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See detailChallenges and opportunities in genome-wide environmental interaction (GWEI) studies.
Aschard, Hugues; Lutz, Sharon; Maus, Bärbel ULg et al

in Human Genetics (2012), 131

The interest in performing gene-environment interaction studies has seen a significant increase with the increase of advanced molecular genetics techniques. Practically, it became possible to investigate ... [more ▼]

The interest in performing gene-environment interaction studies has seen a significant increase with the increase of advanced molecular genetics techniques. Practically, it became possible to investigate the role of environmental factors in disease risk and hence to investigate their role as genetic effect modifiers. The understanding that genetics is important in the uptake and metabolism of toxic substances is an example of how genetic profiles can modify important environmental risk factors to disease. Several rationales exist to set up gene-environment interaction studies and the technical challenges related to these studies-when the number of environmental or genetic risk factors is relatively small-has been described before. In the post-genomic era, it is now possible to study thousands of genes and their interaction with the environment. This brings along a whole range of new challenges and opportunities. Despite a continuing effort in developing efficient methods and optimal bioinformatics infrastructures to deal with the available wealth of data, the challenge remains how to best present and analyze genome-wide environmental interaction (GWEI) studies involving multiple genetic and environmental factors. Since GWEIs are performed at the intersection of statistical genetics, bioinformatics and epidemiology, usually similar problems need to be dealt with as for genome-wide association gene-gene interaction studies. However, additional complexities need to be considered which are typical for large-scale epidemiological studies, but are also related to "joining" two heterogeneous types of data in explaining complex disease trait variation or for prediction purposes. [less ▲]

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See detailHeterogeneous nuclear ribonucleoproteins as targets of autoantibodies in systemic rheumatic diseases.
Op De Beeck, Katrijn; Maes, Liesbeth; Van den Bergh, Karolien et al

in Arthritis and Rheumatism (2012), 64(1), 213-221

BACKGROUND: Heterogeneous nuclear ribonucleoproteins (hnRNP) are abundant nucleoplasmic pre-mRNA-binding proteins. The aim of this study was to unravel the mosaic of autoantibodies to hnRNP's in systemic ... [more ▼]

BACKGROUND: Heterogeneous nuclear ribonucleoproteins (hnRNP) are abundant nucleoplasmic pre-mRNA-binding proteins. The aim of this study was to unravel the mosaic of autoantibodies to hnRNP's in systemic rheumatic diseases. METHODS: Recombinant human hnRNP A1, B1, C1, E1, F, Gi, H1, I, K, and P2 were prepared. Antibodies to these antigens were determined by Western blotting and ELISA (for hnRNP B1, E1, F, and H1) in controls (chronic fatigue syndrome) and in patients with various connective tissue disorders. RESULTS: Western blotting analysis on 106 controls and 298 patients with a connective tissue disorder revealed that antibodies to all tested hnRNP antigens, except hnRNP Gi, were significantly more prevalent in Sjogren's syndrome (SS) than in controls. The highest reactivity was found for hnRNP B1, E1, F, and H1 (reactivity in >45% of patients with SS and in 2.8% of controls). Reactivity to hnRNP B1, E1, F, and H1 was also evaluated by ELISA in controls and in 228 patients with a connective tissue disease. Reactivity to at least 2 of the 4 tested antigens was found in 1.1% of controls, 16% of patients with systemic lupus erythematosus (SLE), and 18% of patients with SS. Reactivity to at least 3 of the 4 antigens was found in none of the controls, in 3.2% of patients with SLE, and in 15% of patients with SS. CONCLUSIONS: several hnRNP's are target antigens in SS. The combined presence of antibodies to several hnRNP's was strongly associated with connective tissue disease in general and SS in particular. [less ▲]

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See detailA family-based association test to detect gene-gene interactions in the presence of linkage
De Lobel, Lizzy; Thijs, L; Kouznetsova, T et al

in European Journal of Human Genetics (2012)

