation markers. These have not been assessed in non-pathological conditions. Our aim was the evaluation of associations between VEGF and CAM/inflammation molecules in a healthy population, and of possible genomic interplays in order to better apprehend the underlying mechanisms leading to the pathology. We examined the associations between VEGF and ICAM-1, VCAM-1, E-, L-, P-selectins, TNF-α, CRP and IL-6 plasma levels in 403 healthy individuals. Gene expression of CAM/inflammation molecules and VEGF isoforms (121, 145, 165, and 189) were quantified in peripheral blood mononuclear cells (PBMCs). The effect of four genetic variants (explaining ∼50% of the heritability of circulating VEGF levels) and of their interactions on plasma and mRNA levels of CAM/inflammation molecules was examined. VEGF was associated with ICAM-1 and E-selectin in plasma. In PBMCs, VEGF145 mRNA was associated with ICAM-1, L-selectin and TNF-α expression. Interactions of the genetic variants were shown to affect ICAM-1, E-selectin, IL-6 and TNF-α plasma levels, while rs4416670 was associated with L-selectin expression. These findings propose a biological connection between VEGF and CAM/inflammation markers. Common genetic and transcriptional mechanisms may link these molecules and control their effect in healthy conditions.

Published
2013

43. A common variant highly associated with plasma VEGFA levels also contributes to the variation of both LDL-C and HDL-C

Author

Sophie Visvikis-Siest, Amélie Bonnefond, Abdelsalam Saleh, Maria G. Stathopoulou, Ndeye Coumba Ndiaye, Gérard Siest, Mohsen Azimi-Nezhad, Said El Shamieh, John Victor Lamont, Marc Rancier, Peter Fitzgerald, Génétique cardiovasculaire (GC), Université Henri Poincaré - Nancy 1 (UHP), Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Randox Laboratories, and UL, IGEPCV

Subjects
Adult, Male, Vascular Endothelial Growth Factor A, Apolipoprotein E, medicine.medical_specialty, Linkage disequilibrium, Blood lipids, Single-nucleotide polymorphism, QD415-436, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, Biochemistry, vascular endothelial growth factor A polymorphism, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Polymorphism (computer science), cardiovascular disease, Internal medicine, lipid metabolism, medicine, Humans, 030304 developmental biology, 0303 health sciences, Cholesterol, Cholesterol, HDL, Reproducibility of Results, Epistasis, Genetic, Lipid metabolism, Cholesterol, LDL, Cell Biology, gene×environment interaction, Vascular endothelial growth factor A, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, epistatic interaction, low density lipoprotein-C, Female, Gene-Environment Interaction, lipids (amino acids, peptides, and proteins), Patient-Oriented and Epidemiological Research, high density lipoprotein-C
Abstract

International audience; ascular endothelial growth factor A (VEGFA) is among the most-significant stimulators of angiogenesis. Its effect on cardiovascular diseases and on the variation of related risk factors such as lipid parameters is considered important, although as yet unclear. Recently, we identified four common variants (rs6921438, rs4416670, rs6993770, and rs10738760) that explain up to 50% of the heritability of plasma VEGFA levels. In the present study, we aimed at assessing the contribution of these variants to the variation of blood lipid levels (including apoE, triglycerides, total cholesterol, low- and high-density lipoprotein cholesterol levels (LDL-C and HDL-C)] in healthy subjects. The effect of these single-nucleotide polymorphisms (SNPs) on lipid levels was assessed using linear regression in discovery and replication samples (n = 1,006 and n = 1,145; respectively), followed by a meta-analysis. Their gene×gene and gene×environment interactions were also assessed. SNP rs6921438 was associated with HDL-C (β = −0.08 mmol/l, Poverall = 1.2 × 10−7) and LDL-C (β = 0.13 mmol/l, Poverall = 1.5 × 10−4). We also identified a significant association between the interaction rs4416670×hypertension and apoE variation (Poverall = 1.7 × 10−5). Therefore, our present study shows a common genetic regulation between VEGFA and cholesterol homeostasis molecules. The SNP rs6921438 is in linkage disequilibrium with variants located in an enhancer- and promoter-associated histone mark region and could have a regulatory effect in the expression of surrounding genes, including VEGFA.

Published
2013

44. Common mutations and polymorphisms predicting adverse cardiovascular events: current view

Author

Sophie Visvikis-Siest, Ndeye Coumba Ndiaye, and Maria G. Stathopoulou

Subjects
Pharmacology, medicine.medical_specialty, Polymorphism, Genetic, business.industry, Mechanism (biology), Public health, Genome-wide association study, Disease, Bioinformatics, Polymorphism, Single Nucleotide, Cardiovascular Diseases, Mutation, Genetics, medicine, Molecular Medicine, Humans, Identification (biology), business, Genotyping, Cause of death, Genetic association, Genome-Wide Association Study
Abstract

Cardiovascular diseases (CVDs) are a major public health concern ranked by WHO as the number one cause of death globally. Adverse cardiovascular events will largely contribute to the death of almost 23.6 million people a year by 2030 [101]. CVDs are multifactorial pathologies with a significant genetic component. Tremendous breakthroughs in the identification of the genetic variants involved have been made during the last few decades, notably thanks to the technological development of high-throughput genotyping technologies, especially genome-wide association studies (GWAS) [1], as well as the candidategene studies, which have also offered interesting results. However, for most of the variants revealed, the transition from a statistical association to a causal mechanism has proved far from straightforward. Transcriptional analyses meet difficulties in defining the transcripts likely to mediate the associations, thus blocking the translation of genetic discoveries into an improved understanding of disease biology. Moreover, the clinical usefulness of GWAS-identified CVD loci is almost negligible at this stage.

