gammaMAXT: a fast multiple-testing correction algorithm
Van Lishout, François ; Gadaleta, Francesco ; et al
in ERCIM 2014 Abstract Book (in press)
The purpose of the maxT algorithm (1993) is to control the family-wise error rate (FWER) when assessing significance of multiple tests jointly. However, the requirements in terms of computing time and ... [more ▼]
The purpose of the maxT algorithm (1993) is to control the family-wise error rate (FWER) when assessing significance of multiple tests jointly. However, the requirements in terms of computing time and memory of this procedure are proportional to the number of investigated hypothesis. The memory issue has been solved by Van Lishout’s implementation of maxT (2013), which makes the memory usage independent from the size of the dataset. This algorithm is implemented in MBMDR-3.0.3, a software that is able to identify genetic interactions, for a variety of SNP-SNP based epistasis model,s in an effective way. However, that implementation turned out to be less suitable for genome-wide interaction analysis studies, due to the prohibitive computational burden. Here, we present gammaMAXT, a novel algorithm which is part of MBMDR-4.2.2. We show that, in the abscence of interaction effects, test-statistics produced by the MB-MDR methodology follow a mixture distribution with a point mass at zero and a shifted gamma distribution for the top 10% of the strictly positive values. We show that the gammaMAXT algorithm has a power comparable to maxT and maintains FWER, but requires less computational resources and time. MBMDR-4.2.2 can be downloaded at http://www.statgen.ulg.ac.be. [less ▲]Detailed reference viewed: 50 (5 ULg)
Practical aspects of genome-wide association interaction analysis.
Gusareva, Elena ; Van Steen, Kristel
in Human Genetics (2014), 133(11), 1343-58
Large-scale epistasis studies can give new clues to system-level genetic mechanisms and a better understanding of the underlying biology of human complex disease traits. Though many novel methods have ... [more ▼]
Large-scale epistasis studies can give new clues to system-level genetic mechanisms and a better understanding of the underlying biology of human complex disease traits. Though many novel methods have been proposed to carry out such studies, so far only a few of them have demonstrated replicable results. Here, we propose a minimal protocol for genome-wide association interaction (GWAI) analysis to identify gene–gene interactions from large-scale genomic data. The different steps of the developed protocol are discussed and motivated, and encompass interaction screening in a hypothesis-free and hypothesisdriven manner. In particular, we examine a wide range of aspects related to epistasis discovery in the context of complex traits in humans, hereby giving practical recommendations for data quality control, variant selection or prioritization strategies and analytic tools, replication and meta-analysis, biological validation of statistical findings and other related aspects. The minimal protocol provides guidelines and attention points for anyone involved in GWAI analysis and aims to enhance the biological relevance of GWAI findings. At the same time, the protocol improves a better assessment of strengths and weaknesses of published GWAI methodologies. [less ▲]Detailed reference viewed: 6 (1 ULg)
Genome-Wide Association Interaction Analysis for Alzheimer’s Disease
Gusareva, Elena ; ; et al
in Neurobiology of Aging (2014)
We propose a minimal protocol for exhaustive genome-wide association interaction analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and ... [more ▼]
We propose a minimal protocol for exhaustive genome-wide association interaction 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 (AD) (2259 patients and 6017 controls from France). Particularly, in the exhaustive genome-wide epistasis screening we identified AD-associated interacting SNPs-pair from chromosome 6q11.1 (rs6455128, the KHDRBS2 gene) and 13q12.11 (rs7989332, the CRYL1 gene) (p = 0.006, corrected for multiple testing). A replication analysis in the independent AD cohort from Germany (555 patients and 824 controls) confirmed the discovered epistasis signal (p = 0.036). This signal was also supported by a meta-analysis approach in 5 independent AD cohorts that was applied in the context of epistasis for the first time. Transcriptome analysis revealed negative correlation between expression levels of KHDRBS2 and CRYL1 in both the temporal cortex (β = -0.19, p = 0.0006) and cerebellum (β = -0.23, p < 0.0001) brain regions. This is the first time a replicable epistasis associated with AD was identified using a hypothesis free screening approach. [less ▲]Detailed reference viewed: 32 (8 ULg)
LD-based haplotype encoding scheme with iterative pruning principal component analysis (ipPCA) to retrieve population substructures
