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1. Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome

Author: Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, D., Vatn, S., Ventham, N. A., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, J., Satsangi, J., Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, D., Vatn, S., Ventham, N. A., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, J., and Satsangi, J.
Abstract: Background Epigenetic alterations may provide valuable insights into gene-environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. Methods Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohns disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Results A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [p = 9.11 x 10(-15)] and RPS6KA2 [6.43 x 10(-13)], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [p = 1.53 x 10(-15)]. Age acceleration is seen in IBD [coefficient 0.94, p < 2.2 x 10(-16)]. Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r = -0.32, p = 3.64 x 10(-7) vs non-IBD r = -0.14, p = 0.77]. Multi-omic integration of the methylome, genome and transcriptome also implicated specific pathways that associate with immune activation, response and regulation at disease inception. At follow-up, a signature of three DMPs [TAP1, TESPA1, RPTOR] were associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 [CI: 2.14-12.56], logrank p = 9.70 x 10(-4)). Conclusion These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease., Funding Agencies|European Commission [2858546]; Wellcome Trust [WT097943MA]
Published: 2023
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2. Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome

Author: Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, D., Vatn, S., Ventham, N. A., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, J., Satsangi, J., Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, D., Vatn, S., Ventham, N. A., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, J., and Satsangi, J.
Abstract: Background Epigenetic alterations may provide valuable insights into gene-environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. Methods Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohns disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Results A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [p = 9.11 x 10(-15)] and RPS6KA2 [6.43 x 10(-13)], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [p = 1.53 x 10(-15)]. Age acceleration is seen in IBD [coefficient 0.94, p < 2.2 x 10(-16)]. Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r = -0.32, p = 3.64 x 10(-7) vs non-IBD r = -0.14, p = 0.77]. Multi-omic integration of the methylome, genome and transcriptome also implicated specific pathways that associate with immune activation, response and regulation at disease inception. At follow-up, a signature of three DMPs [TAP1, TESPA1, RPTOR] were associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 [CI: 2.14-12.56], logrank p = 9.70 x 10(-4)). Conclusion These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease., Funding Agencies|European Commission [2858546]; Wellcome Trust [WT097943MA]
Published: 2023
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3. Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome

Author: Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, D., Vatn, S., Ventham, N. A., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, J., Satsangi, J., Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, D., Vatn, S., Ventham, N. A., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, J., and Satsangi, J.
Abstract: Background Epigenetic alterations may provide valuable insights into gene-environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. Methods Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohns disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Results A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [p = 9.11 x 10(-15)] and RPS6KA2 [6.43 x 10(-13)], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [p = 1.53 x 10(-15)]. Age acceleration is seen in IBD [coefficient 0.94, p < 2.2 x 10(-16)]. Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r = -0.32, p = 3.64 x 10(-7) vs non-IBD r = -0.14, p = 0.77]. Multi-omic integration of the methylome, genome and transcriptome also implicated specific pathways that associate with immune activation, response and regulation at disease inception. At follow-up, a signature of three DMPs [TAP1, TESPA1, RPTOR] were associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 [CI: 2.14-12.56], logrank p = 9.70 x 10(-4)). Conclusion These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease., Funding Agencies|European Commission [2858546]; Wellcome Trust [WT097943MA]
Published: 2023
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4. Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome

Author: Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, D., Vatn, S., Ventham, N. A., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, J., Satsangi, J., Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, D., Vatn, S., Ventham, N. A., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, J., and Satsangi, J.
Abstract: Background Epigenetic alterations may provide valuable insights into gene-environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. Methods Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohns disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Results A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [p = 9.11 x 10(-15)] and RPS6KA2 [6.43 x 10(-13)], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [p = 1.53 x 10(-15)]. Age acceleration is seen in IBD [coefficient 0.94, p < 2.2 x 10(-16)]. Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r = -0.32, p = 3.64 x 10(-7) vs non-IBD r = -0.14, p = 0.77]. Multi-omic integration of the methylome, genome and transcriptome also implicated specific pathways that associate with immune activation, response and regulation at disease inception. At follow-up, a signature of three DMPs [TAP1, TESPA1, RPTOR] were associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 [CI: 2.14-12.56], logrank p = 9.70 x 10(-4)). Conclusion These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease., Funding Agencies|European Commission [2858546]; Wellcome Trust [WT097943MA]
Published: 2023
Full Text: View/download PDF

5. Analysis of systemic epigenetic alterations in inflammatory bowel disease : defining geographical, genetic, and immune-inflammatory influences on the circulating methylome

Author: Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, Daniel, Vatn, S., Ventham, N. T., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, J., Pierik, M., D'Amato, M., Gomollón, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, Jonas, Satsangi, J., Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, Daniel, Vatn, S., Ventham, N. T., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, J., Pierik, M., D'Amato, M., Gomollón, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, Jonas, and Satsangi, J.
Abstract: BACKGROUND: Epigenetic alterations may provide valuable insights into gene-environment interactions play in the pathogenesis of Inflammatory Bowel Disease (IBD). METHODS: Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 CD, 161 UC, 28 IBD-U) with covariates of age, sex, and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission. RESULTS: A total of 137 differentially methylated positions (DMP) were identified in IBD, including VMP1/MIR21 (p=9.11×10 -15) and RPS6KA2 (6.43×10 -13); with consistency seen across Scandinavia and UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 (p=1.53×10 -15). Age acceleration is seen in IBD (coefficient 0.94, p<2.2x10 -16). Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r -0.32, p 3.64×10 -7 vs. non-IBD r -0.14, p=0.77). Multi-omic integration of methylome, genome and transcriptome also implicate specific pathways that associate with immune activation, response and regulation at disease inception. At follow up, a signature of 3 DMPs (TAP1, TESPA1, RPTOR) associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 (CI:2.14-12.56, logrank p=9.70×10 -4). CONCLUSION: These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease.
Published: 2023
Full Text: View/download PDF

6. Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome

Author: Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, D., Vatn, S., Ventham, N. A., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, J., Satsangi, J., Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, D., Vatn, S., Ventham, N. A., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, J., and Satsangi, J.
Abstract: Background Epigenetic alterations may provide valuable insights into gene-environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. Methods Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohns disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Results A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [p = 9.11 x 10(-15)] and RPS6KA2 [6.43 x 10(-13)], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [p = 1.53 x 10(-15)]. Age acceleration is seen in IBD [coefficient 0.94, p < 2.2 x 10(-16)]. Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r = -0.32, p = 3.64 x 10(-7) vs non-IBD r = -0.14, p = 0.77]. Multi-omic integration of the methylome, genome and transcriptome also implicated specific pathways that associate with immune activation, response and regulation at disease inception. At follow-up, a signature of three DMPs [TAP1, TESPA1, RPTOR] were associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 [CI: 2.14-12.56], logrank p = 9.70 x 10(-4)). Conclusion These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease., Funding Agencies|European Commission [2858546]; Wellcome Trust [WT097943MA]
Published: 2023
Full Text: View/download PDF

7. Trans-continental analysis of over, 2000 Inflammatory Bowel Disease patients implicates geography, disease type, and exposure to immunosuppression as drivers of SARS-CoV-2 seroprevalence : data from the ICARUS-IBD Consortium

Author: Wong, S. Y., Helmus, D., Marlow, L., Pazos, V. Martinez, Brann, S., Wellens, J., Kedia, S., Mak, J. W. Y., Bergemalm, Daniel, Argollo, M., Zaltman, C., Steinwurz, F., Rubin, D., Allez, M., Halfvarson, J., Abreu, M. T., Lindsay, J., Dutta, U., Silverberg, M. S., Ng, S. C., Ahuja, V., Watanabe, K., Vermeire, S., Colombel, J. F., Satsangi, J., Wong, S. Y., Helmus, D., Marlow, L., Pazos, V. Martinez, Brann, S., Wellens, J., Kedia, S., Mak, J. W. Y., Bergemalm, Daniel, Argollo, M., Zaltman, C., Steinwurz, F., Rubin, D., Allez, M., Halfvarson, J., Abreu, M. T., Lindsay, J., Dutta, U., Silverberg, M. S., Ng, S. C., Ahuja, V., Watanabe, K., Vermeire, S., Colombel, J. F., and Satsangi, J.
Published: 2022
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8. Trans-continental analysis of over, 2000 Inflammatory Bowel Disease patients implicates geography, disease type, and exposure to immunosuppression as drivers of SARS-CoV-2 seroprevalence : data from the ICARUS-IBD Consortium

Author: Wong, S. Y., Helmus, D., Marlow, L., Pazos, V. Martinez, Brann, S., Wellens, J., Kedia, S., Mak, J. W. Y., Bergemalm, Daniel, Argollo, M., Zaltman, C., Steinwurz, F., Rubin, D., Allez, M., Halfvarson, J., Abreu, M. T., Lindsay, J., Dutta, U., Silverberg, M. S., Ng, S. C., Ahuja, V., Watanabe, K., Vermeire, S., Colombel, J. F., Satsangi, J., Wong, S. Y., Helmus, D., Marlow, L., Pazos, V. Martinez, Brann, S., Wellens, J., Kedia, S., Mak, J. W. Y., Bergemalm, Daniel, Argollo, M., Zaltman, C., Steinwurz, F., Rubin, D., Allez, M., Halfvarson, J., Abreu, M. T., Lindsay, J., Dutta, U., Silverberg, M. S., Ng, S. C., Ahuja, V., Watanabe, K., Vermeire, S., Colombel, J. F., and Satsangi, J.
Published: 2022
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9. Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease

Author: Kalla, R., Adams, A. T., Bergemalm, D., Vatn, S., Kennedy, N. A., Ricanek, P., Lindstrom, J., Ocklind, A., Hjelm, F., Ventham, N. T., Ho, G. T., Petren, C., Repsilber, D., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Jahnsen, J., Vatn, M. H., Halfvarson, J., Satsangi, J., Kalla, R., Adams, A. T., Bergemalm, D., Vatn, S., Kennedy, N. A., Ricanek, P., Lindstrom, J., Ocklind, A., Hjelm, F., Ventham, N. T., Ho, G. T., Petren, C., Repsilber, D., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Jahnsen, J., Vatn, M. H., Halfvarson, J., and Satsangi, J.
Abstract: Background: Success in personalized medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay [PEA] to identify diagnostic and prognostic biomarkers in inflammatory bowel disease [IBD]. Methods: We conducted a prospective case-control study in an inception cohort of 552 patients [328 IBD, 224 non-IBD], profiling proteins recruited across six centres. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross-validation was used to examine the performance of diagnostic and prognostic proteins. Results: A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls, including matrix metallopeptidase-12 [MMP-12; Holm-adjusted p=4.1x10(-23)] and oncostatin-M [OSM; p=3.7x10(-16)]. Nine of these proteins are associated with cis-germline variation [59 independent single nucleotide polymorphisms]. Fifteen proteins, all members of tumour necrosis factor-independent pathways including interleukin-1 (IL-1) and OSM, predicted escalation, over a median follow-up of 518 [interquartile range 224-756] days. Nested cross-validation of the entire data set allowed characterization of five-protein models [96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7 and IL8], which define a high-risk subgroup in IBD [hazard ratio 3.90, confidence interval: 2.43-6.26], or allowed distinct two- and three-protein models for ulcerative colitis and Crohns disease respectively. Conclusion: We have characterized a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and to predict future disease course. Further prospective work is required to validate our findings., Funding Agencies|EU FP7 grant: IBD-CHARACTER [2858546]; Wellcome TrustWellcome TrustEuropean Commission
Published: 2021
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10. Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease

