Sequencing of DISC1 pathway genes reveals increased burden of rare missense variants in schizophrenia patients from a northern Swedish population.
; ; et al
in PloS one (2011), 6(8), 23450
In recent years, DISC1 has emerged as one of the most credible and best supported candidate genes for schizophrenia and related neuropsychiatric disorders. Furthermore, increasing evidence--both genetic ... [more ▼]
In recent years, DISC1 has emerged as one of the most credible and best supported candidate genes for schizophrenia and related neuropsychiatric disorders. Furthermore, increasing evidence--both genetic and functional--indicates that many of its protein interaction partners are also involved in the development of these diseases. In this study, we applied a pooled sample 454 sequencing strategy, to explore the contribution of genetic variation in DISC1 and 10 of its interaction partners (ATF5, Grb2, FEZ1, LIS-1, PDE4B, NDE1, NDEL1, TRAF3IP1, YWHAE, and ZNF365) to schizophrenia susceptibility in an isolated northern Swedish population. Mutation burden analysis of the identified variants in a population of 486 SZ patients and 514 control individuals, revealed that non-synonymous rare variants with a MAF<0.01 were significantly more present in patients compared to controls (8.64% versus 4.7%, P = 0.018), providing further evidence for the involvement of DISC1 and some of its interaction partners in psychiatric disorders. This increased burden of rare missense variants was even more striking in a subgroup of early onset patients (12.9% versus 4.7%, P = 0.0004), highlighting the importance of studying subgroups of patients and identifying endophenotypes. Upon investigation of the potential functional effects associated with the identified missense variants, we found that approximately 90% of these variants reside in intrinsically disordered protein regions. The observed increase in mutation burden in patients provides further support for the role of the DISC1 pathway in schizophrenia. Furthermore, this study presents the first evidence supporting the involvement of mutations within intrinsically disordered protein regions in the pathogenesis of psychiatric disorders. As many important biological functions depend directly on the disordered state, alteration of this disorder in key pathways may represent an intriguing new disease mechanism for schizophrenia and related neuropsychiatric diseases. Further research into this unexplored domain will be required to elucidate the role of the identified variants in schizophrenia etiology. [less ▲]Detailed reference viewed: 24 (8 ULg)
A report of the first biennial meeting on Capita Selecta in Complex Disease Analysis (CSCDA2010), Leuven, Belgium, August 25-27, 2010.
Van Steen, Kristel ;
in Annals of Human Genetics (2011), 75(4), 554-7
There is a need for interdisciplinary assessments and interpretations of -omics underpinnings of human complex diseases. However, often investigators from different, yet overlapping, disciplines ... [more ▼]
There is a need for interdisciplinary assessments and interpretations of -omics underpinnings of human complex diseases. However, often investigators from different, yet overlapping, disciplines experience difficulties in understanding the other discipline's language and there is a clear need for establishing a platform that nourishes interdisciplinary team processes and allows tearing down the professional's tower of Babel. To accommodate these needs, the biennial mini-conference Capita Selecta in Complex Disease Analysis was instigated. Abstracts are freely available online [http://www.aimontefiore.org/cscda2010/]. [less ▲]Detailed reference viewed: 7 (4 ULg)
Levels of C-reactive protein are associated with response to infliximab therapy in patients with Crohn's disease.
; Mahachie John, Jestinah ; et al
in Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of The American Gastroenterological Association (2011), 9(5), 421-71
BACKGROUND & AIMS: Infliximab is an antibody against tumor necrosis factor-alpha that is used to treat patients with moderate to severe Crohn's disease (CD). C-reactive protein (CRP) is a marker used to ... [more ▼]
BACKGROUND & AIMS: Infliximab is an antibody against tumor necrosis factor-alpha that is used to treat patients with moderate to severe Crohn's disease (CD). C-reactive protein (CRP) is a marker used to identify and follow individuals with CD. We analyzed changes in levels of CRP in a large cohort of patients with CD undergoing treatment with infliximab. METHODS: Serial levels of CRP were analyzed in 718 CD patients. Blood was collected before each infusion; a total of 8845 CRP levels were available for analysis. The correlations between CRP levels and need for dose adjustment, outcomes, and mucosal healing (based on endoscopic analysis of 253 patients) were evaluated. Therapy adjustment was considered successful if therapy continued without need for change. Subgroup analysis was performed by using data from 268 patients who received 8 weeks of maintenance therapy. RESULTS: More patients with high baseline levels of CRP responded to infliximab than patients with normal levels (90.8% vs 82.6%; P = .014). Early normalization of CRP levels correlated with sustained long-term response (P < .001). CRP levels remained significantly higher among patients who lost their response to infliximab, compared with those with a sustained response (P = .001). At time of loss of response, CRP levels were significantly increased (median, 11.2 mg/L) and did not return to baseline levels (median, 18.2 mg/L; P = .039). CRP correlated with mucosal healing (P = .033). CONCLUSIONS: CRP is a good marker of disease activity in patients treated with infliximab. Increased levels of CRP indicate mucosal inflammation and a likelihood of clinical relapse. [less ▲]Detailed reference viewed: 21 (3 ULg)
Identification of a novel autoantigen in inflammatory bowel disease by protein microarray.
