Showing papers by "Stephan Brand published in 2013"
Wellcome Trust Sanger Institute1, University of Oslo2, Oslo University Hospital3, University of Kiel4, Norwich University5, Max Planck Society6, University of Groningen7, Hannover Medical School8, University of Calgary9, University of Toronto10, National Institute for Health Research11, University of Barcelona12, Mayo Clinic13, Pomeranian Medical University14, Ludwig Maximilian University of Munich15, University of Hamburg16, Charité17, University of Cambridge18, University of Thessaly19, University of Bonn20, Technische Universität München21, University of California, Berkeley22, University of Mainz23, University of Alberta24, University of Helsinki25, National Institutes of Health26, Sapienza University of Rome27, University of Padua28, University of Virginia29, University of California, San Diego30, University of Lübeck31, Norwegian University of Science and Technology32, Katholieke Universiteit Leuven33, Queen Mary University of London34, Akershus University Hospital35, Mount Sinai Hospital, Toronto36, University of Pittsburgh37, Karolinska University Hospital38, Casa Sollievo della Sofferenza39, Cleveland Clinic40, Cleveland Clinic Lerner Research Institute41, University of Paris42, University of California, Davis43, Université de Montréal44, Montreal Heart Institute45, Yale University46
TL;DR: This analysis compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip to identify 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16.
Abstract: Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.
309 citations
04 Jul 2013
Abstract: Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.
288 citations
TL;DR: New onset psoriasiform skin lesions develop in nearly 5% of anti-TNF-treated patients with IBD, and smoking is identified as a main risk factor for developing these lesions.
Abstract: Background We analysed incidence, predictors, histological features and specific treatment options of anti-tumour necrosis factor α (TNF-α) antibody-induced psoriasiform skin lesions in patients with inflammatory bowel diseases (IBD). Design Patients with IBD were prospectively screened for anti-TNF-induced psoriasiform skin lesions. Patients were genotyped for IL23R and IL12B variants. Skin lesions were examined for infiltrating Th1 and Th17 cells. Patients with severe lesions were treated with the anti-interleukin (IL)-12/IL-23 p40 antibody ustekinumab. Results Among 434 anti-TNF-treated patients with IBD, 21 (4.8%) developed psoriasiform skin lesions. Multiple logistic regression revealed smoking (p=0.007; OR 4.24, 95% CI 1.55 to 13.60) and an increased body mass index (p=0.029; OR 1.12, 95% CI 1.01 to 1.24) as main predictors for these lesions. Nine patients with Crohn9s disease and with severe psoriasiform lesions and/or anti-TNF antibody-induced alopecia were successfully treated with the anti-p40-IL-12/IL-23 antibody ustekinumab (response rate 100%). Skin lesions were histologically characterised by infiltrates of IL-17A/IL-22-secreting T helper 17 (Th17) cells and interferon (IFN)-γ-secreting Th1 cells and IFN-α-expressing cells. IL-17A expression was significantly stronger in patients requiring ustekinumab than in patients responding to topical therapy (p=0.001). IL23R genotyping suggests disease-modifying effects of rs11209026 (p.Arg381Gln) and rs7530511 (p.Leu310Pro) in patients requiring ustekinumab. Conclusions New onset psoriasiform skin lesions develop in nearly 5% of anti-TNF-treated patients with IBD. We identified smoking as a main risk factor for developing these lesions. Anti-TNF-induced psoriasiform skin lesions are characterised by Th17 and Th1 cell infiltrates. The number of IL-17A-expressing T cells correlates with the severity of skin lesions. Anti-IL-12/IL-23 antibody therapy is a highly effective therapy for these lesions.
266 citations
University of Kiel1, Technische Universität München2, Charité3, University of Bonn4, Boston Children's Hospital5, Hannover Medical School6, University of Düsseldorf7, University of Tokyo8, University of Michigan9, Veterans Health Administration10, Anhui Medical University11, University of Basel12, University of Pittsburgh13, Ludwig Maximilian University of Munich14, RWTH Aachen University15, Our Lady's Children's Hospital16, University of Dundee17
TL;DR: The number of atopic dermatitis risk loci reported in individuals of European ancestry is increased to 11, and it is estimated that these susceptibility loci together account for 14.4% of the heritability for atopy dermatitis.