Chaichoompu, Kridsadakorn ; Fouladi, Ramouna ; et al
Poster (2014, April 29)
Objective To identify and differentiate between subpopulations using a rich set of genetic markers, as using reduced sets of genetic markers for these purposes can become challenging, especially when ... [more ▼]
Objective To identify and differentiate between subpopulations using a rich set of genetic markers, as using reduced sets of genetic markers for these purposes can become challenging, especially when similar geographic regions are involved or when spurious patterns are likely to exist. Method Single Nucleotide Polymorphisms (SNPs) are commonly used to capture variations between populations and often genome-wide SNP data are pruned based on linkage disequilibrium (LD) patterns. Notably, haplotype composition and the pattern of LD between markers may vary between larger populations but may also play a role within more confined geographic regions. Indeed, knowledge about haplotypes in unrelated individuals can reveal useful information about genetic ancestry. Here, we use iterative pruning principal component analysis (ipPCA)  to identify and characterize subpopulations in an unsupervised way. As input data, either pruned genome-wide SNP data are used (using PLINK 1.9 with the "indep-pairwise" option, window size = 100k, r2 < 0.25) or multilocus haplotype information derived from the genome-wide SNP panel (using BEAGLE 3.3.2 to infer haplotype). These approaches are applied to real-life data from 992 Thai individuals . Result Preliminary results indicate that ipPCA applied to pruned SNP data or ipPCA that explicitly uses multilocus information (haplotypes) give complementary information about population substructure for geographically confined populations such as the Thai samples in this study. Both methods address different aspects of population structure. Detailed simulation studies are needed to identify the optimal scenarios for haplotype-based ipPCA. Conclusion In this work, we propose to combine an LD-based haplotype encoding scheme with the ipPCA machinery to retrieve fine population substructures. Despite the complexities that are associated with haplotype inference, added value can be obtained when the LD structure between SNPs is exploited in the search for relevant population strata. References 1. Intarapanich, A., et al., Iterative pruning PCA improves resolution of highly structured populations. BMC Bioinformatics, 2009. 10: p. 382. 2. Wangkumhang, P., et al., Insight into the peopling of Mainland Southeast Asia from Thai population genetic structure. PLoS One, 2013. 8(11): p. e79522. [less ▲]Detailed reference viewed: 62 (5 ULg)
Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood.
; Mahachie John, Jestinah ; 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 ▲]Detailed reference viewed: 37 (3 ULg)
Genome-wide environmental interaction analysis using multidimensional data reduction principles to identify asthma pharmacogenetic loci in relation to corticosteroid therapy
Van Lishout, François ; Bessonov, Kyrylo ; 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 ▲]Detailed reference viewed: 41 (10 ULg)
Replication of large-scale epistasis studies: an example on ankylosing spondylitis
Bessonov, Kyrylo ; Van Steen, Kristel
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 , using the advanced non-parametric Model-Based Multifactor Dimensionality Reduction (MB-MDR) method  and an adapted [*] BOolean Operation-based Screening and Testing (BOOST) algorithm . [*] A BOOST  like implementation based on the original BOOST algorithm which accounts for missing genotypes [less ▲]Detailed reference viewed: 24 (3 ULg)
Therapeutic Strategy and Patient Outcome during the First 2 Years of Pediatric Crohn’s Disease
; Mahachie John, Jestinah ; et al
in Journal of Pediatric Gastroenterology and Nutrition (2013, May)Detailed reference viewed: 32 (7 ULg)
An efficient algorithm to perform multiple testing in epistasis screening
Van Lishout, François ; Mahachie John, Jestinah ; Gusareva, Elena 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 ▲]Detailed reference viewed: 56 (17 ULg)
Therapeutic Strategy and Patient Outcome during the First 2 Years of Pediatric Crohn’s Disease
; Mahachie John, Jestinah ; et al
in Acta Gastro-Enterologica Belgica (2013)Detailed reference viewed: 17 (2 ULg)
Profile of pediatric Crohn's disease in Belgium.
; Mahachie John, Jestinah ; 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 ▲]Detailed reference viewed: 55 (24 ULg)
Genetic association and functional role of Crohn disease risk alleles involved in microbial sensing, autophagy, and endoplasmic reticulum (ER) stress.
; ; 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 ▲]Detailed reference viewed: 22 (1 ULg)
Behind the (impedance) baseline in children.