Author: Kalla, R., Adams, A. T., Bergemalm, Daniel, Vatn, S., Kennedy, N. A., Ricanek, P., Lindstrom, J., Ocklind, A., Hjelm, F., Ventham, N. T., Ho, G. T., Petren, C., Repsilber, Dirk, Söderholm, J., Pierik, M., D'Amato, M., Gomollón, F., Olbjorn, C., Jahnsen, J., Vatn, M. H., Halfvarson, Jonas, Satsangi, J., Kalla, R., Adams, A. T., Bergemalm, Daniel, Vatn, S., Kennedy, N. A., Ricanek, P., Lindstrom, J., Ocklind, A., Hjelm, F., Ventham, N. T., Ho, G. T., Petren, C., Repsilber, Dirk, Söderholm, J., Pierik, M., D'Amato, M., Gomollón, F., Olbjorn, C., Jahnsen, J., Vatn, M. H., Halfvarson, Jonas, and Satsangi, J.
Abstract: BACKGROUND: Success in personalised medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay (PEA) to identify diagnostic and prognostic biomarkers in inflammatory bowel disease (IBD). METHODS: We conducted a prospective case-control study in an inception cohort of 552 patients (328 IBD, 224 non-IBD), profiling proteins recruited across 6 centres. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross validation was used to examine the performance of diagnostic and prognostic proteins. RESULTS: A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls including MMP-12 (Holm adjusted p=4.1×10 -23 ) and OSM (p=3.7×10 -16). Nine of these proteins associate with cis- germline variation (59 independent SNPs). Fifteen proteins, all members of TNF independent pathways including IL-1 and OSM predicted escalation, over a median follow-up of 518 (IQR 224-756) days. Nested cross-validation of the entire data set allows characterisation of 5-protein-models (96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7, and IL8) which define a high-risk subgroup in IBD (HR 3.90, CI: 2.43-6.26), or allows distinct 2, and 3 protein models for UC and CD respectively. CONCLUSION: We have characterised a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and to predict future disease course. Further prospective work is required to validate our findings.
Published: 2021
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11. Precision medicine in inflammatory bowel disease: Concept, progress and challenges.

Author: Satsangi J., Kalla R., Borg-Bartolo S.P., Boyapati R.K., Satsangi J., Kalla R., Borg-Bartolo S.P., and Boyapati R.K.
Abstract: Crohn's disease and ulcerative colitis are increasingly prevalent, relapsing and remitting inflammatory bowel diseases (IBDs) with variable disease courses and complications. Their aetiology remains unclear but current evidence shows an increasingly complex pathophysiology broadly centring on the genome, exposome, microbiome and immunome. Our increased understanding of disease pathogenesis is providing an ever-expanding arsenal of therapeutic options, but these can be expensive and patients can lose response or never respond to certain therapies. Therefore, there is now a growing need to personalise therapies on the basis of the underlying disease biology and a desire to shift our approach from 'reactive' management driven by disease complications to 'proactive' care with an aim to prevent disease sequelae. Precision medicine is the tailoring of medical treatment to the individual patient, encompassing a multitude of data-driven (and multi-omic) approaches to foster accurate clinical decision-making. In IBD, precision medicine would have significant benefits, enabling timely therapy that is both effective and appropriate for the individual. In this review, we summarise some of the key areas of progress towards precision medicine, including predicting disease susceptibility and its course, personalising therapies in IBD and monitoring response to therapy. We also highlight some of the challenges to be overcome in order to deliver this approach.Copyright © 2020 Borg-Bartolo SP et al.
Published: 2020

12. Precision medicine in inflammatory bowel disease: Concept, progress and challenges.

Author: Satsangi J., Kalla R., Borg-Bartolo S.P., Boyapati R.K., Satsangi J., Kalla R., Borg-Bartolo S.P., and Boyapati R.K.
Abstract: Crohn's disease and ulcerative colitis are increasingly prevalent, relapsing and remitting inflammatory bowel diseases (IBDs) with variable disease courses and complications. Their aetiology remains unclear but current evidence shows an increasingly complex pathophysiology broadly centring on the genome, exposome, microbiome and immunome. Our increased understanding of disease pathogenesis is providing an ever-expanding arsenal of therapeutic options, but these can be expensive and patients can lose response or never respond to certain therapies. Therefore, there is now a growing need to personalise therapies on the basis of the underlying disease biology and a desire to shift our approach from 'reactive' management driven by disease complications to 'proactive' care with an aim to prevent disease sequelae. Precision medicine is the tailoring of medical treatment to the individual patient, encompassing a multitude of data-driven (and multi-omic) approaches to foster accurate clinical decision-making. In IBD, precision medicine would have significant benefits, enabling timely therapy that is both effective and appropriate for the individual. In this review, we summarise some of the key areas of progress towards precision medicine, including predicting disease susceptibility and its course, personalising therapies in IBD and monitoring response to therapy. We also highlight some of the challenges to be overcome in order to deliver this approach.Copyright © 2020 Borg-Bartolo SP et al.
Published: 2020

13. Whole Blood Profiling of T-cell-Derived microRNA Allows the Development of Prognostic models in Inflammatory Bowel Disease

Author: Kalla, R., Adams, A. T., Ventham, N. T., Kennedy, N. A., White, R., Clarke, C., Ivens, A., Bergemalm, D., Vatn, S., Lopez-Jimena, B., Ricanek, P., Vatn, M. H., Söderholm, Johan D, Gomollon, F., Nowak, J. K., Jahnsen, J., Halfvarson, J., McTaggart, S., Ho, G. T., Buck, A., Satsangi, J., Kalla, R., Adams, A. T., Ventham, N. T., Kennedy, N. A., White, R., Clarke, C., Ivens, A., Bergemalm, D., Vatn, S., Lopez-Jimena, B., Ricanek, P., Vatn, M. H., Söderholm, Johan D, Gomollon, F., Nowak, J. K., Jahnsen, J., Halfvarson, J., McTaggart, S., Ho, G. T., Buck, A., and Satsangi, J.
Abstract: Background: MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. Methods: In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohns disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. Results: In stage 1, each leukocyte subset [CD4(+) and CD8(+)T-cells and CD14(+) monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4(+) T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20-3.27; logrank p = 1.80 x 10(-3)), in particular CD [HR 2.81; IQR: 1.11-3.53, p = 6.50 x 10(-4)]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met. Interpretation: We have identified and validated unique CD4(+) T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated., Funding Agencies|Crohns and Colitis UK [CCUK] [M2016/2]; LifeArc, EdinburghBiotechnology and Biological Sciences Research Council (BBSRC)
Published: 2020
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14. Whole Blood Profiling of T-cell-Derived microRNA Allows the Development of Prognostic models in Inflammatory Bowel Disease

Author: Kalla, R., Adams, A. T., Ventham, N. T., Kennedy, N. A., White, R., Clarke, C., Ivens, A., Bergemalm, D., Vatn, S., Lopez-Jimena, B., Ricanek, P., Vatn, M. H., Söderholm, Johan D, Gomollon, F., Nowak, J. K., Jahnsen, J., Halfvarson, J., McTaggart, S., Ho, G. T., Buck, A., Satsangi, J., Kalla, R., Adams, A. T., Ventham, N. T., Kennedy, N. A., White, R., Clarke, C., Ivens, A., Bergemalm, D., Vatn, S., Lopez-Jimena, B., Ricanek, P., Vatn, M. H., Söderholm, Johan D, Gomollon, F., Nowak, J. K., Jahnsen, J., Halfvarson, J., McTaggart, S., Ho, G. T., Buck, A., and Satsangi, J.
Abstract: Background: MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. Methods: In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohns disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. Results: In stage 1, each leukocyte subset [CD4(+) and CD8(+)T-cells and CD14(+) monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4(+) T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20-3.27; logrank p = 1.80 x 10(-3)), in particular CD [HR 2.81; IQR: 1.11-3.53, p = 6.50 x 10(-4)]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met. Interpretation: We have identified and validated unique CD4(+) T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated., Funding Agencies|Crohns and Colitis UK [CCUK] [M2016/2]; LifeArc, EdinburghBiotechnology and Biological Sciences Research Council (BBSRC)
Published: 2020
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15. Whole Blood Profiling of T-cell-Derived microRNA Allows the Development of Prognostic models in Inflammatory Bowel Disease

Author: Kalla, R., Adams, A. T., Ventham, N. T., Kennedy, N. A., White, R., Clarke, C., Ivens, A., Bergemalm, D., Vatn, S., Lopez-Jimena, B., Ricanek, P., Vatn, M. H., Söderholm, Johan D, Gomollon, F., Nowak, J. K., Jahnsen, J., Halfvarson, J., McTaggart, S., Ho, G. T., Buck, A., Satsangi, J., Kalla, R., Adams, A. T., Ventham, N. T., Kennedy, N. A., White, R., Clarke, C., Ivens, A., Bergemalm, D., Vatn, S., Lopez-Jimena, B., Ricanek, P., Vatn, M. H., Söderholm, Johan D, Gomollon, F., Nowak, J. K., Jahnsen, J., Halfvarson, J., McTaggart, S., Ho, G. T., Buck, A., and Satsangi, J.
Abstract: Background: MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. Methods: In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohns disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. Results: In stage 1, each leukocyte subset [CD4(+) and CD8(+)T-cells and CD14(+) monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4(+) T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20-3.27; logrank p = 1.80 x 10(-3)), in particular CD [HR 2.81; IQR: 1.11-3.53, p = 6.50 x 10(-4)]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met. Interpretation: We have identified and validated unique CD4(+) T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated., Funding Agencies|Crohns and Colitis UK [CCUK] [M2016/2]; LifeArc, EdinburghBiotechnology and Biological Sciences Research Council (BBSRC)
Published: 2020
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16. Whole Blood Profiling of T-cell-Derived microRNA Allows the Development of Prognostic models in Inflammatory Bowel Disease