Abstract: Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis.
165 citations
University of Kiel1, Sichuan University2, University of Cambridge3, University of California, San Diego4, Rutgers University5, Saarland University6, Harvard University7, Broad Institute8, University of Oxford9, Lithuanian University of Health Sciences10, Max Planck Society11, Greifswald University Hospital12, Erasmus University Rotterdam13, University Medical Center Groningen14, University of Amsterdam15, St George's, University of London16, University of Bristol17, Katholieke Universiteit Leuven18, National Health Service19, King's College London20, University of Bonn21, University of Pittsburgh22, Charité23, Ludwig Maximilian University of Munich24, RWTH Aachen University25, Technische Universität München26, Hannover Medical School27, Casa Sollievo della Sofferenza28, Örebro University29, Karolinska Institutet30, University of Bergen31, Oslo University Hospital32
TL;DR: Evidence is provided that variants in PRDM1 and NDP52 determine susceptibility to CD, and this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.
150 citations
TL;DR: IRGM is confirmed as susceptibility gene for CD in the German population, supporting a role for the autophagy genes IRGM and ATG16L1 in the pathogenesis of CD.
Abstract: Genome-wide association studies identified the autophagy gene IRGM to be strongly associated with Crohn's disease (CD) but its impact in ulcerative colitis (UC), its phenotypic effects and potential epistatic interactions with other IBD susceptibility genes are less clear which we therefore analyzed in this study.
Genomic DNA from 2060 individuals including 817 CD patients, 283 UC patients, and 961 healthy, unrelated controls (all of Caucasian origin) was analyzed for six IRGM single nucleotide polymorphisms (SNPs) (rs13371189, rs10065172 = p.Leu105Leu, rs4958847, rs1000113, rs11747270, rs931058). In all patients, a detailed genotype-phenotype analysis and testing for epistasis with the three major CD susceptibility genes NOD2, IL23R and ATG16L1 were performed. Our analysis revealed an association of the IRGM SNPs rs13371189 (p = 0.02, OR 1.31 [95% CI 1.05-1.65]), rs10065172 = p.Leu105Leu (p = 0.016, OR 1.33 [95% CI 1.06-1.66]) and rs1000113 (p = 0.047, OR 1.27 [95% CI 1.01-1.61]) with CD susceptibility. There was linkage disequilibrium between these three IRGM SNPs. In UC, several IRGM haplotypes were weakly associated with UC susceptibility (p<0.05). Genotype-phenotype analysis revealed no significant associations with a specific IBD phenotype or ileal CD involvement. There was evidence for weak gene-gene-interaction between several SNPs of the autophagy genes IRGM and ATG16L1 (p<0.05), which, however, did not remain significant after Bonferroni correction.
Our results confirm IRGM as susceptibility gene for CD in the German population, supporting a role for the autophagy genes IRGM and ATG16L1 in the pathogenesis of CD.
59 citations
TL;DR: The role of DMBT1 single nucleotide polymorphisms regarding inflammatory bowel disease (IBD) susceptibility and their functional impact on transcription factor binding and downstream gene expression are analyzed to suggest an important role of this gene in CD pathogenesis.
Abstract: Objectives: DMBT is an antibacterial pattern recognition and scavenger receptor In this study, we analyzed the role of DMBT1 single nucleotide polymorphisms (SNPs) regarding inflammatory bowel disease (IBD) susceptibility and examined their functional impact on transcription factor binding and downstream gene expression Methods: Seven SNPs in the DMBT1 gene region were analyzed in 2073 individuals including 818 Crohn’s disease (CD) patients and 972 healthy controls in two independent case-control panels Comprehensive epistasis analyses for the known CD susceptibility genes NOD2, IL23R and IL27 were performed The influence of IL23R variants on DMBT1 expression was analyzed Functional analysis included siRNA transfection, quantitative PCR, western blot, electrophoretic mobility shift and luciferase assays Results: IL-22 induces DMBT1 protein expression in intestinal epithelial cells dependent on STAT3, ATF-2 and CREB1 IL-22 expression-modulating, CD risk-associated IL23R variants influence DMBT1 expression in CD patients and DMBT1 levels are increased in the inflamed intestinal mucosa of CD patients Several DMBT1 SNPs were associated with CD susceptibility SNP rs2981804 was most strongly associated with CD in the combined panel (p=30610 27 , OR 142; 95% CI 124–163) All haplotype groups tested showed highly significant associations with CD (including omnibus P-values as low as 61610 218 ) The most strongly CD risk-associated, non-coding DMBT1 SNP rs2981804 modifies the DNA binding sites for the transcription factors CREB1 and ATF-2 and the respective genomic region comprising rs2981804 is able to act as a transcriptional regulator in vitro Intestinal DMBT1 expression is decreased in CD patients carrying the rs2981804 CD risk
25 citations
TL;DR: The administration of JWH-133 or GP 1a represents a promising new treatment option for portal hypertension triggered by microbiological products and plays a functional role in this novel pathway.
