References of "Van Steen, Kristel"
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See detailDiscovering main genetic interactions with LABNet LAsso-based network inference.
Gadaleta, Francesco ULg; Van Steen, Kristel ULg

in PloS one (2014), 9(11), 110451

Genome-wide association studies can potentially unravel the mechanisms behind complex traits and common genetic diseases. Despite the valuable results produced thus far, many questions remain unanswered ... [more ▼]

Genome-wide association studies can potentially unravel the mechanisms behind complex traits and common genetic diseases. Despite the valuable results produced thus far, many questions remain unanswered. For instance, which specific genetic compounds are linked to the risk of the disease under investigation; what biological mechanism do they act through; or how do they interact with environmental and other external factors? The driving force of computational biology is the constantly growing amount of big data generated by high-throughput technologies. A practical framework that can deal with this abundance of information and that consent to discovering genetic associations and interactions is provided by means of networks. Unfortunately, high dimensionality, the presence of noise and the geometry of data can make the aforementioned problem extremely challenging. We propose a penalised linear regression approach that can deal with the aforementioned issues that affect genetic data. We analyse the gene expression profiles of individuals with a common trait to infer the network structure of interactions among genes. The permutation-based approach leads to more stable and reliable networks inferred from synthetic microarray data. We show that a higher number of permutations determines the number of predicted edges, improves the overall sensitivity and controls the number of false positives. [less ▲]

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See detailA comparison of multivariate genome-wide association methods.
Galesloot, Tessel E.; Van Steen, Kristel ULg; Kiemeney, Lambertus A. L. M. et al

in PloS one (2014), 9(4), 95923

Joint association analysis of multiple traits in a genome-wide association study (GWAS), i.e. a multivariate GWAS, offers several advantages over analyzing each trait in a separate GWAS. In this study we ... [more ▼]

Joint association analysis of multiple traits in a genome-wide association study (GWAS), i.e. a multivariate GWAS, offers several advantages over analyzing each trait in a separate GWAS. In this study we directly compared a number of multivariate GWAS methods using simulated data. We focused on six methods that are implemented in the software packages PLINK, SNPTEST, MultiPhen, BIMBAM, PCHAT and TATES, and also compared them to standard univariate GWAS, analysis of the first principal component of the traits, and meta-analysis of univariate results. We simulated data (N = 1000) for three quantitative traits and one bi-allelic quantitative trait locus (QTL), and varied the number of traits associated with the QTL (explained variance 0.1%), minor allele frequency of the QTL, residual correlation between the traits, and the sign of the correlation induced by the QTL relative to the residual correlation. We compared the power of the methods using empirically fixed significance thresholds (alpha = 0.05). Our results showed that the multivariate methods implemented in PLINK, SNPTEST, MultiPhen and BIMBAM performed best for the majority of the tested scenarios, with a notable increase in power for scenarios with an opposite sign of genetic and residual correlation. All multivariate analyses resulted in a higher power than univariate analyses, even when only one of the traits was associated with the QTL. Hence, use of multivariate GWAS methods can be recommended, even when genetic correlations between traits are weak. [less ▲]

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See detailDiagnosing and treating pediatric Crohn's disease patients: is there a difference between adult and pediatric gastroenterologist's practices ? Results of the BELCRO cohort.
De Greef, E.; Maus, B.; Smets, F. et al

in Acta gastro-enterologica Belgica (2014), 77(1), 25-9

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See detailLetter to the Editor: On the term 'interaction' and related phrases in the literature on Random Forests.
Boulesteix, Anne-Laure; Janitza, Silke; Hapfelmeier, Alexander et al

in Briefings in bioinformatics (2014)

In an interesting and quite exhaustive review on Random Forests (RF) methodology in bioinformatics Touw et al. address-among other topics-the problem of the detection of interactions between variables ... [more ▼]

In an interesting and quite exhaustive review on Random Forests (RF) methodology in bioinformatics Touw et al. address-among other topics-the problem of the detection of interactions between variables based on RF methodology. We feel that some important statistical concepts, such as 'interaction', 'conditional dependence' or 'correlation', are sometimes employed inconsistently in the bioinformatics literature in general and in the literature on RF in particular. In this letter to the Editor, we aim to clarify some of the central statistical concepts and point out some confusing interpretations concerning RF given by Touw et al. and other authors. [less ▲]