; ; Van Steen, Kristel et al
in Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus / I.S.D.E (2013)
Impedance baseline is a new parameter recently related to esophageal integrity. The aim of this study was to assess the effect of different factors on impedance baseline in pediatric patients. We analyzed ... [more ▼]
Impedance baseline is a new parameter recently related to esophageal integrity. The aim of this study was to assess the effect of different factors on impedance baseline in pediatric patients. We analyzed the impedance baseline of 800 children with symptoms of gastroesophageal reflux. Mean impedance baseline was automatically calculated throughout 24-hour tracings. The presence of different age groups and of esophagitis was evaluated. Unpaired t-test, Spearman rank correlation, polynomial, and regression plot were used for statistical analysis. Age-related percentile curves were created. We considered a P-value <0.05 as statistically significant. Impedance baseline was significantly (P < 0.001) lower in younger compared to older children up to 48 months. The mean increase of baseline per month was much higher in the first 36 months of life (47.5 vs. 2.9 Ohm in Channel 1 and 29.9 vs. 2.3 Ohm in Channel 6, respectively) than in older ages. Patients with esophagitis showed significantly decreased impedance baseline (P < 0.05). Infants (especially in the first months of life) and young children present a significantly lower impedance baseline compared to older children both in proximal and distal esophagus. The presence of esophagitis may also determine a decreased impedance baseline regardless of the age of the patients. [less ▲]Detailed reference viewed: 8 (1 ULg)
Esophageal impedance baseline is age dependent.
; ; et al
in Journal of pediatric gastroenterology and nutrition (2013), 57(4), 506-13
OBJECTIVE: Esophageal impedance (multichannel intraluminal impedance [MII]) baseline (impedance baseline [IB]) has been recently considered to be related to esophageal integrity. The aim of this study was ... [more ▼]
OBJECTIVE: Esophageal impedance (multichannel intraluminal impedance [MII]) baseline (impedance baseline [IB]) has been recently considered to be related to esophageal integrity. The aim of this study was to analyze the age effect on IB in a large population of pediatric patients. DESIGN: A total of 816 children with symptoms of gastroesophageal reflux and submitted to MII were included. Mean IB was automatically calculated in the different MII channels (Chs) throughout 24-hour tracings by the specific software without removing any episode of increased/decreased IB. Acid and nonacid reflux parameters and age subgroups analysis were performed. Unpaired t test, Spearman rank correlation, polynomial and regression plot, multiple regression analysis, factorial analysis of variance, and the least mean squares method were used for statistical analysis and age-related percentile curves. P < 0.05 was considered as statistically significant. RESULTS: Mean IB was significantly (P < 0.001) lower in younger compared with older children up to 48 months. The mean increase of IB per month was 2.9 Omega in Ch 1 and 2.3 Omega in Ch 6, but much higher in the first 36 months of life (47.5 Omega in Ch 1 and 29.9 Omega in Ch 6, respectively). From 48 months onward, there was no significant increase of the mean IB (P = 0.73). In the multiple regression analysis, only age and reflux index (but no other reflux parameters) significantly correlated with IB. Distal IB was significantly (P < 0.05) lower in patients with esophagitis and in subjects taking proton pump inhibitors compared with subjects off (any) treatment. Percentiles of IB in proximal and distal Chs were provided according to different age groups. CONCLUSIONS: IB is significantly lower in infants (especially in the first months of life) compared with older children. Low IB in both proximal and distal esophagus in young infants may be related to anatomical and functional difference other than the presence of esophagitis. [less ▲]Detailed reference viewed: 18 (1 ULg)
EU Pancreas: An Integrated European Platform for Pancreas Cancer Research - from Basic Science to Clinical and Public Health Interventions for a Rare Disease.
; ; Van Steen, Kristel et al
in Public health genomics (2013), 16(6), 305-12
Background: Large-scale international collaboration is essential to decipher relevant information in the context of omics-scale interrogations in cancer research. This is even more important for rare and ... [more ▼]
Background: Large-scale international collaboration is essential to decipher relevant information in the context of omics-scale interrogations in cancer research. This is even more important for rare and fatal diseases like pancreas cancer (PC). Methods: The COST Action BM1204 is a unique platform to facilitate the collaboration of a broad range of European and international PC multidisciplinary research groups in order to: (1) integrate knowledge and experience in a multidisciplinary way 'from cell to society', (2) promote the application of uniform study tools and protocols, (3) foster their optimal use by early-stage researchers, (4) enhance the mobility and training of researchers, and (5) disseminate the results produced to the broader society. Results: This Action will develop novel interdisciplinary tools for collaborative research to improve our understanding of PC and its prevention, diagnosis and treatment. It also aims to answer questions related to the etiology, early detection, evidence-based and personalized treatment, and health management for PC. Furthermore, the Action will contribute to new insights into PC personalized medicine and beyond as well as to the understanding of complex and rare diseases taking PC as a best practice example. The Action aims at attracting young scholars across a range of disciplines in collaboration with more experienced researchers and enhancing active European participation in the international scenario of PC research. Conclusion: The ultimate aim is to foster PC research in Europe and to coordinate this effort with other international initiatives to reduce disease mortality. (c) 2013 S. Karger AG, Basel. [less ▲]Detailed reference viewed: 19 (5 ULg)
Molecular reclassification of Crohn's disease: a cautionary note on population stratification.