Published
2012

45. Clinical necessity of partitioning of human plasma haptoglobin reference intervals by recently-discovered rs2000999

Author

Payman Shahabi, Gérard Siest, Sophie Visvikis-Siest, Ndeye Coumba Ndiaye, and Bernard Herbeth

Subjects
Adult, Male, Adolescent, Clinical Biochemistry, Population, Physiology, Biology, Biochemistry, White People, Plasma, Sex Factors, Reference Values, Humans, education, Child, Alleles, education.field_of_study, Polymorphism, Genetic, Haptoglobins, Biochemistry (medical), Haptoglobin, Smoking, Age Factors, General Medicine, Plasma levels, Middle Aged, Reference intervals, Minor allele frequency, Phenotype, Human plasma, Reference values, Immunology, biology.protein, Female, Hemoglobin, France
Abstract

Background Very recently, we identified a novel polymorphism, rs2000999, located in haptoglobin gene (HP) as a strong genetic determinant of the haptoglobin levels (Hp). We aim to determine the reference values of Hp on the basis of its main sources of biological variation including the rs2000999 in a large French origin population, the STANISLAS Family Study (SFS). Methods Through a stepwise regression analysis, the main biological variables of Hp levels were identified in 3129 “apparently” disease-free individuals of the SFS. Hp reference ranges were subsequently established in a subgroup of 2923 selected healthy subjects, as the reference population. Results The plasma reference values of Hp ranged 0.08–1.97 g/L in males and 0.08–2.19 g/L in females. Gender, age, smoking, plasma levels of hemoglobin and the newly-discovered HP polymorphism, rs2000999, were found to be the strongest biological predictors of the Hp concentrations in human plasma. Hp levels, in both genders and in all age groups, were negatively associated with the presence and number of rs2000999 minor allele. Conclusion To be reliably interpretable in daily medical practice, the HP polymorphism, rs2000999, should be considered for partitioning its reference values. This polymorphism may also help for setting decision limits for medical interpretation of Hp concentrations.

Published
2012

46. A Genome-Wide Association Study Identifies rs2000999 as a Strong Genetic Determinant of Circulating Haptoglobin Levels

Author

Paul Elliott, M. R. Järvelin, Amélie Bonnefond, Lars Sjöström, Andrew Walley, Anita Morandi, Mario Falchi, Aimo Ruokonen, Aurélie Dechaume, Philippe Froguel, Said El Shamieh, Lena M. S. Carlsson, Sophie Visvikis-Siest, Maria G. Stathopoulou, Rosa-Maria Guéant-Rodriguez, David Meyre, Leonardo Bottolo, Bernard Herbeth, Michel Langlois, George V. Dedoussis, Yann Labrune, Nabila Bouatia-Naji, Joris R. Delanghe, Cécile Lecoeur, Claudio Maffeis, Ndeye Coumba Ndiaye, Peter Jacobson, Gérard Siest, and Medical Research Council (MRC)

Subjects
Male, PEDIGREE ANALYSIS, Epidemiology, lcsh:Medicine, Genome-wide association study, 030204 cardiovascular system & hematology, PHENOTYPE, Pediatrics, genome-wide, 0302 clinical medicine, Risk Factors, Genotype, lcsh:Science, Child, HEMOGLOBIN, 0303 health sciences, Multidisciplinary, Haptoglobin, Genomics, haptoglobin, 3. Good health, ADIPOSE-TISSUE, Infectious Diseases, Cardiovascular Diseases, Science & Technology - Other Topics, Medicine, Female, Public Health, CHRONIC HEPATITIS-C, Research Article, Adult, children, General Science & Technology, Immunology, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, INFLAMMATION, Genome Analysis Tools, Diagnostic Medicine, Diabetes mellitus, MD Multidisciplinary, medicine, Genetics, SNP, Humans, Genetic variability, Genotyping, 030304 developmental biology, Clinical Genetics, Science & Technology, Population Biology, Haptoglobins, MULTIDISCIPLINARY SCIENCES, lcsh:R, Immunity, Biology and Life Sciences, Computational Biology, Human Genetics, medicine.disease, POLYMORPHISM, PLASMA-GLUCOSE LEVELS, CARDIOVASCULAR-DISEASES, RISK-FACTORS, biology.protein, lcsh:Q, Clinical Immunology, Genome-Wide Association Study
Abstract

Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far.We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (P(overall) = 8.1 × 10(-59)), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23 ± 0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P(total cholesterol) = 0.002 and P(LDL) = 0.0008).Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.