; ; et al
in Inflammatory Bowel Diseases (2011), 17(6), 1291-300
BACKGROUND: Patients with inflammatory bowel disease (IBD) display immunoreactivity to self-antigens and microbial antigens. We used a protein microarray approach to identify novel autoantigens in IBD ... [more ▼]
BACKGROUND: Patients with inflammatory bowel disease (IBD) display immunoreactivity to self-antigens and microbial antigens. We used a protein microarray approach to identify novel autoantigens in IBD. METHODS: ProtoArray Human Protein Microarray v4.0 containing 8268 human proteins from Invitrogen (La Jolla, CA) was used. RESULTS: Twenty-five IBD patients and five healthy controls were screened for candidate autoantigens. For 256 antigens, IBD patients had a higher seroreactivity than controls. Twenty antigens were selected for further evaluation in a larger cohort (60 ulcerative colitis [UC] patients, 60 Crohn's disease [CD] patients, 60 healthy controls, and 60 gastrointestinal-diseased controls) by means of a customized protein microarray. Out of these 20 antigens, one antigen, family with sequence similarity 84 member A (FAM84A), was identified as a target antigen in IBD. Antibodies to FAM84A were significantly more prevalent in IBD patients (19%) than in gastrointestinal-diseased controls (1.7%) (P = 0.0008) and healthy controls (5%) (P = 0.01). Anti-FAM84A antibodies were found in 26.6% of UC patients and in 11.7% of CD patients. FAM84A was confirmed as target antigen in IBD by means of Western blotting in a large independent cohort (100 UC patients, 106 CD patients, 102 healthy controls, and 100 gastrointestinal-diseased controls). Antibodies to FAM84A were significantly more prevalent in IBD patients (20%) than in gastrointestinal-diseased controls (5%) (P = 0.0004) and healthy controls (0%) (P < 0.0001). Anti-FAM84A antibodies were found in 18% of UC patients and in 22% of CD patients. CONCLUSIONS: We identified FAM84A as a novel autoantigen in IBD. (Inflamm Bowel Dis 2011;). [less ▲]Detailed reference viewed: 16 (3 ULg)
Investigating Hardy-Weinberg equilibrium in case-control or cohort studies or meta-analysis.
; Van Steen, Kristel ;
in Breast Cancer Research and Treatment (2011), 128(1), 197-201
Yu et al. (Breast Cancer Res Treat 117:675-677, 2009) recently stated that testing for deviation from Hardy-Weinberg equilibrium (HWE) is necessary to identify systematic genotyping errors in case-control ... [more ▼]
Yu et al. (Breast Cancer Res Treat 117:675-677, 2009) recently stated that testing for deviation from Hardy-Weinberg equilibrium (HWE) is necessary to identify systematic genotyping errors in case-control studies. They criticized a meta-analytic study for the deviation from HWE in the case group of one study. The aim of this article is twofold. First, we derive recommendations on how to test for deviations from HWE in different study designs. Second, we develop a meta-analytic framework for assessing compatibility with HWE or measuring deviation from HWE. The authors sketch the possible reasons behind deviation from HWE and provide guidelines for proper investigation of HWE deviations in different study designs. The authors argue that the standard HWE chi(2) lack of fit test is logically flawed and provide a logically unflawed approach for measuring deviation from HWE using confidence intervals. The proposed method is applicable to meta-analyses of both case-control or cohort association studies. The proposed approach is illustrated using the meta-analysis criticized by Yu et al. Heterogeneity between studies can be assessed. The critique of Yu et al. to the article of Frank et al. (Breast Cancer Res Treat 111:139-144, 2008) can be refuted. Even more, validity of HWE can be proven for the pooled control sample. The authors advocate the use of a confidence interval-based approach to assess HWE. The latter should only be investigated in control populations. In multicenter studies or meta-analysis, deviation from HWE should be analyzed using a meta-analytic approach. [less ▲]Detailed reference viewed: 27 (5 ULg)
Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis.