14 citations
TL;DR: This European multicentre study analysed more than 1500 patients with Crohn's disease for CD susceptibility variants, identified in the meta-analysis of genome-wide association studies (GWAS) by Barrett et al, regarding predictors for CD outcomes such as disease localisation and disease behaviour.
Abstract: In the past decade, we have witnessed enormous progress in the understanding of the genetics of inflammatory bowel diseases (IBD), resulting in the discovery and confirmation of 163 IBD susceptibility regions by the end of 20121–3 which is the highest number of susceptibility genes discovered for any complex disease so far. However, clinically highly relevant gene associations are still very limited, thereby also limiting the use of genetic information in the current treatment of IBD patients. The European IBDchip project4 represents a large detailed genotype-phenotype analysis of IBD patients and starts to fill the gap between IBD genetics and clinically relevant information.
This European multicentre study analysed more than 1500 patients with Crohn's disease (CD) for CD susceptibility variants, identified in the meta-analysis of genome-wide association studies (GWAS) by Barrett et al ,5 regarding predictors for CD outcomes such as disease localisation and disease behaviour.4 The main result of this study was the identification of NOD2 as the most important genetic predictor for ileal disease, ileal stenoses, fistula and CD-related surgery. This confirms previous reports showing particularly strong associations with ileal involvement, ileal stenosis and need for surgery in patients homozygous for the p.Leu1007fsX1008 NOD2 variant.6 ,7 An inadequate immune response to bacterial antigens in patients with mutated NOD2 gene resulting in chronic ileal inflammation seems to be the starting point for a sequel of events leading to ileal stenoses and thereby increasing the risk for fistula formation,8 finally requiring surgery.6
Janus kinase 2 ( JAK2 ) was the other gene significantly associated with ileocolonic disease involvement and stenosing disease behaviour, although the disease associations with JAK2 were weaker than that with NOD2 .4 JAK2 is a key component of the signal transduction pathway of several cytokines including interleukin (IL)-12 and IL-23 which …
12 citations
TL;DR: Preliminary results from the international inflammatory bowel disease genetics consortium (IIBDGC) immunochip study show promising results in clinical and molecular characterization of medically refractory acute, severe colitis.
7 citations
TL;DR: The analysis showed a high overall incidence of thoracic injuries in car passengers, with a significant relationship between accident deceleration speed, AIS Thorax and the incidence of pneumothoraces.
Abstract: Thoracic injuries are common in vehicle crashes, but only a few studies thus far have analysed the relationship between injury characteristics and collision details and discussed the possible implications for future vehicle design and prevention. In this study, the crash details were prospectively collected at the scene of injury between 2004 and 2009 for severely injured patients. The collected data included the type of collision, angle of impact and change of velocity on impact as well as injury characteristics and patient demographics, including abbreviated injury scale (AIS) and injury severity score (ISS).There were 5998 accidents involving 8830 patients over this five-year period; 31 met the inclusion criteria (23 males and eight females). The mean ISS was 37 ± 12.68, the mean AIS Thorax was 4.0. Lung contusions were found in 90% of the patients, pneumothoraces in 58% and rib fractures in 81%. There was a significant relationship between accident deceleration speed (ΔV), AIS Thorax (p = 0.02) and th...
TL;DR: The occurrence of the three described cases suggests the possibility of a common exposure in Chicago, and an epidemiologic investigation would have been needed to implicate a venue or a food item; anecdotal exposure data do not suffi ce.