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See detailRisk of malignancies in patients with inflammatory bowel disease treated with thiopurines or anti-TNF alpha antibodies.
Beigel, Florian; Steinborn, Anni; Schnitzler, Fabian et al

in Pharmacoepidemiology and drug safety (2014), 23(7), 735-44

PURPOSE: We aimed to analyse malignancy rates and predictors for the development of malignancies in a large German inflammatory bowel disease (IBD) cohort treated with thiopurines and/or anti-tumour ... [more ▼]

PURPOSE: We aimed to analyse malignancy rates and predictors for the development of malignancies in a large German inflammatory bowel disease (IBD) cohort treated with thiopurines and/or anti-tumour necrosis factor (TNF) antibodies. METHODS: De novo malignancies in 666 thiopurine-treated and/or anti-TNF-treated IBD patients were analysed. Patients (n = 262) were treated with thiopurines alone and never exposed to anti-TNF antibodies (TP group). In addition, patients (n = 404) were exposed to anti-TNF antibodies (TNF+ group) with no (7.4%), discontinued (80.4%) or continued (12.1%) thiopurine therapy. RESULTS: In the TP group, 20 malignancies were observed in 18 patients compared with 8 malignancies in 7 patients in the TNF+ group (hazard ratio 4.15; 95% CI 1.82-9.44; p = 0.0007; univariate Cox regression). Moreover, 18.2% of all patients in the TP group >/=50 years of age developed a malignancy, compared with 3.8% of all patients <50 years of age (p = 0.0008). In the TNF+ group, 6.5% of all patients >/=50 years of age developed malignancies compared with 0.3% of all patients <50 years of age (p = 0.0007). In both groups combined, thiopurine treatment duration >/=4 years was associated with the risk for skin cancer (p = 0.0024) and lymphoma (p = 0.0005). CONCLUSIONS: Our data demonstrate an increased risk for the development of malignancies in IBD patients treated with thiopurines in comparison with patients treated with anti-TNF antibodies with or without thiopurines. [less ▲]

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See detailNeutrophil gelatinase B-associated lipocalin and matrix metalloproteinase-9 complex as a surrogate serum marker of mucosal healing in ulcerative colitis.
de Bruyn, Magali; Arijs, Ingrid; Wollants, Willem-Jan et al

in Inflammatory bowel diseases (2014), 20(7), 1198-207

BACKGROUND: The current standard for the assessment of mucosal healing after therapy in inflammatory bowel diseases is endoscopy. However, a high need exists for noninvasive, accurate surrogate markers ... [more ▼]

BACKGROUND: The current standard for the assessment of mucosal healing after therapy in inflammatory bowel diseases is endoscopy. However, a high need exists for noninvasive, accurate surrogate markers. METHODS: In 2 independent cohorts, levels of serum neutrophil gelatinase B-associated lipocalin and matrix metalloproteinase-9 complex (NGAL-MMP-9) from patients with active ulcerative colitis (UC) before and after first treatment with infliximab and from healthy controls (HC) were determined with zymography and sandwich enzyme-linked immunosorbent assay. The response to infliximab was defined as complete mucosal healing (Mayo endoscopic subscore 0-1) at control endoscopy. Data were analyzed with SPSS, and P values <0.05 were considered significant. RESULTS: In cohort 1 (n = 66; median age, 30 yr; 38% female), serum NGAL-MMP-9 levels significantly increased at baseline in UC patients versus HC (103.8 versus 42.4 ng/mL; P < 0.0001), whereas 55% of the patients had normal C-reactive protein levels. NGAL-MMP-9 levels significantly decreased after therapy in UC responders (from 116.3 ng/mL to 32.0 ng/mL; P < 0.0001) and in nonresponders (from 94.7 ng/mL to 54.1 ng/mL; P = 0.047). In cohort 2 (n = 132; median age, 39 yr; 53% female), NGAL-MMP-9 levels increased at baseline in active UC patients versus HC (86.5 versus 60.4 ng/mL; P = 0.10), whereas 45% of the patients had normal C-reactive protein levels. NGAL-MMP-9 levels significantly decreased after therapy in responders (from 87.5 ng/mL to 16.3 ng/mL; P < 0.0001) but not in nonresponders (from 82.7 ng/mL to 57.8 ng/mL; P = 0.19). After pooling the data, a cutoff value of 97.7 ng/mL for NGAL-MMP-9 complex was determined to predict complete mucosal healing with high specificity (91%). CONCLUSIONS: Serum NGAL-MMP-9 is suggested as a new surrogate marker for the assessment of mucosal healing in UC patients treated with infliximab. [less ▲]