Published
2012

47. Klotho KL-VS genotype is involved in blood pressure regulation

Author

Carlos Labat, Sophie Visvikis-Siest, Bernard Herbeth, Rosine Nzietchueng, Christine Masson, Ndeye Coumba Ndiaye, Said El Shamieh, Hamanou Benachour, and Athanase Benetos

Subjects
Male, medicine.medical_specialty, Genotype, Clinical Biochemistry, Genome-wide association study, Blood Pressure, Biochemistry, Polymerase Chain Reaction, Cohort Studies, Internal medicine, medicine, Humans, Allele, Klotho, Klotho Proteins, Aged, DNA Primers, Glucuronidase, Base Sequence, business.industry, Biochemistry (medical), General Medicine, Middle Aged, medicine.disease, Pulse pressure, Endocrinology, Blood pressure, Chromosomal region, Arterial stiffness, Female, business, Genome-Wide Association Study
Abstract

Genome-wide linkage analysis studies reported the importance of the long arm of chromosome 13 in systolic blood pressure regulation. Therefore, isolating a genetic variant related to this chromosomal region could be challenging. Klotho KL-VS allele is located on this chromosomal region and its relationships with cardio-vascular risk factors need extensive investigations. The aim of the present study is to examine whether the klotho KL-VS genotype is associated with cardio-vascular risk factors, more particularly hypertension, in two independent cohorts. A secondary objective was to investigate relationships with antihypertensive treatment, arterial stiffness and carotid artery parameters.A total of 1023 French individuals were genotyped for klotho KL-VS. Participants were part of the French ERA and STANISLAS cohorts. In both cohorts, klotho KL-VS/KL-VS genotype was significantly associated with lower systolic blood pressure and pulse pressure when compared to homozygous and heterozygous more frequent (WT) allele carriers (p=0.003 and p0.001 respectively). Antihypertensive treatment stratification confirmed the previous significant associations, while a significant interaction between klotho KL-VS genotype and antihypertensive treatment was also interestingly found (0.019 for p interaction).Klotho KL-VS/KL-VS genotype may be associated with decreased cardio-vascular risk and may interact with antihypertensive treatment in order to reduce blood pressure. This finding could lead to identify subgroups of hypertensive adults who might benefit antihypertensive drug therapies.