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See detailAn Efficient Algorithm to Perform Multiple Testing in Epistasis Screening
Van Lishout, François ULg; Cattaert, Tom ULg; Mahachie John, Jestinah ULg et al

Conference (2011, December 13)

Background: Research in epistasis or gene-gene interaction detection for human complex traits has grown exponentially over the last few years. It has been marked by promising methodological developments ... [more ▼]

Background: Research in epistasis or gene-gene interaction detection for human complex traits has grown exponentially over the last few years. It has been marked by promising methodological developments, improved translation efforts of statistical epistasis to biological epistasis and attempts to integrate different omics information sources into the epistasis screening to enhance power. The quest for gene-gene interactions poses severe multiple-testing problems. In this context, the maxT algorithm is one technique to control the false-positive rate. However, the memory needed by this algorithm rises linearly with the amount of hypothesis tests. In main-effects detection, this is not a problem since the memory required is thus proportional to the number of SNPs. In contrast, gene-gene interaction studies will require a memory proportional to the squared amount of SNPs. A genome wide epistasis would therefore require terabytes of memory. Hence, cache problems are likely to occur, increasing the computation time. Methods: In this work we present a new version of maxT, requiring an amount of memory independent from the number of genetic effects to be investigated. This algorithm was implemented in C++ in our epistasis screening software MB-MDR-2.6.2 and compared to MB-MDR's first implementation as an R-package (Calle et al., Bioinformatics 2010). We evaluate the new implementation in terms of memory efficiency and speed using simulated data. The software is illustrated on real-life data for Crohn's disease. Results: The sequential version of MBMDR-2.6.2 is approximately 5,500 times faster than its R counterparts. The parallel version (tested on a cluster composed of 14 blades, containing each 4 quad-cores Intel Xeon CPU E5520@2.27 GHz) is approximately 900,000 times faster than the latter, for results of the same quality on the simulated data. It analyses all gene-gene interactions of a dataset of 100,000 SNPs typed on 1000 individuals within 4 days. Our program found 14 SNP-SNP interactions with a p-value less than 0.05 on the real-life Crohn’s disease data. Conclusions: Our software is able to solve large-scale SNP-SNP interactions problems within a few days, without using much memory. A new implementation to reach genome wide epistasis screening is under construction. In the context of Crohn's disease, MBMDR-2.6.2 found signal in regions well known in the field and our results could be explained from a biological point of view. This demonstrates the power of our software to find relevant phenotype-genotype associations. [less ▲]

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See detailComparison of genetic association strategies in the presence of rare alleles
Mahachie John, Jestinah ULg; Cattaert, Tom ULg; De Lobel, Lizzy et al

in BMC Proceedings (2011)

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See detailRate of Malignancies and Infections in a Large Single Center Cohort of IBD Patients Treated With Thiopurines and Anti-TNF-Antibodies.
Ochsenkühn, T; Steinborn, A; Beigel, F et al

in Gut (2011, October)

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See detailComparison Of Different Methods For Detecting Gene-Gene Interactions In Case-Control Data
Cattaert, Tom ULg; Rial Garcia, J. A.; Gusareva, Elena ULg et al

Poster (2011, September 19)

It is generally believed that epistasis makes an important contribution to the genetic architecture of complex disease, and numerous statistical and bioinformatics methods have been developed to detect it ... [more ▼]