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See detailActive PAI-1 as marker for venous thromboembolism: case-control study using a comprehensive panel of PAI-1 and TAFI assays.
Bollen, Lize; Peetermans, Marijke; Peeters, Miet et al

in Thrombosis research (2014), 134(5), 1097-102

BACKGROUND: Both activated Thrombin Activatable Fibrinolysis Inhibitor (TAFI) and active Plasminogen Activator Inhibitor-1 (PAI-1) attenuate fibrinolysis and may therefore contribute to the ... [more ▼]

BACKGROUND: Both activated Thrombin Activatable Fibrinolysis Inhibitor (TAFI) and active Plasminogen Activator Inhibitor-1 (PAI-1) attenuate fibrinolysis and may therefore contribute to the pathophysiology of Venous ThromboEmbolism (VTE). Whether increased TAFI and/or PAI-1 concentrations are associated with VTE is unclear. OBJECTIVE: To study an association of impaired fibrinolysis and VTE using a comprehensive panel of in-house developed assays measuring intact TAFI, activation peptide of TAFI (AP-TAFI), PAI-1 antigen, endogenous PAI-1:t-PA complex (PAI-1:t-PA) and active PAI-1 levels in 102 VTE patients and in 113 healthy controls (HC). RESULTS: Active PAI-1 was significantly higher in VTE patients compared to HC (20.9 [9.6-37.8] ng/ml vs. 6.2 [3.5-9.7] ng/ml, respectively). Active PAI-1 was the best discriminator with an area under the ROC curve and 95% confidence interval (AUROC [95%CI]) of 0.84 [0.79-0.90] compared to 0.75 [0.68-0.72] for PAI-1:t-PA, 0.65 [0.58-0.73] for PAI-1 antigen, 0.62 [0.54-0.69] for AP-TAFI and 0.51 [0.44-0.59] for intact TAFI. Using ROC analysis, we defined an optimal cut-off of 12.8 ng/ml for active PAI-1, with corresponding sensitivity of 71 [61-79] % and specificity of 89 [82-94] %. A lack of association with the time between VTE event and sample collection or with the intake of anticoagulant treatment suggests that active PAI-1 levels are sustainable high in VTE patients. CONCLUSIONS: This case-control study emphasizes the clinical importance of measuring active PAI-1 instead of PAI-1 antigen and identifies active PAI-1 as a potential marker of VTE. Prognostic studies will need to address the clinical significance of active PAI-1 as biomarker. [less ▲]

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See detailAssociation of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood.
Savenije, Olga E.; Mahachie John, Jestinah ULg; Granell, Raquel et al

in The Journal of allergy and clinical immunology (2014)

BACKGROUND: Genome-wide association studies identified IL33 and IL-1 receptor-like 1 (IL1RL1)/IL18R1 as asthma susceptibility loci. IL33 and IL1RL1 constitute a single ligand-receptor pathway. OBJECTIVE ... [more ▼]