Published
2011

48. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

Author

Stephen W. Scherer, Mònica Gratacòs, Kari Stefansson, Muriel Holder, Unnur Thorsteinsdottir, Lukas Forer, Katharina M. Roetzer, Josette Lucas, Claudia Schurmann, Satu Kaksonen, Armand Valsesia, Carina Wallgren-Pettersson, Barbara Leube, Alexandra I. F. Blakemore, Alexandre Moerman, Marco Belfiore, Anne Faudet, Dominique Gaillard, Roberto Ravazzolo, Dominique Bonneau, Marjo-Riitta Järvelin, Yongguo Yu, Louis Vallée, Bénédicte Demeer, Sophie Visvikis-Siest, Frédérique Béna, Brigitte H. W. Faas, Benoit Arveiler, Georg Homuth, Charles Coutton, Bénédicte de Fréminville, Giorgio Gimelli, Xavier Estivill, Richard I. Fisher, Stefania Gimelli, Wendy Roberts, Jacques S. Beckmann, Emilie Landais, Orah S. Platt, Robin G. Walters, Gudmar Thorleifsson, Alexandre Reymond, Anna-Liisa Hartikainen, Solenn Legallic, James F. Gusella, Peter Vollenweider, Gian Paolo Ramelli, Tõnu Esko, Boris Keren, Nine V A M Knoers, Fanny Morice-Picard, Dominique Campion, Odile Boute, Evica Rajcan-Separovic, Rolph Pfundt, Nathalie Bednarek, Martine Doco-Fenzy, Suzanne M E Lewis, Gérard Didelot, Mylène Beri, Engilbert Sigurdsson, Véronique Satre, Audrey Labalme, Carola Tengstrom, Florian Kronenberg, Florence Petit, Simon Zwolinksi, Philippe Froguel, Paul Elliott, Dorothée Cailley, Christian R. Marshall, Bruno Leheup, Klaus Dieterich, Janina S. Ried, Sylvie Jaillard, Armand Bottani, Stylianos E. Antonarakis, Elisabetta Lapi, Jean-Christophe Cuvellier, Robert M. Witwicki, Gérard Waeber, Christèle Dubourg, Marion Gérard, Lachlan J. M. Coin, Magalie Barth, Anita Kloss-Brandstätter, Vincent Mooser, Cristóbal Richart, Giuseppe Merla, Bénédicte Duban-Bedu, Yiping Shen, Ants Kurg, Audrey Guilmatre, Juliane Hoyer, Susana Jiménez-Murcia, Mafalda Mucciolo, Bai-Lin Wu, Alessandra Ferrarini, Séverine Drunat, Yves Alembik, Páll Magnússon, Han G. Brunner, Maria Antonietta Mencarelli, Dominique Descamps, R. Frank Kooy, Azzedine Aboura, Valérie Layet, Sven Bergmann, Thomas Meitinger, Peter M. Kroisel, Nathalie Van der Aa, Olivier Guillin, Michèle Mathieu-Dramard, Zoltán Kutalik, Elisabeth Flori, Laurent Pasquier, André Reis, Noam D. Beckmann, Bertrand Isidor, Delphine Héron, Philippe Jonveaux, Sergi Villatoro Gomez, Ann Nordgren, José Manuel Fernández-Real, Florence Fellmann, Fernando Fernández-Aranda, Laurence Faivre, Dimitri J. Stavropoulos, Katrin Männik, Christian Gieger, Evald Saemundsen, Agnès Guichet, Jean-Marie Cuisset, R. Touraine, Laura Bernardini, Marie-Ange Delrue, Alessandra Renieri, Omar Gustafsson, Flore Zufferey, David A. Koolen, Massimiliano Rossi, Jacqueline Chrast, Ghislaine Plessis, Faida Walha, Joris Andrieux, Ellen van Binsbergen, Albert David, Catherine Vincent-Delorme, Cédric Le Caignec, Jean Chiesa, Ndeye Coumba Ndiaye, Geraldine Joly Helas, Damien Sanlaville, Anita Rauch, Louise Harewood, Mark I. McCarthy, Bridget A. Fernandez, Sébastien Jacquemont, Hreinn Stefansson, Anneke T. Vulto-van Silfhout, Zdenek Jaros, Matthias Nauck, Hans J. Grabe, Sonia Bouquillon, Mieke M. van Haelst, Andres Metspalu, Loyse Hippolyte, Patrick Callier, Bert B.A. de Vries, Francisco J. Tinahones, Nicole de Leeuw, Julia S. El-Sayed Moustafa, Claudine Rieubland, Kay D. MacDermot, Vittoria Disciglio, Henry Völzke, Caroline Rooryck, Bettina Blaumeiser, Danielle Martinet, Marie-Claude Addor, Bruno Delobel, Jacquemont, S, Reymond, A, Zufferey, F, Harewood, L, Walters, Rg, Kutalik, Z, Martinet, D, Shen, Y, Valsesia, A, Beckmann, Nd, Thorleifsson, G, Belfiore, M, Bouquillon, S, Campion, D, de Leeuw, N, de Vries, Bb, Esko, T, Fernandez, Ba, Fernández-Aranda, F, Fernández-Real, Jm, Gratacòs, M, Guilmatre, A, Hoyer, J, Jarvelin, Mr, Kooy, Rf, Kurg, A, Le Caignec, C, Männik, K, Platt, O, Sanlaville, D, Van Haelst, Mm, Villatoro Gomez, S, Walha, F, Wu, Bl, Yu, Y, Aboura, A, Addor, Mc, Alembik, Y, Antonarakis, Se, Arveiler, B, Barth, M, Bednarek, N, Béna, F, Bergmann, S, Beri, M, Bernardini, L, Blaumeiser, B, Bonneau, D, Bottani, A, Boute, O, Brunner, Hg, Cailley, D, Callier, P, Chiesa, J, Chrast, J, Coin, L, Coutton, C, Cuisset, Jm, Cuvellier, Jc, David, A, de Freminville, B, Delobel, B, Delrue, Ma, Demeer, B, Descamps, D, Didelot, G, Dieterich, K, Disciglio, V, Doco-Fenzy, M, Drunat, S, Duban-Bedu, B, Dubourg, C, El-Sayed Moustafa, J, Elliott, P, Faas, Bh, Faivre, L, Faudet, A, Fellmann, F, Ferrarini, A, Fisher, R, Flori, E, Forer, L, Gaillard, D, Gerard, M, Gieger, C, Gimelli, S, Gimelli, G, Grabe, Hj, Guichet, A, Guillin, O, Hartikainen, Al, Heron, D, Hippolyte, L, Holder, M, Homuth, G, Isidor, B, Jaillard, S, Jaros, Z, Jiménez-Murcia, S, Helas, Gj, Jonveaux, P, Kaksonen, S, Keren, B, Kloss-Brandstätter, A, Knoers, Nv, Koolen, Da, Kroisel, Pm, Kronenberg, F, Labalme, A, Landais, E, Lapi, E, Layet, V, Legallic, S, Leheup, B, Leube, B, Lewis, S, Lucas, J, Macdermot, Kd, Magnusson, P, Marshall, C, Mathieu-Dramard, M, Mccarthy, Mi, Meitinger, T, Mencarelli, Ma, Merla, G, Moerman, A, Mooser, V, Morice-Picard, F, Mucciolo, M, Nauck, M, Ndiaye, Nc, Nordgren, A, Pasquier, L, Petit, F, Pfundt, R, Plessis, G, Rajcan-Separovic, E, Ramelli, Gp, Rauch, A, Ravazzolo, R, Reis, A, Renieri, A, Richart, C, Ried, J, Rieubland, C, Roberts, W, Roetzer, Km, Rooryck, C, Rossi, M, Saemundsen, E, Satre, V, Schurmann, C, Sigurdsson, E, Stavropoulos, Dj, Stefansson, H, Tengström, C, Thorsteinsdóttir, U, Tinahones, Fj, Touraine, R, Vallée, L, van Binsbergen, E, Van der Aa, N, Vincent-Delorme, C, Visvikis-Siest, S, Vollenweider, P, Völzke, H, Vulto-van Silfhout, At, Waeber, G, Wallgren-Pettersson, C, Witwicki, Rm, Zwolinksi, S, Andrieux, J, Estivill, X, Gusella, Jf, Gustafsson, O, Metspalu, A, Scherer, Sw, Stefansson, K, Blakemore, Ai, Beckmann, J, Froguel, P, Faculteit Medische Wetenschappen/UMCG, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Department of Genomics of Common Disease, Imperial College London, Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Laboratory Medicine, Boston Children's Hospital, Center for Human Genetic Research, Massachusetts General Hospital [Boston], Ludwig Institute for Cancer Research, deCODE Genetics, deCODE genetics [Reykjavik], Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Estonian Genome and Medicine, University of Tartu, Department of human genetics, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Institute for Genetic and Metabolic Disorders, Institute of Molecular and Cell Biology, Disciplines of Genetics and Medicine, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona-Biomedical Research Institute 'Dr Josep Trueta'-CIBERobn Fisiopatología de la Obesidad y Nutrición, Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Department of child and adolescent health, University of Oulu-Institute of Health Sciences and Biocenter Oulu-National Institute for Health and Welfare [Helsinki], Antwerp University Hospital [Edegem] (UZA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, University Medical Center [Utrecht], Institutes of Biomedical Science, Fudan University [Shanghai]-Children's Hospital, Shanghai Children's Medical Center, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Génétique médicale, Hôpitaux Universitaires de Genève (HUG), Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université de Reims Champagne-Ardenne (URCA), Department of Molecular Genetics, Weizmann Institute of Science [Rehovot, Israël], Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Service de Génétique clinique, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Cytogénétique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Service de Neuropédiatrie, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), CHU Amiens-Picardie, Centre Hospitalier de Béthune (CH Béthune), GHT de l'Artois, Service de Génétique Clinique, Department of Biotechnology, Università degli Studi di Siena = University of Siena (UNISI)-Medical Genetics, Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Epidemiology and Public Health, Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC), CHU Pitié-Salpêtrière [AP-HP], Institute of human genetics, International Centre for Life, Division of genetic epidemiology, HMNC Brain Health-Molecular and Clinical Pharmacology-Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Department of Obstetrics and Gynecology, University of Oulu-Institute of Clinical Medicine, Laboratorio di citogenetica, G. Gaslini