Author: Kalla, R., Adams, A. T., Ventham, N. T., Kennedy, N. A., White, R., Clarke, C., Ivens, A., Bergemalm, D., Vatn, S., Lopez-Jimena, B., Ricanek, P., Vatn, M. H., Söderholm, Johan D, Gomollon, F., Nowak, J. K., Jahnsen, J., Halfvarson, J., McTaggart, S., Ho, G. T., Buck, A., Satsangi, J., Kalla, R., Adams, A. T., Ventham, N. T., Kennedy, N. A., White, R., Clarke, C., Ivens, A., Bergemalm, D., Vatn, S., Lopez-Jimena, B., Ricanek, P., Vatn, M. H., Söderholm, Johan D, Gomollon, F., Nowak, J. K., Jahnsen, J., Halfvarson, J., McTaggart, S., Ho, G. T., Buck, A., and Satsangi, J.
Abstract: Background: MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. Methods: In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohns disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. Results: In stage 1, each leukocyte subset [CD4(+) and CD8(+)T-cells and CD14(+) monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4(+) T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20-3.27; logrank p = 1.80 x 10(-3)), in particular CD [HR 2.81; IQR: 1.11-3.53, p = 6.50 x 10(-4)]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met. Interpretation: We have identified and validated unique CD4(+) T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated., Funding Agencies|Crohns and Colitis UK [CCUK] [M2016/2]; LifeArc, EdinburghBiotechnology and Biological Sciences Research Council (BBSRC)
Published: 2020
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17. Whole Blood Profiling of T-cell-Derived microRNA Allows the Development of Prognostic models in Inflammatory Bowel Disease

Author: Kalla, R., Adams, A. T., Ventham, N. T., Kennedy, N. A., White, R., Clarke, C., Ivens, A., Bergemalm, D., Vatn, S., Lopez-Jimena, B., Ricanek, P., Vatn, M. H., Söderholm, Johan D, Gomollon, F., Nowak, J. K., Jahnsen, J., Halfvarson, J., McTaggart, S., Ho, G. T., Buck, A., Satsangi, J., Kalla, R., Adams, A. T., Ventham, N. T., Kennedy, N. A., White, R., Clarke, C., Ivens, A., Bergemalm, D., Vatn, S., Lopez-Jimena, B., Ricanek, P., Vatn, M. H., Söderholm, Johan D, Gomollon, F., Nowak, J. K., Jahnsen, J., Halfvarson, J., McTaggart, S., Ho, G. T., Buck, A., and Satsangi, J.
Abstract: Background: MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. Methods: In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohns disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. Results: In stage 1, each leukocyte subset [CD4(+) and CD8(+)T-cells and CD14(+) monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4(+) T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20-3.27; logrank p = 1.80 x 10(-3)), in particular CD [HR 2.81; IQR: 1.11-3.53, p = 6.50 x 10(-4)]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met. Interpretation: We have identified and validated unique CD4(+) T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated., Funding Agencies|Crohns and Colitis UK [CCUK] [M2016/2]; LifeArc, EdinburghBiotechnology and Biological Sciences Research Council (BBSRC)
Published: 2020
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18. Faecal microbiota signatures of IBD and their relation to diagnosis, disease phenotype, inflammation, treatment escalation and anti-TNF response in a European Multicentre Study (IBD-Character)

Author: Vatn, S., Carstens, Adam, Kristoffersen, A. B., Bergemalm, Daniel, Casén, C., Moen, A. E. F., Tannaes, T. M., Lindstrøm, J., Detlie, T. E., Olbjørn, C., Lindqvist, Carl Mårten, Söderholm, J. D., Gomollón, F., Kalla, R., Satsangi, J., Vatn, M. H., Jahnsen, J., Halfvarson, Jonas, Ricanek, P., Vatn, S., Carstens, Adam, Kristoffersen, A. B., Bergemalm, Daniel, Casén, C., Moen, A. E. F., Tannaes, T. M., Lindstrøm, J., Detlie, T. E., Olbjørn, C., Lindqvist, Carl Mårten, Söderholm, J. D., Gomollón, F., Kalla, R., Satsangi, J., Vatn, M. H., Jahnsen, J., Halfvarson, Jonas, and Ricanek, P.
Abstract: Method: We examined faecal samples, using the GA-map (TM) Dysbiosis Test, to associate gut microbiota composition with Crohn's disease (CD) and ulcerative colitis (UC) and to identify markers for future biomarker identification. We conducted a prospective case-control study (EU-ref. no. 305676) in an inception cohort of 324 individuals (64 CD, 84 UC, 116 symptomatic non-IBD controls and 44 healthy controls) across five European centres and examined 54 predetermined bacterial markers. We categorized patients according to the Montreal Classification and calculated the dysbiosis index (DI). Non-parametric tests were used to compare groups and the Bonferroni correction to adjust for multiple comparisons. Results: The fluorescent signals (FSSs) for Firmicutes and Eubacterium hallii were lower in inflammatory bowel disease (IBD) vs. symptomatic controls (p<.05). FSS for Firmicutes, Lachnospiraceae, Eubacterium hallii and Ruminococcus albus/bromii were lower, whereas the signal fo rBacteroides Fragilis was higher in UC vs. symptomatic controls (p<.05). FSS was higher for Bifidobacterium spp., Eubacterium hallii, Actinobacteria and Firmicutes among patients with ulcerative proctitis, compared to extensive colitis (p<.05). In CD, we observed no association with disease location. The DI correlated with faecal-calprotectin in both CD and in UC (p<.001). In terms of treatment escalation and anti-TNF response, differences were observed for some bacterial markers, but none of these associations were statistically significant. Conclusion: Our data reveal that the GA-map (TM) Dysbiosis Test holds the potential to characterize the faecal microbiota composition and to assess the degree of dysbiosis in new-onset IBD. On the other hand, our results cannot demonstrate any proven diagnostic or predictive value of this method to support clinical decision making., Funding Agency:European Union (EU) 2858546
Published: 2020
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19. Whole blood profiling of T-cell derived miRNA allows the development of prognostic models in inflammatory bowel disease

Author: Kalla, R., Adams, A. T., Ventham, N. T., Kennedy, N. A., White, R., Clarke, C., Ivens, A., Bergemalm, Daniel, Vatn, S., Lopez-Jimena, B., Ricanek, P., Vatn, M. H., Söderholm, J., Gomollón, F., Nowak, J. K., Jahnsen, J., Halfvarson, Jonas, McTaggart, S., Ho, G. T., Buck, A., Satsangi, J., Kalla, R., Adams, A. T., Ventham, N. T., Kennedy, N. A., White, R., Clarke, C., Ivens, A., Bergemalm, Daniel, Vatn, S., Lopez-Jimena, B., Ricanek, P., Vatn, M. H., Söderholm, J., Gomollón, F., Nowak, J. K., Jahnsen, J., Halfvarson, Jonas, McTaggart, S., Ho, G. T., Buck, A., and Satsangi, J.
Abstract: BACKGROUND: MicroRNAs (miRNAs) are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in Inflammatory Bowel Disease (IBD) pathogenesis. In our study, we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. METHODS: In a 2-stage prospective multi-centre case control study, Next Generation sequencing was performed on a discovery cohort of immunomagnetically separated leucocytes from 32 patients (9 CD, 14 UC, 8 healthy controls) and differentially expressed signals were validated in whole blood in 294 patients (97 UC, 98 CD, 98 non-IBD) using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. RESULTS: In stage 1, each leucocyte subset (CD4+ and CD8+ T-cells and CD14+ monocytes) was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4+ T-cells, including miR-1307-3p (p=0.01), miR-3615 (p=0.02) and miR-4792 (p=0.01). In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (HR 1.98, IQR:1.20-3.27;logrank p=1.80×10-3), in particular CD (HR 2.81; IQR: 1.11-3.53, p=6.50×10-4). Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if 2 or more criteria were met and 90% for UC if 3 or more criteria are met. INTERPRETATION: We have identified and validated unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated., Funding Agencies:Crohn's and Colitis UK [CCUK] M2016/2Biotechnology and Biological Sciences Research Council (BBSRC)
Published: 2020
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20. Whole Blood Profiling of T-cell-Derived microRNA Allows the Development of Prognostic models in Inflammatory Bowel Disease

Author: Kalla, R., Adams, A. T., Ventham, N. T., Kennedy, N. A., White, R., Clarke, C., Ivens, A., Bergemalm, D., Vatn, S., Lopez-Jimena, B., Ricanek, P., Vatn, M. H., Söderholm, Johan D, Gomollon, F., Nowak, J. K., Jahnsen, J., Halfvarson, J., McTaggart, S., Ho, G. T., Buck, A., Satsangi, J., Kalla, R., Adams, A. T., Ventham, N. T., Kennedy, N. A., White, R., Clarke, C., Ivens, A., Bergemalm, D., Vatn, S., Lopez-Jimena, B., Ricanek, P., Vatn, M. H., Söderholm, Johan D, Gomollon, F., Nowak, J. K., Jahnsen, J., Halfvarson, J., McTaggart, S., Ho, G. T., Buck, A., and Satsangi, J.
Abstract: Background: MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. Methods: In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohns disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. Results: In stage 1, each leukocyte subset [CD4(+) and CD8(+)T-cells and CD14(+) monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4(+) T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20-3.27; logrank p = 1.80 x 10(-3)), in particular CD [HR 2.81; IQR: 1.11-3.53, p = 6.50 x 10(-4)]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met. Interpretation: We have identified and validated unique CD4(+) T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated., Funding Agencies|Crohns and Colitis UK [CCUK] [M2016/2]; LifeArc, EdinburghBiotechnology and Biological Sciences Research Council (BBSRC)
Published: 2020
Full Text: View/download PDF

21. Faecal microbiota signatures of IBD and their relation to diagnosis, disease phenotype, inflammation, treatment escalation and anti-TNF response in a European Multicentre Study (IBD-Character)