; ; Cattaert, Tom et al
in Journal of Allergy and Clinical Immunology (The) (2011), 128(5), 989-9958
BACKGROUND: Approximately 85% of nasal polyps (NPs) in white subjects are characterized by prominent eosinophilia. IL-5 is the key driver of eosinophilic differentiation and survival. OBJECTIVE: We sought ... [more ▼]
BACKGROUND: Approximately 85% of nasal polyps (NPs) in white subjects are characterized by prominent eosinophilia. IL-5 is the key driver of eosinophilic differentiation and survival. OBJECTIVE: We sought to investigate the therapeutic potential of inhibiting IL-5 with a humanized mAb as treatment for severe nasal polyposis. METHODS: Thirty patients with severe nasal polyposis (grade 3 or 4 or recurrent after surgery) refractory to corticosteroid therapy were randomized in a double-blind fashion to receive either 2 single intravenous injections (28 days apart) of 750 mg of mepolizumab (n = 20) or placebo (n = 10). Change from baseline in NP score was assessed monthly until 1 month after the last dose (week 8). Computed tomographic scans were also performed at week 8. RESULTS: Twelve of 20 patients receiving mepolizumab had a significantly improved NP score and computed tomographic scan score compared with 1 of 10 patients receiving placebo at week 8 versus baseline. CONCLUSION: Mepolizumab achieved a statistically significant reduction in NP size for at least 1 month after dosing in 12 of 20 patients. IL-5 inhibition is a potential novel therapeutic approach in patients with severe eosinophilic nasal polyposis. [less ▲]Detailed reference viewed: 25 (8 ULg)
Familial aggregation and antimicrobial response dose-dependently affect the risk for Crohn's disease.
; Van Steen, Kristel ; et al
in Inflammatory Bowel Diseases (2010), 16(1), 58-67
BACKGROUND:: An increased risk of Crohn's disease (CD) has been reported consistently in first-degree relatives of patients. Our aim was to test whether a combination of CD-associated genes involved in ... [more ▼]
BACKGROUND:: An increased risk of Crohn's disease (CD) has been reported consistently in first-degree relatives of patients. Our aim was to test whether a combination of CD-associated genes involved in innate immunity and/or antibody responses to microbial antigens may be valuable in identifying healthy relatives at risk. METHODS:: We investigated 86 families from Belgium and northern France, 45 with at least 3 first-degree relatives with CD, 24 with a single case, and 17 control families without inflammatory bowel disease (IBD). The cohort consisted of 186 CD patients, 290 healthy relatives, and 142 controls (total 618). Genetic (NOD2, NOD1, TLR4, CARD8) and serologic markers (ASCA, ACMA, ALCA, ACCA, ASigmaMA, OmpC, CBir1, I2) were determined in all subjects. All Belgian families were prospectively followed up for 54 months. RESULTS:: In multiple-affected families, an increment of affected first-degree relatives and of positive antibodies were additive risks factors for CD (P < 0.0001), independent of NOD2 mutations. When comparing subjects from multiple-affected families, having 3 additional first-degree relatives with CD and 1 additional positive antibody increased the odds for CD to 9.19 (95% confidence interval [CI]: 4.07-20.80). After a follow-up of 54 months among all Belgian families, a total of 4 new diagnoses of IBD were confirmed in the multiple-affected families only, resulting in a 57-fold increase in incidence within multiple-affected families compared to the known incidence of IBD in our region. CONCLUSIONS:: We found an additive risk increment for CD in subjects from multicase families per additional affected relative and per additional positive antibody, independent of NOD2. Furthermore, a very high disease incidence was observed in these multiple-affected families. Inflamm Bowel Dis 2010. [less ▲]Detailed reference viewed: 31 (3 ULg)
Longitudinal study of European birth cohorts on pet ownership up to age 10 years as a risk for childhood asthma - a GA²LEN project
Mahachie John, Jestinah ; ; et al
in European Respiratory Journal. Supplement (2010), 36(supplement 54),Detailed reference viewed: 31 (6 ULg)
Predictive value of epithelial gene expression profiles for response to infliximab in Crohn’s disease
; ; et al
in Inflammatory Bowel Diseases (2010), 16(12), 2090-2098Detailed reference viewed: 23 (7 ULg)
Presence of IL-5 and Ige-antibodies to staphylococcal enterotoxins in nasal polyps is associated with co-morbid asthma
; ; et al
in Journal of Allergy and Clinical Immunology (The) (2010), 126(5), 962-968Detailed reference viewed: 21 (7 ULg)
Molecular Reclassification of Crohn’s Disease by cluster analysis of genetic variants.