Institute, Department of Psychiatry and Psychotherapy, Universität Greifswald - University of Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Abteilung für Kinder und Jugendheilkunde, Landesklinikum Waldviertel Zwettl, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), The Habilitation Unit of Folkhalsan, Medical University Graz, Medical Genetics Unit, Children's Hospital Anna Meyer, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Institute of Human Genetics and Anthropology, Heinrich-Heine University Hospital Duesseldorf, Child and Family Research Institute-University of British Columbia (UBC), North West Thames Regional Genetics Service, Northwick Park & St Marks Hospital, Child and Adolescent Psychiatry, Landspitali University Hospital, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Genetics, GlaxoSmithKline R&D, GlaxoSmithKline, Institute of Clinical Chemistry and Laboratory Medicine, Génétique cardiovasculaire (GC), Université Henri Poincaré - Nancy 1 (UHP), Molecular Medicine and Surgery department, Karolinska Institutet [Stockholm], Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Pathology, Division of pediatrics, Ospedale San Giovanni, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Department of pediatrics and CEBR, Università degli studi di Genova = University of Genoa (UniGe)-G. Gaslini Institute, Department of Internal Medicine, Universitat Rovira i Virgili-University Hospital Juan XXIII-Instituto Salud Carlos III-Ciber Fisiopatologia Obesidad y Nutricion (CIBEROBN), Division of Human Genetics, Department of Paediatrics, Inselspital-University of Bern, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, State Diagnostic, Counseling Center, University of Iceland [Reykjavik], Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Genetic Services, Rinnekoti Research Foundation, Department of Endocrinology and Nutrition, Instituto Salud Carlos III-Clinic Hospital of Virgen de la Victoria-Ciber Fisiopatologia y Nutricion (CIBEROBN), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Institute for Community Medicine, Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Leenaards Foundation Prize (SJ, DM and AR), the Jérôme Lejeune Foundation (AR), the Telethon Action Suisse Foundation (AR), the Swiss National Science Foundation (AR, JSB, SB and SEA), a SNSF Sinergia grant (SJ, DM, SB, JSB and AR), the European Commission anEUploidy Integrated Project grant 037627 (AR, SB, XE, HGB and SEA), the Ludwig Institute for Cancer Research (AV), the Swiss Institute of Bioinformatics (SB, ZK), an Imperial College Dept of Medicine PhD studentship (JSe-SM), the Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust, and the National Institute for Health Research (PE), the Wellcome Trust and the Medical Research Council (AIFB and PF), the Instituto de Salud Carlos III (ISCIII)-FIS, the German Mental Retardation Network funded through a grant of the German Federal Ministry of Education and Research (NGFNplus 01GS08160) to A Reis and European Union-FEDER (PI081714, PS09/01778), SAF2008-02278 (XE, MG, FFA), the Belgian National Fund for Scientific Research - Flanders (NVA, RFK), the Dutch Organisation for Health Research and Development (ZONMW grant 917-86-319) and Hersenstichting Nederland (BBAdV), grant 81000346 from the Chinese National Natural Science Foundation (YGY), the Simons Foundation Autism Research Initiative, Autism Speaks and NIH grant GM061354 (JFG), and the OENB grant 13059 (AK-B). YS holds a Young Investigator Award from the Children's Tumor Foundation and Catalyst Award from Harvard Medical School, and BLW, a Fudan Scholar Research Award from Fudan University, a grant from Chinese National '973' project on Population and Health (2010CB529601) and a grant from Science and Technology Council of Shanghai (09JC1402400). ERS and SL, recipients of the Michael Smith Foundation for Health Research Scholar award, acknowledge the CIHR MOP 74502 operational grant. EGCUT received support from the EU Centre of Excellence in Genomics and FP7 grants #201413 and #245536, from Estonian Government SF0180142s08, SF0180026s09 and SF0180027s10 (AM, KM, AK). The Helmholtz Zentrum Munich and the State of Bavaria financed KORA, also supported by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823), the German Federal Ministry of Education and Research (BMBF), and the Munich Center of Health Sciences (MC Health, LMUinnovativ). CIBEROBN and CIBERESP are initiatives of ISCIII (Spain). SWS holds the GlaxoSmithKline-Canadian Institutes of Health (CIHR) Chair in Genetics, Genomics at the University of Toronto and the Hospital for Sick Children and is supported by Genome Canada and the McLaughlin Centre. deCODE was funded in part by NIH grant MH071425 (KS), EU grant HEALTH-2007-2.2.1-10-223423 (Project PsychCNV) and EU grant IMI-JU-NewMeds., Centre de génomique intégrative, Université de Lausanne (UNIL), Swiss Institute of Bioinformatics (SIB), Swiss Institute of Bioinformatics, Memorial University of Newfoundland [St. John's], Friedrich Alexander University [Erlangen-Nürnberg], Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Weizmann Institute of Science, IRCCS Casa Sollievo della Sofferenza Hospital, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Etienne-Hôpital nord, Hôpital Saint Vincent de Paul-GHICL, Centre hospitalier de Béthune, Università degli Studi di Siena (UNISI)-Medical Genetics, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Innsbruck Medical University [Austria] (IMU)-HMNC Brain Health-Molecular and Clinical Pharmacology, Czech Academy of Sciences [Prague] (ASCR), University of Oxford [Oxford], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, University of Zürich [Zürich] (UZH), Universita degli studi di Genova -G. Gaslini Institute, University of Toronto-The Hospital for Sick Children, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), De Villemeur, Hervé, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland., Other departments, Reymond, Alexandre, Antonarakis, Stylianos, Sloan Bena, Frédérique, Bottani, Armand, Callier, Patrick, Gimelli, Stefania, Merla, Giuseppe, Vollenweider, Peter, Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Université de Lille-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Aging, Transcription, Genetic, Adolescent, Adult, Aged, Body Height, Body Mass Index, Case-Control Studies, Child, Child, Preschool, Chromosomes, Human, Pair 16, Cohort Studies, Comparative Genomic Hybridization, Developmental Disabilities, Energy Metabolism, Europe, Female, Gene Dosage, Gene Duplication, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Head, Heterozygote, Humans, Infant, Infant, Newborn, Mental Disorders, Middle Aged, Mutation, North America, Obesity, Phenotype, RNA, Messenger, Sequence Deletion, Thinness, Young Adult, Physiology, RNA, Messenger/analysis/genetics, Genome-wide association study, HIDDEN-MARKOV MODEL, 0302 clinical medicine, Sequence Deletion/genetics, ddc:576.5, 0303 health sciences, education.field_of_study, Body Height/genetics, Genetic Predisposition to Disease/genetics, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, population characteristics, Chromosomes, Human, Pair 16/genetics, Human, Locus (genetics), Gene Duplication/genetics, Article, 03 medical and health sciences, Genetic, education, SNP GENOTYPING DATA, Thinness/genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Pair 16, Case-control study, nutritional and metabolic diseases, social sciences, medicine.disease, DEPENDENT PROBE AMPLIFICATION, Human medicine, Body mass index, 030217 neurology & neurosurgery, Messenger, Obesity/genetics, FAILURE-TO-THRIVE, [SDV.GEN] Life Sciences [q-bio]/Genetics, Head/anatomy & histology, METABOLIC SYNDROME, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, Genetics, Multidisciplinary, TIME QUANTITATIVE PCR, Failure to thrive, medicine.symptom, Underweight, Transcription, geographic locations, Mutation/genetics, Population, Biology, Chromosomes, 150 000 MR Techniques in Brain Function, medicine, Preschool, 030304 developmental biology, COPY NUMBER VARIATION, Mental Disorders/genetics, Energy Metabolism/genetics, RELATIVE QUANTIFICATION, Gene Dosage/genetics, Newborn, BODY-MASS INDEX, CIRCULAR BINARY SEGMENTATION, RNA, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], human activities, Developmental Disabilities/genetics
Abstract