Author: Vatn, S., Carstens, A., Kristoffersen, A. B., Bergemalm, D., Casen, C., Moen, A. E. F., Tannaes, T. M., Lindstrom, J., Detlie, T. E., Olbjorn, C., Lindquist, C. M., Söderholm, Johan D., Gomollon, F., Kalla, R., Satsangi, J., Vatn, M. H., Jahnsen, J., Halfvarson, J., Ricanek, P., Vatn, S., Carstens, A., Kristoffersen, A. B., Bergemalm, D., Casen, C., Moen, A. E. F., Tannaes, T. M., Lindstrom, J., Detlie, T. E., Olbjorn, C., Lindquist, C. M., Söderholm, Johan D., Gomollon, F., Kalla, R., Satsangi, J., Vatn, M. H., Jahnsen, J., Halfvarson, J., and Ricanek, P.
Abstract: Method We examined faecal samples, using the GA-map (TM) Dysbiosis Test, to associate gut microbiota composition with Crohns disease (CD) and ulcerative colitis (UC) and to identify markers for future biomarker identification. We conducted a prospective case-control study (EU-ref. no. 305676) in an inception cohort of 324 individuals (64 CD, 84 UC, 116 symptomatic non-IBD controls and 44 healthy controls) across five European centres and examined 54 predetermined bacterial markers. We categorized patients according to the Montreal Classification and calculated the dysbiosis index (DI). Non-parametric tests were used to compare groups and the Bonferroni correction to adjust for multiple comparisons. Results The fluorescent signals (FSSs) forFirmicutesandEubacterium halliiwere lower in inflammatory bowel disease (IBD) vs. symptomatic controls (p<.05). FSS for Firmicutes,Lachnospiraceae, Eubacterium halliiandRuminococcus albus/bromiiwere lower, whereas the signal forBacteroides Fragiliswas higher in UC vs. symptomatic controls (p<.05). FSS was higher forBifidobacterium spp.,Eubacterium hallii, Actinobacteria and Firmicutes among patients with ulcerative proctitis, compared to extensive colitis (p<.05). In CD, we observed no association with disease location. The DI correlated with faecal-calprotectin in both CD and in UC (p<.001). In terms of treatment escalation and anti-TNF response, differences were observed for some bacterial markers, but none of these associations were statistically significant. Conclusion Our data reveal that the GA-map (TM) Dysbiosis Test holds the potential to characterize the faecal microbiota composition and to assess the degree of dysbiosis in new-onset IBD. On the other hand, our results cannot demonstrate any proven diagnostic or predictive value of this method to support clinical decision making., Funding Agencies|EU FP7 Grant: IBD-CHARACTEREuropean Union (EU) [2858546]
Published: 2020
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22. Serum N-glycomic biomarkers predict treatment escalation in inflammatory bowel disease

Author: Shubhakar, A., Jansen, B., Adams, A., Reiding, K., Ventham, N., Bergemalm, D., Urbanowicz, P., Gardner, R., Halfvarson, Jonas, Satsangi, J., Fernandes, D., Wuhrer, M., Spencer, D., Shubhakar, A., Jansen, B., Adams, A., Reiding, K., Ventham, N., Bergemalm, D., Urbanowicz, P., Gardner, R., Halfvarson, Jonas, Satsangi, J., Fernandes, D., Wuhrer, M., and Spencer, D.
Published: 2019
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23. Top-down in the long term in Crohn's disease.

Author: Ho G.T., Satsangi J., Boyapati R.K., Ho G.T., Satsangi J., and Boyapati R.K.
Published: 2018

24. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes

Author: Momozawa, Y. (Yukihide), Dmitrieva, J. (Julia), Théâtre, E. (Emilie), Deffontaine, V. (Valérie), Rahmouni, S. (Souad), Charloteaux, B. (Benoît), Crins, F. (François), Docampo, E. (Elisa), Elansary, M. (Mahmoud), Gori, A.-S. (Ann-Stephan), Lecut, C. (Christelle), Mariman, R. (Rob), Mni, M. (Myriam), Oury, C. (Cécile), Altukhov, I. (Ilya), Alexeev, D. (Dmitry), Aulchenko, Y.S. (Yurii), Amininejad, L. (Leila), Bouma, G. (Gerd), Hoentjen, F., Löwenberg, M., Oldenburg, B. (Bas), Pierik, M. (Marieke), Vander Meulen-De Jong, A.E. (Andrea E.), Woude, C.J. (Janneke) van der, Visschedijk, M. (Marijn), Lathrop, M. (Mark), Hugot, J.P. (J.), Weersma, R.K. (Rinse), De Vos, M. (Martine), Franchimont, D. (Denis), Vermeire, S. (Séverine), Kubo, M. (Michiaki), Louis, E. (Edouard), Georges, M. (Michel), Abraham, C. (Clara), Achkar, J.-P. (Jean-Paul), Ahmad, T. (Tariq), Ananthakrishnan, A.N. (Ashwin N.), Andersen, V. (Vibeke), Anderson, C.A. (Carl A.), Andrews, J.M. (Jane M.), Annese, V. (Vito), Aumais, G. (Guy), Baidoo, L. (Leonard), Baldassano, R.N. (Robert), Bampton, P.A. (Peter A.), Barclay, M. (Murray), Barrett, J.C. (Jeffrey), Bayless, T.M. (Theodore M.), Bethge, J. (Johannes), Bitton, A., Boucher, G. (Gabrielle), Brand, S. (Stephan), Brandt, B. (Berenice), Brant, S.R. (Steven R.), Büning, C. (Carsten), Chew, A. (Angela), Cho, J.H. (Judy H.), Cleynen, I. (Isabelle), Cohain, A. (Ariella), Croft, A. (Anthony), Daly, M.J. (Mark J.), D'Amato, M. (Mauro), Danese, S. (Silvio), De Jong, D.J. (Dirk J.), Denapiene, G. (Goda), Denson, L.A. (Lee A.), Devaney, K.L. (Kathy L.), Dewit, O. (Olivier), D'Inca, R. (Renata), Dubinsky, M. (Marla), Duerr, R.H. (Richard), Edwards, C. (Cathryn), Ellinghaus, D. (David), Essers, J.B. (Jonah), Ferguson, L.R. (Lynnette R.), Festen, E.A.M. (Eleonora), Fleshner, P. (Philip), Florin, T. (Tim), Franke, A. (Andre), Fransen, K. (Karin), Gearry, R. (Richard), Gieger, C. (Christian), Glas, J. (Jürgen), Goyette, P. (Philippe), Green, T. (Todd), Griffiths, A.M. (Anne), Guthery, S.L. (Stephen L.), Hakonarson, H. (Hakon), Halfvarson, J. (Jonas), Hanigan, K. (Katherine), Haritunians, T. (Talin), Hart, A. (Ailsa), Hawkey, S., Hayward, N.K. (Nicholas K.), Hedl, M. (Matija), Henderson, P. (Paul), Hu, X. (Xinli), Huang, H. (Hailiang), Hui, K.Y. (Ken Y.), Imielinski, M. (Marcin), Ippoliti, A. (Andrew), Jonaitis, L. (Laimas), Jostins, L. (Luke), Karlsen, T.H. (Tom), Kennedy, N.A. (Nicholas A.), Khan, M.A. (Mohammed Azam), Kiudelis, G. (Gediminas), Krishnaprasad, K. (Krupa), Kugathasan, S. (Subra), Kupcinskas, L. (Limas), Latiano, A. (Anna), Laukens, D. (Debby), Lawrance, I.C. (Ian C.), Lee, J.C. (James C.), Lees, C.W. (Charlie), Leja, M. (Marcis), Van Limbergen, J. (Johan), Lionetti, P. (Paolo), Liu, J.Z. (Jimmy Z.), Mahy, G. (Gillian), Mansfield, J. (John), Massey, D. (Dunecan), Mathew, J. (Joseph), McGovern, D.P.B. (Dermot P.B.), Milgrom, R. (Raquel), Mitrovic, M. (Mitja), Montgomery, G.W. (Grant W.), Mowat, C. (Craig), Newman, W.G. (William G.), Ng, A. (Aylwin), Ng, S.C. (Siew C.), Ng, S.M.E. (Sok Meng Evelyn), Nikolaus, S. (Susanna), Ning, K. (Kaida), Nöthen, M.M. (Markus), Oikonomou, I. (Ioannis), Palmieri, O. (Orazio), Parkes, M. (Miles), Phillips, A. (Anne), Ponsioen, C.Y. (Cyril), Potocnik, U. (Uros), Prescott, N.J. (Natalie J.), Proctor, D.D. (Deborah D.), Radford-Smith, G. (Graham), Rahier, J.F. (J.), Raychaudhuri, S. (Soumya), Regueiro, M. (Miguel), Rieder, F. (Florian), Rioux, J.D. (John), Ripke, S. (Stephan), Roberts, R. (Rebecca), Russell, R.K. (Richard), Sanderson, J.D. (Jeremy), Sans, S. (Susana), Satsangi, J. (Jack), Schadt, E.E. (Eric), Schreiber, S. (Stefan), Schulte, D. (Dominik), Schumm, L.P. (L. Philip), Scott, R. (Regan), Seielstad, M. (Mark), Sharma, Y. (Yashoda), Silverberg, M. (Mark), Simms, L.A. (Lisa A.), Skieceviciene, J. (Jurgita), Spain, S.L. (Sarah L.), Steinhart, A.H. (A. Hillary), Stempak, J.M. (Joanne M.), Stronati, L. (Laura), Sventoraityte, J. (Jurgita), Targan, S.R. (Stephan R.), Taylor, K.M. (Kirstin M.), Ter Velde, A. (Anje), Torkvist, L. (Leif), Tremelling, M. (Mark), Van Sommeren, S. (Suzanne), Vasiliauskas, E. (Eric), Verspaget, H.W., Walters, T. (Thomas), Wang, K. (Kai), Wang, M.-H. (Ming-Hsi), Wei, Z. (Zhi), Whiteman, D.C. (David C.), Wijmenga, C. (Cisca), Wilson, D.C. (David C.), Winkelmann, B., Xavier, R.J. (Ramnik J.), Zhang, B. (Bin), Zhang, C.K. (Clarence K.), Zhang, H. (Hu), Zhang, W. (Wei), Zhao, H. (Hongyu), Zhao, Z.Z. (Zhen Z.), Momozawa, Y. (Yukihide), Dmitrieva, J. (Julia), Théâtre, E. (Emilie), Deffontaine, V. (Valérie), Rahmouni, S. (Souad), Charloteaux, B. (Benoît), Crins, F. (François), Docampo, E. (Elisa), Elansary, M. (Mahmoud), Gori, A.-S. (Ann-Stephan), Lecut, C. (Christelle), Mariman, R. (Rob), Mni, M. (Myriam), Oury, C. (Cécile), Altukhov, I. (Ilya), Alexeev, D. (Dmitry), Aulchenko, Y.S. (Yurii), Amininejad, L. (Leila), Bouma, G. (Gerd), Hoentjen, F., Löwenberg, M., Oldenburg, B. (Bas), Pierik, M. (Marieke), Vander Meulen-De Jong, A.E. (Andrea E.), Woude, C.J. (Janneke) van der, Visschedijk, M. (Marijn), Lathrop, M. (Mark), Hugot, J.P. (J.), Weersma, R.K. (Rinse), De Vos, M. (Martine), Franchimont, D. (Denis), Vermeire, S. (Séverine), Kubo, M. (Michiaki), Louis, E. (Edouard), Georges, M. (Michel), Abraham, C. (Clara), Achkar, J.-P. (Jean-Paul), Ahmad, T. (Tariq), Ananthakrishnan, A.N. (Ashwin N.), Andersen, V. (Vibeke), Anderson, C.A. (Carl A.), Andrews, J.M. (Jane M.), Annese, V. (Vito), Aumais, G. (Guy), Baidoo, L. (Leonard), Baldassano, R.N. (Robert), Bampton, P.A. (Peter A.), Barclay, M. (Murray), Barrett, J.C. (Jeffrey), Bayless, T.M. (Theodore M.), Bethge, J. (Johannes), Bitton, A., Boucher, G. (Gabrielle), Brand, S. (Stephan), Brandt, B. (Berenice), Brant, S.R. (Steven R.), Büning, C. (Carsten), Chew, A. (Angela), Cho, J.H. (Judy H.), Cleynen, I. (Isabelle), Cohain, A. (Ariella), Croft, A. (Anthony), Daly, M.J. (Mark J.), D'Amato, M. (Mauro), Danese, S. (Silvio), De Jong, D.J. (Dirk J.), Denapiene, G. (Goda), Denson, L.A. (Lee A.), Devaney, K.L. (Kathy L.), Dewit, O. (Olivier), D'Inca, R. (Renata), Dubinsky, M. (Marla), Duerr, R.H. (Richard), Edwards, C. (Cathryn), Ellinghaus, D. (David), Essers, J.B. (Jonah), Ferguson, L.R. (Lynnette R.), Festen, E.A.M. (Eleonora), Fleshner, P. (Philip), Florin, T. (Tim), Franke, A. (Andre), Fransen, K. (Karin), Gearry, R. (Richard), Gieger, C. (Christian), Glas, J. (Jürgen), Goyette, P. (Philippe), Green, T. (Todd), Griffiths, A.M. (Anne), Guthery, S.L. (Stephen L.), Hakonarson, H. (Hakon), Halfvarson, J. (Jonas), Hanigan, K. (Katherine), Haritunians, T. (Talin), Hart, A. (Ailsa), Hawkey, S., Hayward, N.K. (Nicholas K.), Hedl, M. (Matija), Henderson, P. (Paul), Hu, X. (Xinli), Huang, H. (Hailiang), Hui, K.Y. (Ken Y.), Imielinski, M. (Marcin), Ippoliti, A. (Andrew), Jonaitis, L. (Laimas), Jostins, L. (Luke), Karlsen, T.H. (Tom), Kennedy, N.A. (Nicholas A.), Khan, M.A. (Mohammed Azam), Kiudelis, G. (Gediminas), Krishnaprasad, K. (Krupa), Kugathasan, S. (Subra), Kupcinskas, L. (Limas), Latiano, A. (Anna), Laukens, D. (Debby), Lawrance, I.C. (Ian C.), Lee, J.C. (James C.), Lees, C.W. (Charlie), Leja, M. (Marcis), Van Limbergen, J. (Johan), Lionetti, P. (Paolo), Liu, J.Z. (Jimmy Z.), Mahy, G. (Gillian), Mansfield, J. (John), Massey, D. (Dunecan), Mathew, J. (Joseph), McGovern, D.P.B. (Dermot P.B.), Milgrom, R. (Raquel), Mitrovic, M. (Mitja), Montgomery, G.W. (Grant W.), Mowat, C. (Craig), Newman, W.G. (William G.), Ng, A. (Aylwin), Ng, S.C. (Siew C.), Ng, S.M.E. (Sok Meng Evelyn), Nikolaus, S. (Susanna), Ning, K. (Kaida), Nöthen, M.M. (Markus), Oikonomou, I. (Ioannis), Palmieri, O. (Orazio), Parkes, M. (Miles), Phillips, A. (Anne), Ponsioen, C.Y. (Cyril), Potocnik, U. (Uros), Prescott, N.J. (Natalie J.), Proctor, D.D. (Deborah D.), Radford-Smith, G. (Graham), Rahier, J.F. (J.), Raychaudhuri, S. (Soumya), Regueiro, M. (Miguel), Rieder, F. (Florian), Rioux, J.D. (John), Ripke, S. (Stephan), Roberts, R. (Rebecca), Russell, R.K. (Richard), Sanderson, J.D. (Jeremy), Sans, S. (Susana), Satsangi, J. (Jack), Schadt, E.E. (Eric), Schreiber, S. (Stefan), Schulte, D. (Dominik), Schumm, L.P. (L. Philip), Scott, R. (Regan), Seielstad, M. (Mark), Sharma, Y. (Yashoda), Silverberg, M. (Mark), Simms, L.A. (Lisa A.), Skieceviciene, J. (Jurgita), Spain, S.L. (Sarah L.), Steinhart, A.H. (A. Hillary), Stempak, J.M. (Joanne M.), Stronati, L. (Laura), Sventoraityte, J. (Jurgita), Targan, S.R. (Stephan R.), Taylor, K.M. (Kirstin M.), Ter Velde, A. (Anje), Torkvist, L. (Leif), Tremelling, M. (Mark), Van Sommeren, S. (Suzanne), Vasiliauskas, E. (Eric), Verspaget, H.W., Walters, T. (Thomas), Wang, K. (Kai), Wang, M.-H. (Ming-Hsi), Wei, Z. (Zhi), Whiteman, D.C. (David C.), Wijmenga, C. (Cisca), Wilson, D.C. (David C.), Winkelmann, B., Xavier, R.J. (Ramnik J.), Zhang, B. (Bin), Zhang, C.K. (Clarence K.), Zhang, H. (Hu), Zhang, W. (Wei), Zhao, H. (Hongyu), and Zhao, Z.Z. (Zhen Z.)
Abstract: GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.
Published: 2018
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25. Top-down in the long term in Crohn's disease.