; Mahachie John, Jestinah ; et al
in Acta Gastro-Enterologica Belgica (2010)Detailed reference viewed: 38 (20 ULg)
Tolerability of shortened infliximab infusion times in patients with inflammatory bowel disease: a single center cohort study
; ; et al
in Gut (2010)Detailed reference viewed: 4 (1 ULg)
Intestinal mucosal gene expression of endothelial cell adhesion molecules in patients with inflammatory bowel disease before and after first infliximab treatment.
; ; et al
in Acta Gastro-Enterologica Belgica (2010)Detailed reference viewed: 27 (12 ULg)
The impact of infliximab therapy on intestinal mucosal gene expression of endothelial cell adhesion molecules in patients with inflammatory bowel disease
; ; et al
in Gastroenterology (2010), 138(5 Suppl I), -677Detailed reference viewed: 9 (3 ULg)
A screening methodology based on Random Forests to improve the detection of gene-gene interactions
; Geurts, Pierre ; et al
in European Journal of Human Genetics (2010), 18(1127), 1132
The search for susceptibility loci in gene-gene interactions imposes a methodological and computational challenge for statisticians because of the large dimensionality inherent to the modelling of gene ... [more ▼]
The search for susceptibility loci in gene-gene interactions imposes a methodological and computational challenge for statisticians because of the large dimensionality inherent to the modelling of gene-gene interactions or epistasis. In an era in which genome-wide scans have become relatively common, new powerful methods are required to handle the huge amount of feasible gene-gene interactions and to weed out false positives and negatives from these results. One solution to the dimensionality problem is to reduce data by preliminary screening of markers to select the best candidates for further analysis. Ideally, this screening step is statistically independent of the testing phase. Initially developed for small numbers of markers, the Multifactor Dimensionality Reduction (MDR) method is a nonparametric, model-free data reduction technique to associate sets of markers with optimal predictive properties to disease. In this study, we examine the power of MDR in larger data sets and compare it with other approaches that are able to identify gene-gene interactions. Under various interaction models (purely and not purely epistatic), we use a Random Forest (RF)-based prescreening method, before executing MDR, to improve its performance. We find that the power of MDR increases when noisy SNPs are first removed, by creating a collection of candidate markers with RFs. We validate our technique by extensive simulation studies and by application to asthma data from the European Committee of Respiratory Health Study II.European Journal of Human Genetics advance online publication, 12 May 2010; doi:10.1038/ejhg.2010.48. [less ▲]Detailed reference viewed: 50 (12 ULg)
Kinetics of C-Reactive Protein (CRP) following maintenance infliximab treatment in Crohn's disease identifies profiles of patients with better outcome
; Mahachie John, Jestinah ; et al
in Gastroenterology (2010), 138(5 (Suppl I)), -686Detailed reference viewed: 18 (9 ULg)
In utero smoke exposure and impaired response to inhaled corticosteroids in children with asthma
; ; Van Steen, Kristel et al
in Journal of Allergy and Clinical Immunology (The) (2010), 126(3), 491-497Detailed reference viewed: 20 (7 ULg)
Intestinal mucosal gene expression of endothelial cell adhesion molecules in patients with inflammatory bowel disease and the impact of infliximab therapy.
; ; et al
in Journal of Crohn’s and Colitis [=JCC] (2010)Detailed reference viewed: 19 (12 ULg)
mbmdr: an R package for exploring gene-gene interactions associated with binary or quantitative traits
; ; Van Steen, Kristel
in Bioinformatics (2010), 26(17), 2198-2199Detailed reference viewed: 43 (7 ULg)