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance. Leenaards Foundation Jerome Lejeune Foundation Telethon Action Suisse Foundation Swiss National Science Foundation European Commission 037627 QLG1-CT-2000-01643 Ludwig Institute for Cancer Research Swiss Institute of Bioinformatics Imperial College Department of Medicine Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust National Institute for Health Research Wellcome Trust Medical Research Council Instituto de Salud Carlos III (ISCIII)-FIS German Mental Retardation Network German Federal Ministry of Education and Research NGFNplus 01GS08160 European Union PI081714 PS09/01778 201413 245536 info:eu-repo/grantAgreement/EC/FP7/223423 Belgian National Fund for Scientific Research, Flanders Dutch Organisation for Health Research and Development (ZON-MW) 917-86-319 Hersenstichting Nederland (B.B.A.d.V.) Chinese National Natural Science Foundation 81000346 Simons Foundation Autism Research Initiative Autism Speaks NIH GM061354 MH071425 Oesterreichische Nationalbank (OENB) 13059 Children's Tumor Foundation Harvard Medical School Fudan University Chinese National '973' project on Population and Health 2010CB529601 Science and Technology Council of Shanghai 09JC1402400 Michael Smith Foundation for Health CIHR MOP 74502 Estonian Government SF0180142s08 SF0180026s09 SF0180027s10 Helmholtz Zentrum Munich State of Bavaria German National Genome Research Network 01GS0823 German Federal Ministry of Education and Research (BMBF) Munich Center of Health Sciences (MC Health, LMUinnovativ) Genome Canada McLaughlin Centre Academy of Finland 104781 120315 129269 1114194 University Hospital Oulu Biocenter University of Oulu, Finland 75617 NHLBI 5R01HL087679-02 1RL1MH083268-01 NIH/NIMH 5R01MH63706:02 ENGAGE project Medical Research Council, UK G0500539 G0600705 Academy of Finland Biocentrum Helsinki SAF2008-02278 HEALTH-F4-2007-201413