Author: Ho G.T., Satsangi J., Boyapati R.K., Ho G.T., Satsangi J., and Boyapati R.K.
Published: 2018

26. Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease

Author: Bergmann, S, Baillie, JK, Bretherick, A, Haley, CS, Clohisey, S, Grays, A, Neyton, LPA, Barrett, J, Stahl, EA, Tenesa, A, Andersson, R, Brown, JB, Faulkner, GJ, Lizio, M, Schaefer, U, Daub, C, Itoh, M, Kondo, N, Lassmann, T, Kawai, J, Mole, D, Bajic, VB, Heutink, P, Rehli, M, Kawaji, H, Sandelin, A, Suzuki, H, Satsangi, J, Wells, CA, Hacohen, N, Freeman, TC, Hayashizaki, Y, Carninci, P, Forrest, ARR, Hume, DA, Bergmann, S, Baillie, JK, Bretherick, A, Haley, CS, Clohisey, S, Grays, A, Neyton, LPA, Barrett, J, Stahl, EA, Tenesa, A, Andersson, R, Brown, JB, Faulkner, GJ, Lizio, M, Schaefer, U, Daub, C, Itoh, M, Kondo, N, Lassmann, T, Kawai, J, Mole, D, Bajic, VB, Heutink, P, Rehli, M, Kawaji, H, Sandelin, A, Suzuki, H, Satsangi, J, Wells, CA, Hacohen, N, Freeman, TC, Hayashizaki, Y, Carninci, P, Forrest, ARR, and Hume, DA
Abstract: Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits.
Published: 2018

27. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes

Author: Momozawa, Y, Dmitrieva, J, Theatre, E, Deffontaine, V, Rahmouni, S, Charloteaux, B, Crins, F, Docampo, E, Elansary, M, Gori, AS, Lecut, C, Mariman, R, Mni, M, Oury, C, Altukhov, I, Alexeev, D, Aulchenko, Y, Amininejad, L, Bouma, G, Hoentjen, F, Lowenberg, M, Oldenburg, B, Pierik, MJ, de Jong, AE, van der Woude, C.J., Visschedijk, MC, Lathrop, M, Hugot, JP, Weersma, RK, Vos, M, Franchimont, D, Vermeire, S, Kubo, M, Louis, E, Georges, M, Abraham, C, Achkar, JP, Ahmad, T, Ananthakrishnan, AN, Andersen, V, Anderson, CA, Andrews, JM, Annese, V, Aumais, G, Baidoo, L, Baldassano, RN, Bampton, PA, Barclay, M, Barrett, JC, Bayless, TM, Bethge, J, Bitton, A, Boucher, G, Brand, S, Brandt, B, Brant, SR, Buning, C, Chew, A, Cho, JH, Cleynen, I, Cohain, A, Croft, A, Daly, MJ, D'Amato, M, Danese, S, Jong, D, Denapiene, G, Denson, LA, Devaney, KL, Dewit, O, D'Inca, R, Dubinsky, M, Duerr, RH, Edwards, C, Ellinghaus, D, Essers, J, Ferguson, LR, Festen, EA, Fleshner, P, Florin, T, Franke, A, Fransen, K, Gearry, R, Gieger, C, Glas, J, Goyette, P, Green, T, Griffiths, AM, Guthery, SL, Hakonarson, H, Halfvarson, J, Hanigan, K, Haritunians, T, de Hart, A, Hawkey, C, Hayward, NK, Hedl, M, Henderson, P, Hu, XH, Huang, HL, Hui, KY, Imielinski, M, Ippoliti, A, Jonaitis, L, Jostins, L, Karlsen, TH, Kennedy, NA, Khan, MA, Kiudelis, G, Krishnaprasad, K, Kugathasan, S, Kupcinskas, L, Latiano, A, Laukens, D, Lawrance, IC, Lee, JC, Lees, CW, Leja, M, van Limbergen, J, Lionetti, P, Liu, JZ, Mahy, G, Mansfield, J, Massey, D, Mathew, CG, McGovern, DPB, Milgrom, R, Mitrovic, M, Montgomery, GW, Mowat, C, Newman, W, Ng, A, Ng, SC, Ng, SME, Nikolaus, S, Ning, K, Nothen, M, Oikonomou, I, Palmieri, O, Parkes, M, Phillips, A, Ponsioen, CY, Potocnik, U, Prescott, NJ, Proctor, DD, Radford-Smith, G, Rahier, JF, Raychaudhuri, S, Regueiro, M, Rieder, F, Rioux, JD, Ripke, S, Roberts, R, Russell, RK, Sanderson, JD, Sans, M, Satsangi, J, Schadt, EE, Schreiber, S, Schulte, D, Schumm, LP, Scott, R, Seielstad, M, Sharma, Y, Silverberg, MS, Simms, LA, Skieceviciene, J, Spain, SL, Steinhart, AH, Stempak, JM, Stronati, L, Sventoraityte, J, Targan, SR, Taylor, KM, Velde, A, Torkvist, L, Tremelling, M, van Sommeren, S, Vasiliauskas, E, Verspaget, HW, Walters, T, Wang, K, Wang, MH, Wei, Z, Whiteman, D, Wijmenga, C, Wilson, DC, Winkelmann, J, Xavier, RJ, Zhang, B, Zhang, CK, Zhang, H, Zhang, W, Zhao, HY, Zhao, ZZ, Momozawa, Y, Dmitrieva, J, Theatre, E, Deffontaine, V, Rahmouni, S, Charloteaux, B, Crins, F, Docampo, E, Elansary, M, Gori, AS, Lecut, C, Mariman, R, Mni, M, Oury, C, Altukhov, I, Alexeev, D, Aulchenko, Y, Amininejad, L, Bouma, G, Hoentjen, F, Lowenberg, M, Oldenburg, B, Pierik, MJ, de Jong, AE, van der Woude, C.J., Visschedijk, MC, Lathrop, M, Hugot, JP, Weersma, RK, Vos, M, Franchimont, D, Vermeire, S, Kubo, M, Louis, E, Georges, M, Abraham, C, Achkar, JP, Ahmad, T, Ananthakrishnan, AN, Andersen, V, Anderson, CA, Andrews, JM, Annese, V, Aumais, G, Baidoo, L, Baldassano, RN, Bampton, PA, Barclay, M, Barrett, JC, Bayless, TM, Bethge, J, Bitton, A, Boucher, G, Brand, S, Brandt, B, Brant, SR, Buning, C, Chew, A, Cho, JH, Cleynen, I, Cohain, A, Croft, A, Daly, MJ, D'Amato, M, Danese, S, Jong, D, Denapiene, G, Denson, LA, Devaney, KL, Dewit, O, D'Inca, R, Dubinsky, M, Duerr, RH, Edwards, C, Ellinghaus, D, Essers, J, Ferguson, LR, Festen, EA, Fleshner, P, Florin, T, Franke, A, Fransen, K, Gearry, R, Gieger, C, Glas, J, Goyette, P, Green, T, Griffiths, AM, Guthery, SL, Hakonarson, H, Halfvarson, J, Hanigan, K, Haritunians, T, de Hart, A, Hawkey, C, Hayward, NK, Hedl, M, Henderson, P, Hu, XH, Huang, HL, Hui, KY, Imielinski, M, Ippoliti, A, Jonaitis, L, Jostins, L, Karlsen, TH, Kennedy, NA, Khan, MA, Kiudelis, G, Krishnaprasad, K, Kugathasan, S, Kupcinskas, L, Latiano, A, Laukens, D, Lawrance, IC, Lee, JC, Lees, CW, Leja, M, van Limbergen, J, Lionetti, P, Liu, JZ, Mahy, G, Mansfield, J, Massey, D, Mathew, CG, McGovern, DPB, Milgrom, R, Mitrovic, M, Montgomery, GW, Mowat, C, Newman, W, Ng, A, Ng, SC, Ng, SME, Nikolaus, S, Ning, K, Nothen, M, Oikonomou, I, Palmieri, O, Parkes, M, Phillips, A, Ponsioen, CY, Potocnik, U, Prescott, NJ, Proctor, DD, Radford-Smith, G, Rahier, JF, Raychaudhuri, S, Regueiro, M, Rieder, F, Rioux, JD, Ripke, S, Roberts, R, Russell, RK, Sanderson, JD, Sans, M, Satsangi, J, Schadt, EE, Schreiber, S, Schulte, D, Schumm, LP, Scott, R, Seielstad, M, Sharma, Y, Silverberg, MS, Simms, LA, Skieceviciene, J, Spain, SL, Steinhart, AH, Stempak, JM, Stronati, L, Sventoraityte, J, Targan, SR, Taylor, KM, Velde, A, Torkvist, L, Tremelling, M, van Sommeren, S, Vasiliauskas, E, Verspaget, HW, Walters, T, Wang, K, Wang, MH, Wei, Z, Whiteman, D, Wijmenga, C, Wilson, DC, Winkelmann, J, Xavier, RJ, Zhang, B, Zhang, CK, Zhang, H, Zhang, W, Zhao, HY, and Zhao, ZZ
Published: 2018

28. Can Thiopurines Prevent Formation of Antibodies Against Tumor Necrosis Factor Antagonists After Failure of These Therapies?.

Author: Boyapati R.K., Satsangi J., Ho G.-T., Boyapati R.K., Satsangi J., and Ho G.-T.
Published: 2017

29. Can Thiopurines Prevent Formation of Antibodies Against Tumor Necrosis Factor Antagonists After Failure of These Therapies?.

Author: Boyapati R.K., Satsangi J., Ho G.-T., Boyapati R.K., Satsangi J., and Ho G.-T.
Published: 2017

30. Epigenetic alterations at diagnosis predict susceptibility, prognosis and treatment escalation in inflammatory bowel disease – ibd character

Author: Kalla, R., Adams, A. T., Vatn, S., Bonfiglio, F., Nimmo, E. R., Kennedy, N. A., Ventham, N., Vatn, M. H., Ricanek, P., Bergemalm, Daniel, Halfvarson, Jonas, Söderholm, J. D., Pierik, M., Torkvist, L., Gomollon, F., Gut, I., Jahnsen, J., Satsangi, J., Kalla, R., Adams, A. T., Vatn, S., Bonfiglio, F., Nimmo, E. R., Kennedy, N. A., Ventham, N., Vatn, M. H., Ricanek, P., Bergemalm, Daniel, Halfvarson, Jonas, Söderholm, J. D., Pierik, M., Torkvist, L., Gomollon, F., Gut, I., Jahnsen, J., and Satsangi, J.
Published: 2017
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31. Proximity extension assay based proteins show immune cell specificity and can diagnose and predict outcomes in inflammatory bowel diseases : ibd character study

Author: Kalla, R., Adams, A. T., Vatn, S., Bergemalm, Daniel, Ricanek, P., Lindstrom, J. C., Ocklind, A., Nordberg, N., Kennedy, N. A., Ventham, N., Vatn, M. H., Söderholm, J. D., Pierik, M., Torkvist, L., Gomollon, F., Jahnsen, J., Halfvarson, Jonas, Satsangi, J., Kalla, R., Adams, A. T., Vatn, S., Bergemalm, Daniel, Ricanek, P., Lindstrom, J. C., Ocklind, A., Nordberg, N., Kennedy, N. A., Ventham, N., Vatn, M. H., Söderholm, J. D., Pierik, M., Torkvist, L., Gomollon, F., Jahnsen, J., Halfvarson, Jonas, and Satsangi, J.
Published: 2017
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32. Epigenetic alterations at diagnosis predict susceptibility, prognosis and treatment escalation in inflammatory bowel disease - IBD Character

Author: Adams, A., Kalla, R., Vatn, S., Bonfiglio, F., Nimmo, E., Kennedy, N., Ventham, N., Vatn, M., Ricanek, P., Bergemalm, Daniel, Halfvarson, Jonas, Söderholm, J., Pierik, M., Törkvist, L., Gomollon, F., Gut, I., Jahnsen, J., Satsangi, J., Adams, A., Kalla, R., Vatn, S., Bonfiglio, F., Nimmo, E., Kennedy, N., Ventham, N., Vatn, M., Ricanek, P., Bergemalm, Daniel, Halfvarson, Jonas, Söderholm, J., Pierik, M., Törkvist, L., Gomollon, F., Gut, I., Jahnsen, J., and Satsangi, J.
Published: 2017
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33. Proximity extension assay based proteins show immune cell specificity and can diagnose and predict outcomes in inflammatory bowel diseases : IBD Character study

Author: Kalla, R., Adams, A., Vatn, S., Bergemalm, Daniel, Ricanek, P., Lindström, J., Ocklind, A., Nordberg, N., Kennedy, N., Ventham, N., Vatn, M., Söderholm, J., Pierik, M., Törkvist, L., Gomollon, F., Jahnsen, J., Halfvarson, Jonas, Satsangi, J., Kalla, R., Adams, A., Vatn, S., Bergemalm, Daniel, Ricanek, P., Lindström, J., Ocklind, A., Nordberg, N., Kennedy, N., Ventham, N., Vatn, M., Söderholm, J., Pierik, M., Törkvist, L., Gomollon, F., Jahnsen, J., Halfvarson, Jonas, and Satsangi, J.
Published: 2017
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34. Microbiota related disease activity and distribution in subgroups of inflammatory bowel disease

Author: Ricanek, P., Rahul, K., Ber, Y., Vatn, S., Finnby, L., Lindahl, T., Bergemalm, Daniel, Carstens, Adam, Söderholm, J., Jahnsen, J., Gomollon, F., Halfvarson, Jonas, Satsangi, J., Casen, C., Vatn, M. H., Ricanek, P., Rahul, K., Ber, Y., Vatn, S., Finnby, L., Lindahl, T., Bergemalm, Daniel, Carstens, Adam, Söderholm, J., Jahnsen, J., Gomollon, F., Halfvarson, Jonas, Satsangi, J., Casen, C., and Vatn, M. H.
Published: 2017
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35. Biomarkers in Search of Precision Medicine in IBD.