It is generally believed that epistasis makes an important contribution to the genetic architecture of complex disease, and numerous statistical and bioinformatics methods have been developed to detect it. We compare several state-of-the-art epistasis detection methods in terms of empirical power, type-I error control, and CPU time. The methods compared include Model-Based Multifactor Dimensionality Reduction (MB-MDR) [1, 2], BOolean Operation-based Screening and Testing (BOOST) [3], EPIBLASTER [4], Random Jungle (RJ) [5], Logistic Regression and PLINK. Our comparative study is based on an extensive simulation study using different two-locus models, exhibiting both main effects and epistasis [3]. In these simulations, 100 SNPs are generated, no LD between them. All genotypes are assumed to be in Hardy-Weinberg equilibrium. Furthermore, 2 disease-associated SNPs are selected, with MAFs set to 0.1, 0.2 and 0.4. The MAFs of the non-disease associated SNPs are uniformly distributed on [0.05, 0.5]. In order to achieve high accuracy in empirical power estimation, all simulation settings involve 1000 replicates. All methods are applied to WTCCC Crohn's Disease data. [1] Calle, M.L. et al. (2008), Tech. Rep. No. 24, Dep. of Systems Biology, Univ. de Vic [2] Cattaert, T. et al. (2011), Ann. Hum. Gen. 75, 78-89 [3] Wan, X. et al. (2010), Am. J. Hum. Gen. 87, 325-340 [4] Kam-Thong, T. et al. (2011), Eur. J. Hum. Gen. 19, 465-471 [5] Schwartz, D.F. et al. (2010), Bioinf. 26, 1752-1758 [less ▲]

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See detailA robustness study to investigate the performance of parametric and non-parametric tests used in Model-Based Multifactor Dimensionality Reduction Epistasis Detection.
Mahachie John, Jestinah ULg; Gusareva, Elena ULg; Van Lishout, François ULg et al

Poster (2011, September 19)

Model-Based Multifactor Dimensionality Reduction (MB-MDR) is data mining technique to identify gene-gene interactions among 1000nds of SNPs in a fast way, without making assumptions about the mode of ... [more ▼]

Model-Based Multifactor Dimensionality Reduction (MB-MDR) is data mining technique to identify gene-gene interactions among 1000nds of SNPs in a fast way, without making assumptions about the mode of genetic interactions. By construction, one of the implementations of MB-MDR involves testing one multi-locus genotype cell versus the remaining cells, hereby creating two imbalanced groups for trait distribution comparison. To date, for continuous traits, we have adopted a standard F-test to compare these groups. When normality assumption or homoscedasticity no longer hold, highly inflated results are to be expected. The power and type I error control of MB-MDR under these assumptions has been thoroughly investigated in Mahachie John et al [1]. The aim of this study is to assess, through simulations, the effects of ANOVA model violations on the performance of Model-Based Multifactor Dimensionality Reduction (MB-MDR). We quantify their effect on MB-MDR using default options, but at the same time introduce alternative options with increased performance. The better handling of imbalanced data using robust approaches [2] within a MB-MDR context is exemplified on real data for asthma-related phenotypes. 1. EJHG (2011), Early view 2. David Freedman, Statistical Models: Theory and Practice, Cambridge University Press (2000), ISBN 978-0521671057 [less ▲]

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See detailGenome-wide epistasis screening for Crohns’ disease
Gusareva, Elena ULg; Van Steen, Kristel ULg

Poster (2011, September 19)

Genome-wide association (GWA) studies of Crohn's disease have identified numerous genes. However, a substantial portion of the heritability of this disease remains unexplained. Some gene variants, not ... [more ▼]

Genome-wide association (GWA) studies of Crohn's disease have identified numerous genes. However, a substantial portion of the heritability of this disease remains unexplained. Some gene variants, not detectable via main effects GWA study, may manifest themselves only in interaction with other variants. To search for interacting genes involved in the regulation of Crohn's disease, we performed GWA epistasis screening in a large human cohort (1851 cases/2938 controls) belonging to the Wellcome Trust Case Control Consortium (WTCCC). All subjects were genotyped with the GeneChip 500K Mapping Array Set (Affymetrix chip). SNPs that passed our quality control (359,479 SNPs) were processed in Biofilter (a software package that looks for candidate epistatic genes contributing to disease risk) giving rise to 14,185 SNPs. Subsequent MB-MDR epistasis screening discovered four pairs of interacting SNPs on chromosome 4q35.1 and eight pairs on chromosome 11q23.2. The identified pairs of SNPs were confirmed with synergy-based measures. Notably, despite their mapping to the same genomic regions, the interacting SNPs were not in LD (r^2 < 0.5). Our findings support the idea of close chromosomal localization of two pairs of interacting genes that are involved in development of Crohn's disease. [less ▲]