Published
2011

49. Genetic profiling in healthy subjects from the Stanislas cohort based on 24 polymorphisms: effects on biological variables

Author

Nicolas Jay, Ndeye-Coumba Ndiaye, Sandy Maumus, François Kohler, Gérard Siest, Bérangère Marie, Sophie Visvikis-Siest, and Eliane Albuisson

Subjects
Adult, Genetic Markers, Male, Multivariate analysis, Clinical Biochemistry, Physiology, Cohort Studies, Polymorphism (computer science), Reference Values, Risk Factors, Genotype, Medicine, Humans, Genetic variability, Triglycerides, Genetics, Lipoprotein lipase, Apolipoprotein C-III, Polymorphism, Genetic, business.industry, Biochemistry (medical), General Medicine, Middle Aged, Lipoprotein Lipase, Cholesterol, Cardiovascular Diseases, Cohort, Multivariate Analysis, Selectins, Apolipoprotein C3, Female, business, Lipoproteins, HDL, Cohort study, Follow-Up Studies
Abstract

Background: The association of genetic profiles with biological or clinical assessments is not clearly established especially among apparently healthy subjects. Methods: A multivariate statistical analysis was performed on 24 polymorphisms related to the main metabolic pathways involved in cardiovascular diseases (CVDs). They were collected among 1551 healthy subjects of the Stanislas cohort to obtain genetic profiles. Association with biological variables was then studied at baseline (to) and 5 years later (t 5 ). Results: Six genetic clusters were identified with relevant profiles and five polymorphisms from the selectin, apolipoprotein C3 and lipoprotein lipase genes (SELE-98G/T, APOC3-3175C/G, APOC3-482C/T, APOC3-1100C/T, LPL-93T/G) were sufficiently characteristic to associate 99.6% of the subjects with their corresponding cluster. A 5-year follow-up showed that clinical and biological measurements in relation to CVD risk factors already differ with triglyceride (p=0.009 for to and p=0.005 for t 5 ) and high-density lipoprotein cholesterol (p=0.014 for to and p=0.003 for t 5 ) for these previous genetic clusters. Conclusions: This study presents the hypothesis that SELE could be protective, whereas APOC3 could be associated with risk. It remains to be seen whether these polymorphisms will be predictive of CVD events among the selected clusters of different metabolic subtypes after a 10-year follow-up.

Published
2007

50. What Is the Contribution of Two Genetic Variants Regulating VEGF Levels to Type 2 Diabetes Risk and to Microvascular Complications?