; ; Mahachie John, Jestinah et al
in PloS one (2013), 8(10), 77720
Complex human diseases commonly differ in their phenotypic characteristics, e.g., Crohn's disease (CD) patients are heterogeneous with regard to disease location and disease extent. The genetic ... [more ▼]
Complex human diseases commonly differ in their phenotypic characteristics, e.g., Crohn's disease (CD) patients are heterogeneous with regard to disease location and disease extent. The genetic susceptibility to Crohn's disease is widely acknowledged and has been demonstrated by identification of over 100 CD associated genetic loci. However, relating CD subphenotypes to disease susceptible loci has proven to be a difficult task. In this paper we discuss the use of cluster analysis on genetic markers to identify genetic-based subgroups while taking into account possible confounding by population stratification. We show that it is highly relevant to consider the confounding nature of population stratification in order to avoid that detected clusters are strongly related to population groups instead of disease-specific groups. Therefore, we explain the use of principal components to correct for population stratification while clustering affected individuals into genetic-based subgroups. The principal components are obtained using 30 ancestry informative markers (AIM), and the first two PCs are determined to discriminate between continental origins of the affected individuals. Genotypes on 51 CD associated single nucleotide polymorphisms (SNPs) are used to perform latent class analysis, hierarchical and Partitioning Around Medoids (PAM) cluster analysis within a sample of affected individuals with and without the use of principal components to adjust for population stratification. It is seen that without correction for population stratification clusters seem to be influenced by population stratification while with correction clusters are unrelated to continental origin of individuals. [less ▲]Detailed reference viewed: 15 (1 ULg)
Unique gene expression and MR T2 relaxometry patterns define chronic murine dextran sodium sulphate colitis as a model for connective tissue changes in human Crohn's disease.
; ; et al
in PloS one (2013), 8(7), 68876
INTRODUCTION: Chronically relapsing inflammation, tissue remodeling and fibrosis are hallmarks of inflammatory bowel diseases. The aim of this study was to investigate changes in connective tissue in a ... [more ▼]
INTRODUCTION: Chronically relapsing inflammation, tissue remodeling and fibrosis are hallmarks of inflammatory bowel diseases. The aim of this study was to investigate changes in connective tissue in a chronic murine model resulting from repeated cycles of dextran sodium sulphate (DSS) ingestion, to mimic the relapsing nature of the human disease. MATERIALS AND METHODS: C57BL/6 mice were exposed to DSS in drinking water for 1 week, followed by a recovery phase of 2 weeks. This cycle of exposure was repeated for up to 3 times (9 weeks in total). Colonic inflammation, fibrosis, extracellular matrix proteins and colonic gene expression were studied. In vivo MRI T 2 relaxometry was studied as a potential non-invasive imaging tool to evaluate bowel wall inflammation and fibrosis. RESULTS: Repeated cycles of DSS resulted in a relapsing and remitting disease course, which induced a chronic segmental, transmural colitis after 2 and 3 cycles of DSS with clear induction of fibrosis and remodeling of the muscular layer. Tenascin expression mirrored its expression in Crohn's colitis. Microarray data identified a gene expression profile different in chronic colitis from that in acute colitis. Additional recovery was associated with upregulation of unique genes, in particular keratins, pointing to activation of molecular pathways for healing and repair. In vivo MRI T2 relaxometry of the colon showed a clear shift towards higher T2 values in the acute stage and a gradual regression of T2 values with increasing cycles of DSS. CONCLUSIONS: Repeated cycles of DSS exposure induce fibrosis and connective tissue changes with typical features, as occurring in Crohn's disease. Colonic gene expression analysis revealed unique expression profiles in chronic colitis compared to acute colitis and after additional recovery, pointing to potential new targets to intervene with the induction of fibrosis. In vivo T2 relaxometry is a promising non-invasive assessment of inflammation and fibrosis. [less ▲]Detailed reference viewed: 9 (1 ULg)
Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease.