Author: Ho G.-T., Boyapati R.K., Kalla R., Satsangi J., Ho G.-T., Boyapati R.K., Kalla R., and Satsangi J.
Abstract: The completion of the human genome project in 2003 represented a major scientific landmark, ushering in a new era with hopes and expectations of fresh insights into disease mechanisms and treatments. In inflammatory bowel disease (IBD), many important discoveries soon followed, notably the identification of >200 genetic susceptibility loci and characterization of the gut microbiome. As "big data", driven by advances in technology, becomes increasingly available and affordable, individuals with IBD and clinicians alike yearn for tangible outcomes from the promise of "precision medicine" - precise diagnosis, monitoring, and treatment. Here, we provide a commentary on the prospects and challenges of precision medicine and biomarkers in IBD. We focus on the three key areas where precision IBD will have the most impact: (1) disease susceptibility, activity, and behavior; (2) prediction of drug response and adverse effects; and (3) identification of subphenotypic mechanisms to facilitate drug discovery and selection of new treatments in IBD.Copyright © 2016 by the American College of Gastroenterology.
Published: 2016

36. Biomarkers in Search of Precision Medicine in IBD.

Author: Ho G.-T., Boyapati R.K., Kalla R., Satsangi J., Ho G.-T., Boyapati R.K., Kalla R., and Satsangi J.
Abstract: The completion of the human genome project in 2003 represented a major scientific landmark, ushering in a new era with hopes and expectations of fresh insights into disease mechanisms and treatments. In inflammatory bowel disease (IBD), many important discoveries soon followed, notably the identification of >200 genetic susceptibility loci and characterization of the gut microbiome. As "big data", driven by advances in technology, becomes increasingly available and affordable, individuals with IBD and clinicians alike yearn for tangible outcomes from the promise of "precision medicine" - precise diagnosis, monitoring, and treatment. Here, we provide a commentary on the prospects and challenges of precision medicine and biomarkers in IBD. We focus on the three key areas where precision IBD will have the most impact: (1) disease susceptibility, activity, and behavior; (2) prediction of drug response and adverse effects; and (3) identification of subphenotypic mechanisms to facilitate drug discovery and selection of new treatments in IBD.Copyright © 2016 by the American College of Gastroenterology.
Published: 2016

37. Proximity extension assay immunoassay technology identifies novel serum biomarkers that can diagnose and classify inflammatory bowel diseases : IBD Character Consortium

Author: Kalla, R., Ocklind, A., Petren, C., Nordberg, N., Kennedy, N., Ventham, N., Pettersson, E., Bergemalm, Daniel, Lindstrom, J., Vatn, S., Hjortswang, H., Nimmo, E., Drummond, H., Ricanek, P., Dahl, F., Wilson, D., Jahnsen, J., Gomollon, F., Pierik, M., Soderholm, J., Vatn, M., Halfvarson, Jonas, Satsangi, J., Kalla, R., Ocklind, A., Petren, C., Nordberg, N., Kennedy, N., Ventham, N., Pettersson, E., Bergemalm, Daniel, Lindstrom, J., Vatn, S., Hjortswang, H., Nimmo, E., Drummond, H., Ricanek, P., Dahl, F., Wilson, D., Jahnsen, J., Gomollon, F., Pierik, M., Soderholm, J., Vatn, M., Halfvarson, Jonas, and Satsangi, J.
Published: 2016
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38. Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease

Author: Ventham, N. T., Kennedy, N. A., Adams, A. T., Kalla, R., Heath, S., O'Leary, K. R., Drummond, H., IBD CHARACTER, consortium, Wilson, D. C., Gut, I. G., Nimmo, E. R., Satsangi, J., Ventham, N. T., Kennedy, N. A., Adams, A. T., Kalla, R., Heath, S., O'Leary, K. R., Drummond, H., IBD CHARACTER, consortium, Wilson, D. C., Gut, I. G., Nimmo, E. R., and Satsangi, J.
Abstract: Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8(+) T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression.
Published: 2016
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39. Genetic sharing and heritability of paediatric age of onset autoimmune diseases

Author: Li, YR, Zhao, SD, Li, J, Bradfield, JP, Mohebnasab, M, Steel, L, Kobie, J, Abrams, DJ, Mentch, FD, Glessner, JT, Guo, Y, Wei, Z, Connolly, JJ, Cardinale, CJ, Bakay, M, Li, D, Maggadottir, SM, Thomas, KA, Qui, H, Chiavacci, RM, Kim, CE, Wang, F, Snyder, J, Flato, B, Forre, O, Denson, LA, Thompson, SD, Becker, ML, Guthery, SL, Latiano, A, Perez, E, Resnick, E, Strisciuglio, C, Staiano, A, Miele, E, Silverberg, MS, Lie, BA, Punaro, M, Russell, RK, Wilson, DC, Dubinsky, MC, Monos, DS, Annese, V, Munro, JE, Wise, C, Chapel, H, Cunningham-Rundles, C, Orange, JS, Behrens, EM, Sullivan, KE, Kugathasan, S, Griffiths, AM, Satsangi, J, Grant, SFA, Sleiman, PMA, Finkel, TH, Polychronakos, C, Baldassano, RN, Prak, ETL, Ellis, JA, Li, H, Keating, BJ, Hakonarson, H, Li, YR, Zhao, SD, Li, J, Bradfield, JP, Mohebnasab, M, Steel, L, Kobie, J, Abrams, DJ, Mentch, FD, Glessner, JT, Guo, Y, Wei, Z, Connolly, JJ, Cardinale, CJ, Bakay, M, Li, D, Maggadottir, SM, Thomas, KA, Qui, H, Chiavacci, RM, Kim, CE, Wang, F, Snyder, J, Flato, B, Forre, O, Denson, LA, Thompson, SD, Becker, ML, Guthery, SL, Latiano, A, Perez, E, Resnick, E, Strisciuglio, C, Staiano, A, Miele, E, Silverberg, MS, Lie, BA, Punaro, M, Russell, RK, Wilson, DC, Dubinsky, MC, Monos, DS, Annese, V, Munro, JE, Wise, C, Chapel, H, Cunningham-Rundles, C, Orange, JS, Behrens, EM, Sullivan, KE, Kugathasan, S, Griffiths, AM, Satsangi, J, Grant, SFA, Sleiman, PMA, Finkel, TH, Polychronakos, C, Baldassano, RN, Prak, ETL, Ellis, JA, Li, H, Keating, BJ, and Hakonarson, H
Abstract: Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.
Published: 2015

40. Proximity Extension Assay technology identifies novel serum biomarkers for predicting Inflammatory Bowel Disease : IBD Character Consortium

Author: Kalla, R., Kennedy, N., Hjelm, F., Modig, E., Sundell, M., Andreassen, B., Bergemalm, Daniel, Ricanek, P., Söderholm, J., Vatn, M., Halfvarson, Jonas, Gullberg, M., Satsangi, J., Kalla, R., Kennedy, N., Hjelm, F., Modig, E., Sundell, M., Andreassen, B., Bergemalm, Daniel, Ricanek, P., Söderholm, J., Vatn, M., Halfvarson, Jonas, Gullberg, M., and Satsangi, J.
Published: 2015
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41. Two-stage genome-wide methylation profiling in childhood-onset Crohn's disease implicates epigenetic alterations at the VMP1/MIR21 and HLA loci

Author: Adams, AT, Kennedy, NA, Hansen, R, Ventham, NT, O'Leary, KR, Drummond, HE, Noble, CL, El-Omar, E, Russell, RK, Wilson, DC, Nimmo, ER, Hold, GL, Satsangi, J, Adams, AT, Kennedy, NA, Hansen, R, Ventham, NT, O'Leary, KR, Drummond, HE, Noble, CL, El-Omar, E, Russell, RK, Wilson, DC, Nimmo, ER, Hold, GL, and Satsangi, J
Abstract: Background: As a result of technological and analytical advances, genome-wide characterization of key epigenetic alterations is now feasible in complex diseases. We hypothesized that this may provide important insights into gene-environmental interactions in Crohn's disease (CD) and is especially pertinent to early onset disease. Methods: The Illumina 450K platform was applied to assess epigenome-wide methylation profiles in circulating leukocyte DNA in discovery and replication pediatric CD cohorts and controls. Data were corrected for differential leukocyte proportions. Targeted replication was performed in adults using pyrosequencing. Methylation changes were correlated with gene expression in blood and intestinal mucosa. Results: We identified 65 individual CpG sites with methylation alterations achieving epigenome-wide significance after Bonferroni correction (P < 1.1 × 10-7), and 19 differently methylated regions displaying unidirectional methylation change. There was a highly significant enrichment of methylation changes around GWAS single nucleotide polymorphisms (P = 3.7 × 10-7), notably the HLA region and MIR21. Two-locus discriminant analysis in the discovery cohort predicted disease in the pediatric replication cohort with high accuracy (area under the curve, 0.98). The findings strongly implicate the transcriptional start site of MIR21 as a region of extended epigenetic alteration, containing the most significant individual probes (P = 1.97 × 10-15) within a GWAS risk locus. In extension studies, we confirmed hypomethylation of MIR21 in adults (P = 6.6 × 10-5, n = 172) and show increased mRNA expression in leukocytes (P < 0.005, n = 66) and in the inflamed intestine (P = 1.4 × 10-6, n = 99). Conclusions: We demonstrate highly significant and replicable differences in DNA methylation in CD, defining the disease-associated epigenome. The data strongly implicate known GWAS loci, with compelling evidence implicating MIR21 and the HLA region.
Published: 2014