BACKGROUND: Genome-wide association studies identified IL33 and IL-1 receptor-like 1 (IL1RL1)/IL18R1 as asthma susceptibility loci. IL33 and IL1RL1 constitute a single ligand-receptor pathway. OBJECTIVE: In 2 birth cohorts, the Prevalence and Incidence of Asthma and Mite Allergy (PIAMA) study and Avon Longitudinal Study of Parents and Children (ALSPAC), we analyzed associations of longitudinal wheezing phenotypes and asthma with single nucleotide polymorphisms (SNPs) of 8 genes encoding IL-33, IL1RL1, its coreceptor IL1RAcP, its adaptors myeloid differentiation primary response gene 88 (MyD88) and Toll-IL-11 receptor domain containing adaptor protein (TIRAP), and the downstream IL-1 receptor-associated kinase 1, IL-1 receptor-associated kinase 4, and TNF receptor-associated factor 6 (TRAF6). Furthermore, we investigated whether SNPs in this pathway show replicable evidence of gene-gene interaction. METHODS: Ninety-four SNPs were investigated in 2007 children in the PIAMA study and 7247 children in ALSPAC. Associations with wheezing phenotypes and asthma at 8 years of age were analyzed in each cohort and subsequently meta-analyzed. Gene-gene interactions were assessed through model-based multifactor dimensionality reduction in the PIAMA study, and gene-gene interactions of 10 SNP pairs were further evaluated. RESULTS: Intermediate-onset wheeze was associated with SNPs in several genes in the IL33-IL1RL1 pathway after applying multiple testing correction in the meta-analysis: 2 IL33 SNPs (rs4742170 and rs7037276), 1 IL-1 receptor accessory protein (IL1RAP) SNP (rs10513854), and 1 TRAF6 SNP (rs5030411). Late-onset wheeze was associated with 2 IL1RL1 SNPs (rs10208293 and rs13424006), and persistent wheeze was associated with 1 IL33 SNP (rs1342326) and 1 IL1RAP SNP (rs9290936). IL33 and IL1RL1 SNPs were nominally associated with asthma. Three SNP pairs showed interaction for asthma in the PIAMA study but not in ALSPAC. CONCLUSIONS: IL33-IL1RL1 pathway polymorphisms are associated with asthma and specific wheezing phenotypes; that is, most SNPs are associated with intermediate-onset wheeze, a phenotype closely associated with sensitization. We speculate that IL33-IL1RL1 pathway polymorphisms affect development of wheeze and subsequent asthma through sensitization in early childhood. [less ▲]

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See detailGenome-wide environmental interaction analysis using multidimensional data reduction principles to identify asthma pharmacogenetic loci in relation to corticosteroid therapy
Van Lishout, François ULg; Bessonov, Kyrylo ULg; Duan, Quingling et al

Poster (2013, October 25)

Genome-wide gene-environment (GxE) and gene-gene (GxG) interaction studies share a lot of challenges via the common genetic component they involve. GWEI studies may therefore benefit from the abundance of ... [more ▼]

Genome-wide gene-environment (GxE) and gene-gene (GxG) interaction studies share a lot of challenges via the common genetic component they involve. GWEI studies may therefore benefit from the abundance of methodologies that are available in the context of genome-wide epistasis detection methods. One of these is Model-Based Multifactor Dimensionality Reduction (MB-MDR), which does not make any assumption about the genetic inheritance model. MB-MDR involves reducing a high-dimensional GxE space to GxE factor levels that either exhibit high or low or no evidence for their association to disease outcome. In contrast to logistic regression and random forests, MB-MDR can be used to detect GxE interactions in the absence of any main effects or when sample sizes are too small to be able to model all main and GxE interaction effects. In this ongoing study, we demonstrate the opportunities and challenges of MB-MDR for genome-wide GxE interaction analysis and analyzed the difference in prebronchodilator FEV1 following 8 weeks of inhaled corticosteroid therapy, for 565 pediatric Caucasian CAMP (ages 5-12) from the SHARE project. [less ▲]

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See detailGenome-wide association interaction analysis for Alzheimer’s disease.
Gusareva, Elena ULg; Bellenguez, C; Cuyvers, E et al

Speech/Talk (2013)

Identification of epistasis is a challenging task that when successful gives new clues to systems-level genetics where the complexity of underling biology of human disease can be better understood. Though ... [more ▼]

Identification of epistasis is a challenging task that when successful gives new clues to systems-level genetics where the complexity of underling biology of human disease can be better understood. Though many novel methods for detecting epistasis have been proposed and many studies for epistasis detection have been conducted, so far few studies can demonstrate replicable epistasis. In the present work, we propose a minimal protocol for exhaustive genome-wide association interaction (GWAI) analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and statistical tools. The different steps of this protocol are illustrated on a real-life data application for Alzheimer’s disease (a large cohort of 2259 patients and 6017 controls from France). Using this protocol, we identified AD-associated interacting SNPs-pair from chromosome 6q11.1 (rs6455128, the KHDRBS2 gene) and 13q12.11 (rs7989332, the CRYL1 gene) and male-specific epistasis between SNPs from chromosome 5q34 (rs729149 and rs3733980, the WWC1 gene) and 15q22.2 (rs9806612, rs9302230 and rs7175766, the TLN2 gene). The transcriptome analysis revealed negative correlation between expression levels of KHDRBS2 and CRYL1 in both the temporal cortex and cerebellum brain regions and positive correlation between the expression levels of CRYL1 and WWC1 in the temporal cortex brain region. A replication analysis strategy and a meta-analysis approach in independent data confirmed effects of some of the discovered interactions. [less ▲]