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See detailGenome-wide epistasis screening for asthma associated traits
Gusareva, Elena ULg; Huyghe, Jeroen; Van Steen, Kristel ULg

Poster (2011, August 01)

Genome-wide association (GWA) studies of asthma and associated traits have identified numerous genes. A substantial portion of the heritability of these traits remains unexplained. Some variants, not ... [more ▼]

Genome-wide association (GWA) studies of asthma and associated traits have identified numerous genes. A substantial portion of the heritability of these traits remains unexplained. Some variants, not detectable via main effects GWA study may manifest themselves only in interaction with other variants. To search for interacting genes involved in regulation of asthma associated traits (total IgE, eosinophils, FEV1, FVC, FEV1/FVC) we performed GWA epistasis screening in two family groups of asthma patients:CAMP (Childhood Asthma Management Program:814 cases and 467 trios) and CARE (Childhood Asthma Research and Education:796 cases and 338 trios) [dbGaP accession number phs000166.v1.p1.c1]. Individuals were genotyped with the Aymetrix 6.0 array. After quality control 574922 and 575010 SNPs in CAMP and CARE respectively, were tested with FBAT. No main effects genome-wide significant associations were found. We prioritized candidate pairs of SNPs for MB-MDR epistasis screening using Biofilter leading to 7632 SNPs for CAMP and 7603 SNPs for CARE. The most significant pair-wise interaction was identified between SNPs from loci 7p21.1 and 12q23.3 influencing eosinophil level in asthmatics. [less ▲]

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See detailRate of Malignancies and Infections in a Large Single Center Cohort of IBD Patients Treated With Thiopurines and Anti-TNF-Antibodies.
Ochsenkühn, T; Steinborn, A; Beigel, F et al

in American Journal of Gastroenterology (2011, May)

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See detailTolerability of shortened infliximab infusion times in patients with inflammatory bowel diseases: a single center cohort study
Breynaert, C; Ferrante, M; Fidder, H et al

in Acta Gastro-Enterologica Belgica (2011, February)

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See detailRisk Of Malignancies In A Single Center Cohort Of IBD-Patients Treated with Immunosuppressives and Anti-TNF-antibodies
Steinborn, A; Beigel, F; Breiteneicher, S et al

in American Journal of Gastroenterology (2011)

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See detailRisk Of Malignancies In A Single Center Cohort Of IBD-Patients Treated with Immunosuppressives and Anti-TNF-antibodies
Steinborn, A; Beigel, F; Breiteneicher, S et al

in Journal of Crohn’s and Colitis (2011)

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See detailRate of Malignancies and Infections in a Large Single Center Cohort of IBD Patients Treated With Thiopurines and Anti-TNF-Antibodies.
Ochsenkühn, T; Steinborn, A; Beigel, F et al

in Journal of Crohn’s and Colitis (2011)

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See detailTravelling the world of gene-gene interactions
Van Steen, Kristel ULg

in Briefings in Bioinformatics (2011), 13(1), 1-19

Over the last few years, main effect genetic association analysis has proven to be a successful tool to unravel genetic risk components to a variety of complex diseases. In the quest for disease ... [more ▼]