Author

Torsten Lauritzen, Julia S. El-Sayed Moustafa, Mohsen Azimi Nezhad, Oluf Pedersen, Aurélie Dechaume, Beverley Balkau, Torben Hansen, Philippe Froguel, Sophie Visvikis-Siest, Serge Hercberg, Guillaume Charpentier, Michel Marre, Olivier Lantieri, Ronan Roussel, Samy Hadjadj, Niels Grarup, Ndeye Coumba Ndiaye, Maria G. Stathopoulou, Pierre-Jean Saulnier, Amélie Bonnefond, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d' investigation clinique-plurithématique du CHU de Poitiers, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Steno Diabetes Center and Hagedorn Research Institute, Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Service d'endocrinologie, diabétologie et nutrition [CHU Bichat], Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Déterminants génétiques du diabète de type 2 et de ses complications vasculaires ((U 695)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut inter-Régional pour la SAnté (IRSA), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Research Unit for General Practice, Aarhus, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Department of Genomics of Common Disease, Imperial College London, Service d'Endocrinologie et de Diabétologie [Corbeil-Essonne], Hôpital de Corbeil-ESsonnes, Service Endocrinologie [CHU Poitiers], Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), BioIntelligence project, French minister of health (PHRC-Poitiers), French minister of health (PHRC-IR), AFD (Research Grant), GEMMS (Groupe d'Etude des Maladies Metaboliques et Systemiques [Poitiers, France]), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, INSERM CIC 0802 (INSERM - CHU de Poitiers), Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), UL, IGEPCV, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)

Subjects
Male, Vascular Endothelial Growth Factor A, Oncology, Heredity, Epidemiology, lcsh:Medicine, Type 2 diabetes, 030204 cardiovascular system & hematology, Polymerase Chain Reaction, Diabetic nephropathy, chemistry.chemical_compound, Endocrinology, 0302 clinical medicine, Risk Factors, Diabetic Nephropathies, Longitudinal Studies, lcsh:Science, 0303 health sciences, education.field_of_study, Multidisciplinary, Diabetic retinopathy, Middle Aged, 3. Good health, Vascular endothelial growth factor, Medicine, Female, Research Article, Retinopathy, medicine.medical_specialty, Genotype, Clinical Research Design, Population, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Polymorphism, Single Nucleotide, Diabetes Complications, 03 medical and health sciences, Diabetes mellitus, Internal medicine, Genetics, Genome-Wide Association Studies, medicine, Humans, Genetic Predisposition to Disease, education, Biology, Genetic Association Studies, 030304 developmental biology, Hemoglobin A, Glycosylated, Glycated Hemoglobin, Diabetic Endocrinology, Evolutionary Biology, Diabetic Retinopathy, Quantitative Traits, Population Biology, Complex Traits, business.industry, lcsh:R, Computational Biology, Human Genetics, Diabetes Mellitus Type 2, medicine.disease, Diabetes Mellitus, Type 2, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, chemistry, Case-Control Studies, Genetics of Disease, Genetic Polymorphism, lcsh:Q, Glycated hemoglobin, business, Population Genetics, Genome-Wide Association Study
Abstract

International audience; Vascular endothelial growth factor (VEGF) is a key chemokine involved in tissue growth and organ repair processes, particularly angiogenesis. Elevated circulating VEGF levels are believed to play a role in type 2 diabetes (T2D) microvascular complications, especially diabetic retinopathy. Recently, a genome-wide association study identified two common single nucleotide polymorphisms (SNPs; rs6921438 and rs10738760) explaining nearly half of the variance in circulating VEGF levels. Considering the putative contribution of VEGF to T2D and its complications, we aimed to assess the effect of these VEGF-related SNPs on the risk of T2D, nephropathy and retinopathy, as well as on variation in related traits. SNPs were genotyped in several case-control studies: French and Danish T2D studies (N cases = 6,920-N controls = 3,875 and N cases = 3,561-N controls = 2,623; respectively), two French studies one for diabetic nephropathy (N cases = 1,242-N controls = 860) and the other for diabetic retinopathy (N cases = 1,336-N controls = 1,231). The effects of each SNP on quantitative traits were analyzed in a French general population-based cohort (N = 4,760) and two French T2D studies (N = 3,480). SNP associations were assessed using logistic or linear regressions. In the French population, we found an association between the G-allele of rs6921438, shown to increase circulating VEGF levels, and increased T2D risk (OR = 1.15; P = 3.7610 25). Furthermore, the same allele was associated with higher glycated hemoglobin levels (b = 0.02%; P = 9.2610 23). However, these findings were not confirmed in the Danes. Conversely, the SNP rs10738760 was not associated with T2D in the French or Danish populations. Despite having adequate statistical power, we did not find any significant effects of rs6921438 or rs10738760 on diabetic microvascular complications or the variation in related traits in T2D patients. In spite of their impact on the variance in circulating VEGF, we did not find any association between SNPs rs6921438 and rs10738760, and the risk of T2D, diabetic nephropathy or retinopathy. The link between VEGF and T2D and its complications might be indirect and more complex than expected.

Published
2013

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