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See detailReplication of large-scale epistasis studies: an example on ankylosing spondylitis
Bessonov, Kyrylo ULg; Van Steen, Kristel ULg

Poster (2013, September 17)

Ankylosing spondylitis (AS) is a common form of inflammatory arthritis occurring in approximately 5 out of 1,000 adults of European descent. Recently, the Australo-Anglo-American Spondyloarthritis ... [more ▼]

Ankylosing spondylitis (AS) is a common form of inflammatory arthritis occurring in approximately 5 out of 1,000 adults of European descent. Recently, the Australo-Anglo-American Spondyloarthritis Consortium and the WTCCC2 showed that polymorphisms of ERAP1 only affect AS risk in HLA-B27-positive individuals, hereby establishing an interaction between ERAP1 and HLA in the TASC, WTCCC2 and replication datasets [2,5]. We were able to confirm this interaction although using other SNPs. In this study, we use the aforementioned data from WTTCC2 on AS to address unresolved issues when performing large-scale SNP-SNP interaction studies, so as to better guarantee “stable” and “truly replicable” results. These issues are 1) the choice of variable selection method (e.g., of known loci mapping to genes part of know pathways), 2) the choice of SNPs representing a genomic region (e.g., SNPs with modest versus negligible LD between them), 3) the choice of analysis method (e.g., regression-based versus data-reduction (non-parametric) based), 4) different adjustment schemes for lower-order effects (using additive/co-dominant genetic models). We show that even modest changes in 1)-4) may give rise to quite varying epistasis findings for AS, and motivate some “optimal” choices via extensive simulation studies. In this work we rely on a minimal GWAI protocol for genome-wide epistasis detection using SNPs, as developed in our lab [6][9], using the advanced non-parametric Model-Based Multifactor Dimensionality Reduction (MB-MDR) method [1] and an adapted [*] BOolean Operation-based Screening and Testing (BOOST) algorithm [4]. [*] A BOOST [4] like implementation based on the original BOOST algorithm which accounts for missing genotypes [less ▲]

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See detailTherapeutic Strategy and Patient Outcome during the First 2 Years of Pediatric Crohn’s Disease
Veereman, G; Mahachie John, Jestinah ULg; De Greef, E et al

in Journal of Pediatric Gastroenterology and Nutrition (2013, May)

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See detailGenome-wide association interaction analysis for complex diseases: an example on Alzheimer’s disease.
Gusareva, Elena ULg; Cuyvers, E; Colon, S et al

Speech/Talk (2013)

Objectives: Common genetic mutations that can be detected via a genome-wide association (GWA) study and at the same time have a strong contribution to disease risk are fairly limited. Some of the genetic ... [more ▼]

Objectives: Common genetic mutations that can be detected via a genome-wide association (GWA) study and at the same time have a strong contribution to disease risk are fairly limited. Some of the genetic variants in humans are either rare, thus more difficult to be identified, or they are common, but exert relatively small or even no individual effects that are masked or enhanced by one or several genes. The discovery of interacting genetic variants, possibly explaining part of the hidden genetic heritability, requires the development of sophisticated strategies and bioinformatics tools. Methods: In the present study, we propose a minimal protocol for genome-wide association interaction (GWAI) analysis that involves screening over large-scale genomic data in the search for epistatic or synergetic effects. The different steps of this minimal protocol are illustrated on a real-life data application for Alzheimer disease (AlzD) (large human cohort of 2,259 cases and 6,017 controls from France) and the pros and cons of the approaches are discussed. Results: Using the protocol, we identified two pairs of AlzD-associated interacting SNPs: from chromosome 6q11.1 and 13q12.11 and male-specific epistasis between SNPs from chromosome 5q34 and 15q22.2. Conclusion: In the present work we developed and applied an epistasis detection protocol to perform a comprehensive genome-wide search for AlzD-associated epistatic effects, hereby combining the strengths of different strategies, methods and statistical tools. It is the first time an epistasis study of this magnitude has been conducted in the context of AlzD. We show the advantages of viewing and analyzing data from different angles. A replication analysis strategy adapted to the epistasis detection context, as well as a meta-analytic approach confirmed effects of the discovered interactions. Apart from the biological and clinical importance, the present work offers a roadmap for future investigations in the field of epistasis detection and interpretation. [less ▲]