Over the last few years, main effect genetic association analysis has proven to be a successful tool to unravel genetic risk components to a variety of complex diseases. In the quest for disease susceptibility factors and the search for the 'missing heritability', supplementary and complementary efforts have been undertaken. These include the inclusion of several genetic inheritance assumptions in model development, the consideration of different sources of information, and the acknowledgement of disease underlying pathways of networks. The search for epistasis or gene-gene interaction effects on traits of interest is marked by an exponential growth, not only in terms of methodological development, but also in terms of practical applications, translation of statistical epistasis to biological epistasis and integration of omics information sources. The current popularity of the field, as well as its attraction to interdisciplinary teams, each making valuable contributions with sometimes rather unique viewpoints, renders it impossible to give an exhaustive review of to-date available approaches for epistasis screening. The purpose of this work is to give a perspective view on a selection of currently active analysis strategies and concerns in the context of epistasis detection, and to provide an eye to the future of gene-gene interaction analysis. [less ▲]

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See detailMucosal gene expression of cell adhesion molecules, chemokines, and chemokine receptors in patients with inflammatory bowel disease before and after infliximab treatment.
Arijs, Ingrid; De Hertogh, Gert; Machiels, Kathleen et al

in Acta Gastro-Enterologica Belgica (2011), 106(4), 748-61

OBJECTIVES: Inflammatory bowel disease (IBD) is characterized by a continuous influx of leukocytes into the gut wall. This migration is regulated by cell adhesion molecules (CAMs), and selective ... [more ▼]

OBJECTIVES: Inflammatory bowel disease (IBD) is characterized by a continuous influx of leukocytes into the gut wall. This migration is regulated by cell adhesion molecules (CAMs), and selective antimigration therapies have been developed. This study investigated the effect of infliximab therapy on the mucosal gene expression of CAMs in IBD. METHODS: Mucosal gene expression of 69 leukocyte/endothelial CAMs and E-cadherin was investigated in 61 IBD patients before and after first infliximab infusion and in 12 normal controls, using Affymetrix gene expression microarrays. Quantitative reverse transcriptase-PCR (qRT-PCR), immunohistochemistry, and western blotting were used to confirm the microarray data. RESULTS: When compared with control colons, the colonic mucosal gene expression of most leukocyte/endothelial adhesion molecules was upregulated and E-cadherin gene expression was downregulated in active colonic IBD (IBDc) before therapy, with no significant colonic gene expression differences between ulcerative colitis and colonic Crohn's disease. Infliximab therapy restored the upregulations of leukocyte CAMs in IBDc responders to infliximab that paralleled the disappearance of the inflammatory cells from the colonic lamina propria. Also, the colonic gene expression of endothelial CAMs and of most chemokines/chemokine receptors returned to normal after therapy in IBDc responders, and only CCL20 and CXCL1-2 expression remained increased after therapy in IBDc responders vs. control colons. When compared with control ileums, the ileal gene expression of MADCAM1, THY1, PECAM1, CCL28, CXCL1, -2, -5, -6, and -11, and IL8 was increased and CD58 expression was decreased in active ileal Crohn's disease (CDi) before therapy, and none of the genes remained dysregulated after therapy in CDi responders vs. control ileums. This microarray study identified a number of interesting targets for antiadhesion therapy including PECAM1, IL8, and CCL20, besides the currently studied alpha4beta7 integrin-MADCAM1 axis. CONCLUSIONS: Our data demonstrate that many leukocyte/endothelial CAMs and chemokines/chemokine receptors are upregulated in inflamed IBD mucosa. Controlling the inflammation with infliximab restores most of these dysregulations in IBD. These results show that at least part of the mechanism of anti-tumor necrosis factor-alpha therapy goes through downregulation of certain adhesion molecules. [less ▲]

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See detailMucosal gene expression of cell adhesion molecules, chemokines, and chemokine receptors in patients with inflammatory bowel disease before and after infliximab treatment.
Arijs, Ingrid; De Hertogh, Gert; Machiels, Kathleen et al

in American Journal of Gastroenterology (2011)

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See detailGenetic variation in the autophagy gene ULK1 and risk of Crohn's disease
Henckaerts, Liesbeth; Cleynen, Isabelle; Brinar, Marko et al

in Inflammatory Bowel Diseases (2011), 17(6), 1392-1397

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