; ; et al
in Gut (2013)
OBJECTIVE: Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their ... [more ▼]
OBJECTIVE: Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their inhibitors to maintain gut homeostasis. Unrestrained or excessive proteolysis can lead to pathological gastrointestinal conditions. The aim was to validate the identified protease IBD candidates from a previously performed systematic review through a genetic association study and functional follow-up. DESIGN: We performed a genetic association study in a large multicentre cohort of patients with Crohn's disease (CD) and UC from five European IBD referral centres in a total of 2320 CD patients, 2112 UC patients and 1796 healthy controls. Subsequently, we did an extensive functional assessment of the candidate genes to explore their causality in IBD pathogenesis. RESULTS: Ten single nucleotide polymorphisms (SNPs) in four genes were significantly associated with CD: CYLD, USP40, APEH and USP3. CYLD was the most significant gene with the intronically located rs12324931 the strongest associated SNP (pFDR=1.74e-17, OR=2.24 (1.83 to 2.74)). Five SNPs in four genes were significantly associated with UC: USP40, APEH, DAG1 and USP3. CYLD, as well as some of the other associated genes, is part of the ubiquitin proteasome system (UPS). We therefore determined if the IBD-associated adherent-invasive Escherichia coli (AIEC) can modulate the UPS functioning. Infection of intestinal epithelial cells with the AIEC LF82 reference strain modulated the UPS turnover by reducing poly-ubiquitin conjugate accumulation, increasing 26S proteasome activities and decreasing protein levels of the NF-kappaB regulator CYLD. This resulted in IkappaB-alpha degradation and NF-kappaB activation. This activity was very important for the pathogenicity of AIEC since decreased CYLD resulted in increased ability of AIEC LF82 to replicate intracellularly. CONCLUSIONS: Our results reveal the UPS, and CYLD specifically, as an important contributor to IBD pathogenesis, which is favoured by both genetic and microbial factors. [less ▲]Detailed reference viewed: 20 (1 ULg)
Genetic variations in toll-like receptor pathway and lung function decline in Cystic fibrosis patients.
; Mahachie John, Jestinah ; Van Steen, Kristel et al
in Human immunology (2013), 74(12), 1649-55
The toll-like receptor (TLR) family maintains pulmonary homeostasis by pathogen recognition, clearance and regulation of inflammation. Genes affecting inflammation response play a key role in modifying ... [more ▼]
The toll-like receptor (TLR) family maintains pulmonary homeostasis by pathogen recognition, clearance and regulation of inflammation. Genes affecting inflammation response play a key role in modifying Cystic fibrosis (CF) lung disease severity. We assessed the impact of single nucleotide polymorphisms (SNPs) of TLR genes (TLR1 to TLR10, CD14, lipopolyssacharide-binding protein (LBP)) on lung function in CF patients. Each SNP was tested for time-dependent effect on FEV1, using six genetic models. In addition, we investigated associations between SNP genotypes and extreme subject specific slopes of FEV1 decline. Variant alleles of polymorphisms of TLR2 rs1898830, rs5743708, and rs3804100 demonstrated a consistent association with lung disease severity (p = 0.008, p = 0.006 and p = 0.029 respectively). Patients homozygous for variant C allele of TLR5 polymorphism rs5744174 are more frequently associated with extreme fast FEV1 decline (OR: 20 (95% Confidence Interval:1.85-216.18)). Patients homozygous AA for TLR1 polymorphism rs5743551 are more frequently associated with faster decline of FEV1 compared to heterozygous genotype (OR:7.33 (95% CI:1.63-33.11). Our findings indicate that variations in TLR1, TLR2 and TLR5 genes may influence CF lung function decline. Further functional analysis is required to provide new insights into the pathogenesis of TLRs in CF lung disease severity. [less ▲]Detailed reference viewed: 11 (1 ULg)
Large Sample Size, Wide Variant Spectrum, and Advanced Machine-Learning Technique Boost Risk Prediction for Inflammatory Bowel Disease.
; ; et al
in American Journal of Human Genetics (2013)
We performed risk assessment for Crohn's disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory bowel disease (IBD), by using data from the International IBD Genetics Consortium's ... [more ▼]
We performed risk assessment for Crohn's disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory bowel disease (IBD), by using data from the International IBD Genetics Consortium's Immunochip project. This data set contains ?17,000 CD cases, ?13,000 UC cases, and ?22,000 controls from 15 European countries typed on the Immunochip. This custom chip provides a more comprehensive catalog of the most promising candidate variants by picking up the remaining common variants and certain rare variants that were missed in the first generation of GWAS. Given this unprecedented large sample size and wide variant spectrum, we employed the most recent machine-learning techniques to build optimal predictive models. Our final predictive models achieved areas under the curve (AUCs) of 0.86 and 0.83 for CD and UC, respectively, in an independent evaluation. To our knowledge, this is the best prediction performance ever reported for CD and UC to date. [less ▲]Detailed reference viewed: 9 (1 ULg)