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See detailAn efficient algorithm to perform multiple testing in epistasis screening
Van Lishout, François ULg; Mahachie John, Jestinah ULg; Gusareva, Elena ULg et al

in BMC Bioinformatics (2013), 14

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

Background: Research in epistasis or gene-gene interaction detection for human complex traits has grown 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. Gene-gene interaction studies will require a memory proportional to the squared number of SNPs. A genome-wide epistasis search would therefore require terabytes of memory. Hence, cache problems are likely to occur, increasing the computation time. 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 MBMDR-3.0.3. 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: In the case of a binary (affected/unaffected) trait, the parallel workflow of MBMDR-3.0.3 analyzes all gene-gene interactions with a dataset of 100,000 SNPs typed on 1000 individuals within 4 days and 9 hours, using 999 permutations of the trait to assess statistical significance, on a cluster composed of 10 blades, containing each four Quad-Core AMD Opteron Processor 2352 2.1 GHz. In the case of a continuous trait, a similar run takes 9 days. Our program found 14 SNP-SNP interactions with a multiple-testing corrected p-value of less than 0.05 on real-life Crohn's disease data. Conclusions: Our software is the first implementation of the MB-MDR methodology able to solve large-scale SNP-SNP interactions problems within a few days, without using much memory, while adequately controlling the type I error rates. A new implementation to reach genome-wide epistasis screening is under construction. In the context of Crohn's disease, MBMDR-3.0.3 could identify epistasis involving regions that are well known in the field and could be explained from a biological point of view. This demonstrates the power of our software to find relevant phenotype-genotype higher-order associations. [less ▲]

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See detailGenome-wide Epistasis Screening for Alzheimer‘s Disease
Gusareva, Elena ULg; Bellenguez, C; Sleegers, K et al

Poster (2013, March)

Objectives: Alzheimer disease (AlzD) is a complex, progressive neurodegenerative disease where dementia symptoms (memory and other intellectual abilities loss) gradually worsen over a number of years. The ... [more ▼]

Objectives: Alzheimer disease (AlzD) is a complex, progressive neurodegenerative disease where dementia symptoms (memory and other intellectual abilities loss) gradually worsen over a number of years. The disease is characterized by the neuropathologic findings of neurofibrillary tangles and amyloid plaques that accumulate in vulnerable brain regions. AlzD is inherited as complex trait and appears to be highly heritable with 58-79 percent attributable to genetic factors. So far, although a number of main-effect genes have been identified, only a fraction of AlzD cases can be explained by specific gene mutations. In our study we performed an exhaustive and selective genome-wide screening for SNP-SNP interactions associated with AlzD in a large case/control cohort to reveal hidden heritability that can be accounted for by epistasis. Methods: We developed a minimal protocol for genome-wide association interaction (GWAI) analysis that involves screening over large-scale genomic data in the search for epistatic or synergetic effects. The protocol was applied on a large human cohort of 2,259 cases AlzD cases and 6,017 healthy controls from France to search for AlzD-associated epistasic effects. Results: In the exhaustive genome-wide screening, we identified two pairs of AlzD-associated interacting SNPs from chromosomes 6q11.1 and 13q12.11, and male-specific epistasis between SNPs from chromosomes 5q34 and 15q22.2. In the selective epistasis search, screening over the candidate genes for AlzD previously reported to be in interaction, we replicated seven out of twelve AlzD-associated gene pairs (INS / PPARA, IL1A / PPARA, IL10 / PPARA, TF / HFE, MTHFR / IL6, ABCA1 / NPC1, LRP1 / MAPT). Conclusion: It is the first time an epistasis study of this magnitude has been conducted in the context of AlzD. We show the advantages of viewing and analyzing data from different angles. A replication analysis strategy adapted to the epistasis detection context, as well as a meta-analytic approach confirmed effects of the discovered interactions. Apart from the biological and clinical importance, the present work offers a roadmap for future investigations in the field of epistasis detection and interpretation. [less ▲]

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See detailTherapeutic Strategy and Patient Outcome during the First 2 Years of Pediatric Crohn’s Disease
Veereman, G; Mahachie John, Jestinah ULg; De Greef, E et al

in Acta Gastro-Enterologica Belgica (2013)

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See detailProfile of pediatric Crohn's disease in Belgium.
De Greef, E.; Mahachie John, Jestinah ULg; Hoffman, I. et al

in Journal of Crohn's & colitis (2013), 7(11), 588-98

AIM: A Belgian registry for pediatric Crohn's disease, BELCRO, was created. This first report aims at describing disease presentation and phenotype and determining associations between variables at ... [more ▼]

AIM: A Belgian registry for pediatric Crohn's disease, BELCRO, was created. This first report aims at describing disease presentation and phenotype and determining associations between variables at diagnosis and registration in the database. METHODS: Through a collaborative network, children with previously established Crohn's disease and newly diagnosed children and adolescents (under 18 y of age) were recruited over a 2 year period. Data were collected by 23 centers and entered in a database. Statistical association tests analyzed relationships between variables of interest at diagnosis. RESULTS: Two hundred fifty-five patients were included. Median age at diagnosis was 12.5 y (range: 1.6-18 y); median duration of symptoms prior to diagnosis was 3 m (range: 1-12 m). Neonatal history and previous medical history did not influence disease onset nor disease behavior. Fifty three % of these patients presented with a BMI z-score < -1. CRP was an independent predictor of disease severity. Steroids were widely used as initial treatment in moderate to severe and extensive disease. Over time, immunomodulators and biological were prescribed more frequently, reflecting a lower prescription rate for steroids and 5-ASA. A positive family history was the sole significant determinant for earlier use of immunosuppression. CONCLUSION: In Belgium, the median age of children presenting with Crohn's disease is 12.5 y. Faltering growth, extensive disease and upper GI involvement are frequent. CRP is an independent predictive factor of disease activity. A positive family history appears to be the main determinant for initial treatment choice. [less ▲]

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See detailGenetic association and functional role of Crohn disease risk alleles involved in microbial sensing, autophagy, and endoplasmic reticulum (ER) stress.
Hoefkens, Eveline; Nys, Kris; John, Jestinah M. et al

in Autophagy (2013), 9(12), 2046-55

Genome-wide association studies have identified several genes implicated in autophagy (ATG16L1, IRGM, ULK1, LRRK2, and MTMR3), intracellular bacterial sensing (NOD2), and endoplasmic reticulum (ER) stress ... [more ▼]

Genome-wide association studies have identified several genes implicated in autophagy (ATG16L1, IRGM, ULK1, LRRK2, and MTMR3), intracellular bacterial sensing (NOD2), and endoplasmic reticulum (ER) stress (XBP1 and ORMDL3) to be associated with Crohn disease (CD). We studied the known CD-associated variants in these genes in a large cohort of 3451 individuals (1744 CD patients, 793 ulcerative colitis (UC) patients and 914 healthy controls). We also investigated the functional phenotype linked to these genetic variants. Association with CD was confirmed for NOD2, ATG16L1, IRGM, MTMR3, and ORMDL3. The risk for developing CD increased with an increasing number of risk alleles for these genes (P<0.001, OR 1.26 [1.20 to 1.32]). Three times as many (34.8%) CD patients carried a risk allele in all three pathways, in contrast to 13.3% of the controls (P<0.0001, OR = 3.46 [2.77 to 4.32]). For UC, no significant association for one single nucleotide polymorphism (SNP) was found, but the risk for development of UC increased with an increasing total number of risk alleles (P = 0.001, OR = 1.10 [1.04 to 1.17]). We found a genetic interaction between reference SNP (rs)2241880 (ATG16L1) and rs10065172 (IRGM) in CD. Functional experiments hinted toward an association between an increased genetic risk and an augmented inflammatory status, highlighting the relevance of the genetic findings. [less ▲]

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