42. A common biological basis of obesity and nicotine addiction

Author: Thorgeirsson, T.E. (Thorgeir), Gudbjartsson, D.F. (Daniel), Sulem, P. (Patrick), Besenbacher, S. (Søren), Styrkarsdottir, U. (Unnur), Thorleifsson, G. (Gudmar), Walters, G.B. (Bragi), Furberg, H. (Helena), Sullivan, P. (Patrick), Marchini, J. (Jonathan), McCarthy, M.I. (M.), Steinthorsdottir, V. (Valgerdur), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Surakka, I. (Ida), Vink, J.M. (Jacqueline), Amin, N. (Najaf), Geller, F. (Frank), Rafnar, T. (Thorunn), Esko, T. (Tõnu), Walter, S. (Stefan), Gieger, C. (Christian), Rawal, R. (Rajesh), Mangino, M. (Massimo), Prokopenko, I. (Inga), Mägi, R. (Reedik), Keskitalo, K. (Kaisu), Gudjonsdottir, I.H. (Iris), Gretarsdottir, S. (Solveig), Stefansson, H. (Hreinn), Aulchenko, Y.S. (Yurii), Nelis, M. (Mari), Aben, K.K.H. (Katja), Heijer, M. (Martin) den, Soranzo, N. (Nicole), Valdes, A.M. (Ana Maria), Steves, C.J. (Claire), Uitterlinden, A.G. (André), Hofman, A. (Albert), Tönjes, A. (Anke), Kovacs, P. (Peter), Hottenga, J.J. (Jouke Jan), Willemsen, G.A.H.M. (Gonneke), Vogelzangs, N. (Nicole), Döring, A. (Angela), Dahmen, N. (N.), Nitz, B. (Barbara), Ripatti, S. (Samuli), Perola, M. (Markus), Kettunen, J. (Johannes), Hartikainen, A.L., Pouta, A. (Anneli), Laitinen, J. (Jaana), Isohanni, M.K. (Matti), Huei-Yi, S. (Shen), Allen, M. (Maxine), Krestyaninova, M. (Maria), Hall, A. (Anne), Thompson, J.R. (John), Oskarsson, H. (Hogni), Tyrfingsson, T. (Thorarinn), Kiemeney, L.A.L.M. (Bart), Jarvelin, M.-R. (Marjo-Riitta), Salomaa, V. (Veikko), Stumvoll, M. (Michael), Spector, T.D. (Timothy), Wichmann, H.E. (Heinz Erich), Metspalu, A. (Andres), Samani, N.J. (Nilesh), Penninx, B.W.J.H. (Brenda), Oostra, B.A. (Ben), Boomsma, D.I. (Dorret), Tiemeier, H.W. (Henning), Duijn, C.M. (Cornelia) van, Kaprio, J. (Jaakko), Gulcher, J.R. (Jeffrey), Kim, Y. (Yunjung), Dackor, J. (Jennifer), Boerwinkle, E.A. (Eric), Franceschini, N. (Nora), Ardissino, D. (Diego), Bernardinelli, L. (Luisa), Mannucci, P.M. (Pier), Mauri, F. (Francesco), Merlini, P.A. (Piera), Absher, D. (Devin), Assimes, T.L. (Themistocles), Fortmann, S.P. (Stephen), Iribarren, C. (Carlos), Knowles, J.W. (Joshua), Quertermous, T. (Thomas), Ferrucci, L. (Luigi), Tanaka, T. (Toshiko), Bis, J.C. (Joshua), Haritunians, T. (Talin), McKnight, B. (Barbara), Psaty, B.M. (Bruce), Taylor, K.D. (Kent), Thacker, E.L. (Evan), Almgren, P. (Peter), Groop, L. (Leif), Ladenvall, C. (Claes), Boehnke, M. (Michael), Jackson, A.U. (Anne), Mohlke, K.L. (Karen), Stringham, H.M. (Heather), Tuomilehto, J. (Jaakko), Benjamin, E.J. (Emelia), Hwang, S.J., Levy, D. (Daniel), Preis, S.R., Vasan, R.S. (Ramachandran Srini), Duan, J. (Jubao), Gejman, P.V. (Pablo), Levinson, D.F. (Douglas), Sanders, A.R. (Alan), Shi, J. (Jianxin), Lips, E.H. (Esther), McKay, J.D. (James), Agudo, A. (Antonio), Barzan, L. (Luigi), Bencko, V. (Vladimir), Benhamou, S. (Simone), Castellsagué, X. (Xavier), Canova, C. (Cristina), Conway, D.I. (David), Fabianova, E. (Eleonora), Foretova, L. (Lenka), Janout, V. (Vladimir), Healy, C.M. (Claire), Holcátová, I. (Ivana), Kjaerheim, K. (Kristina), Lagiou, P., Lissowska, J. (Jolanta), Lowry, R. (Ray), MacFarlane, T.V. (Tatiana), Mates, D. (Dana), Richiardi, L. (Lorenzo), Rudnai, P. (Peter), Szeszenia-Dabrowska, N. (Neonilia), Zaridze, D., Znaor, A. (Ariana), Lathrop, M. (Mark), Brennan, P. (Paul), Bandinelli, S. (Stefania), Frayling, T.M. (Timothy), Guralnik, J.M. (Jack), Milaneschi, Y. (Yuri), Perry, J.R.B. (John), Altshuler, D. (David), Elosua, R. (Roberto), Kathiresan, S. (Sekar), Lucas, G. (Gavin), Melander, O. (Olle), O'Donnell, C.J. (Christopher), Schwartz, S.M. (Stephen), Voight, B.F. (Benjamin), Smith, A.V. (Davey), Geus, E.J.C. (Eco) de, Chanock, S.J. (Stephen), Gu, F. (Fangyi), Hankinson, S.E. (Susan), Hunter, D. (David), Chasman, D.I. (Daniel), Everett, B.M. (Brendan), Paré, G. (Guillaume), Ridker, P.M. (Paul), Li, M.D. (Ming), Maes, H.H. (Hermine), Audrain-Mcgovern, J. (Janet), Posthuma, D. (Danielle), Thornton, L.M. (Laura), Lerman, C. (Caryn), Rose, J.E. (Jed), Ioannidis, J.P.A. (John), Kraft, P. (Peter), Lin, D.Y. (Dan), Liu, J. (Jason), Muglia, P. (Pierandrea), Waterworth, D. (Dawn), Pillai, A.D. (Ajay), Middleton, L. (Lefkos), Berrettini, W. (Wade), Knouff, C.W. (Christopher), Yuan, X. (Xin), Waeber, G. (Gérard), Vollenweider, P. (Peter), Preisig, M. (Martin), Wareham, N.J. (Nick), Zhao, J.H. (Jing Hua), Loos, R.J.F. (Ruth), Barroso, I.E. (Inês), Khaw, K-T. (Kay-Tee), Grundy, S.M. (Scott), Barter, P. (Phil), Mahley, R. (Robert), Kesaniemi, Y.A. (Antero), McPherson, R. (Ruth), Vincent, J. (John), Strauss, J.S. (John S), Kennedy, J. (James), Farmer, A.E. (Anne E), Mcguffin, P. (Peter), Day, R.N. (Richard), Matthews, K. (Keith), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Lucae, S. (Susanne), Ising, M. (Marcus), Brueckl, T. (Tanja), Horstmann, S. (Sonja), Heinrich, J. (Joachim), Lamina, C. (Claudia), Polasek, O. (Ozren), Zgaga, L. (Lina), Huffman, J.E. (Jennifer), Campbell, S. (Susan), Kooner, J.S. (Jaspal), Chambers, J.C. (John), Burnett, M.S., Devaney, J. (Joseph), Pichard, A.D., Kent, K.M. (Kenneth), Satler, L.F., Lindsay, J.M. (Joseph), Waksman, R. (Ron), Epstein, S.E. (Stephen), Wilson, J.F. (James), Wild, S.H. (Sarah), Campbell, H. (Harry), Vitart, V. (Veronique), Reilly, M.P. (Muredach), Li, M. (Mingyao), Qu, L. (Liming), Wilensky, A. (Asaf), Matthai, W. (William), Hakonarson, H. (Hakon), Rader, D.J. (Daniel), Franke, A. (Andre), Wittig, M. (Michael), Schäfer, A. (Arne), Uda, M. (Manuela), Terracciano, A., Xiao, X. (Xiangjun), Busonero, F., Scheet, P. (Paul), Schlessinger, D., Clair, D.S., Rujescu, D. (Dan), Abecasis, G.R. (Gonçalo), Grabe, H.J. (Hans Jörgen), Teumer, A. (Alexander), Völzke, H. (Henry), Petersmann, A. (Astrid), John, U. (Ulrich), Rudan, I. (Igor), Hayward, C. (Caroline), Wright, A.F. (Alan), Kolcic, I. (Ivana), Wright, B.J. (Benjamin), Balmforth, A.J. (Anthony), Anderson, C. (Carl), Ahmed, T. (Tariq), Mathew, J. (Joseph), Parkes, M. (Miles), Satsangi, J. (Jack), Caulfield, M. (Mark), Munroe, P. (Patricia), Farrall, M. (Martin), Dominiczak, A. (Anna), Worthington, H. (Helen), Thomson, W. (Wendy), Eyre, D.S. (Dylan Samuel), Barton, A. (Anne), Mooser, V. (Vincent), Francks, C. (Clyde), Thorgeirsson, T.E. (Thorgeir), Gudbjartsson, D.F. (Daniel), Sulem, P. (Patrick), Besenbacher, S. (Søren), Styrkarsdottir, U. (Unnur), Thorleifsson, G. (Gudmar), Walters, G.B. (Bragi), Furberg, H. (Helena), Sullivan, P. (Patrick), Marchini, J. (Jonathan), McCarthy, M.I. (M.), Steinthorsdottir, V. (Valgerdur), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Surakka, I. (Ida), Vink, J.M. (Jacqueline), Amin, N. (Najaf), Geller, F. (Frank), Rafnar, T. (Thorunn), Esko, T. (Tõnu), Walter, S. (Stefan), Gieger, C. (Christian), Rawal, R. (Rajesh), Mangino, M. (Massimo), Prokopenko, I. (Inga), Mägi, R. (Reedik), Keskitalo, K. (Kaisu), Gudjonsdottir, I.H. (Iris), Gretarsdottir, S. (Solveig), Stefansson, H. (Hreinn), Aulchenko, Y.S. (Yurii), Nelis, M. (Mari), Aben, K.K.H. (Katja), Heijer, M. (Martin) den, Soranzo, N. (Nicole), Valdes, A.M. (Ana Maria), Steves, C.J. (Claire), Uitterlinden, A.G. (André), Hofman, A. (Albert), Tönjes, A. (Anke), Kovacs, P. (Peter), Hottenga, J.J. (Jouke Jan), Willemsen, G.A.H.M. (Gonneke), Vogelzangs, N. (Nicole), Döring, A. (Angela), Dahmen, N. (N.), Nitz, B. (Barbara), Ripatti, S. (Samuli), Perola, M. (Markus), Kettunen, J. (Johannes), Hartikainen, A.L., Pouta, A. (Anneli), Laitinen, J. (Jaana), Isohanni, M.K. (Matti), Huei-Yi, S. (Shen), Allen, M. (Maxine), Krestyaninova, M. (Maria), Hall, A. (Anne), Thompson, J.R. (John), Oskarsson, H. (Hogni), Tyrfingsson, T. (Thorarinn), Kiemeney, L.A.L.M. (Bart), Jarvelin, M.-R. (Marjo-Riitta), Salomaa, V. (Veikko), Stumvoll, M. (Michael), Spector, T.D. (Timothy), Wichmann, H.E. (Heinz Erich), Metspalu, A. (Andres), Samani, N.J. (Nilesh), Penninx, B.W.J.H. (Brenda), Oostra, B.A. (Ben), Boomsma, D.I. (Dorret), Tiemeier, H.W. (Henning), Duijn, C.M. (Cornelia) van, Kaprio, J. (Jaakko), Gulcher, J.R. (Jeffrey), Kim, Y. (Yunjung), Dackor, J. (Jennifer), Boerwinkle, E.A. (Eric), Franceschini, N. (Nora), Ardissino, D. (Diego), Bernardinelli, L. (Luisa), Mannucci, P.M. (Pier), Mauri, F. (Francesco), Merlini, P.A. (Piera), Absher, D. (Devin), Assimes, T.L. (Themistocles), Fortmann, S.P. (Stephen), Iribarren, C. (Carlos), Knowles, J.W. (Joshua), Quertermous, T. (Thomas), Ferrucci, L. (Luigi), Tanaka, T. (Toshiko), Bis, J.C. (Joshua), Haritunians, T. (Talin), McKnight, B. (Barbara), Psaty, B.M. (Bruce), Taylor, K.D. (Kent), Thacker, E.L. (Evan), Almgren, P. (Peter), Groop, L. (Leif), Ladenvall, C. (Claes), Boehnke, M. (Michael), Jackson, A.U. (Anne), Mohlke, K.L. (Karen), Stringham, H.M. (Heather), Tuomilehto, J. (Jaakko), Benjamin, E.J. (Emelia), Hwang, S.J., Levy, D. (Daniel), Preis, S.R., Vasan, R.S. (Ramachandran Srini), Duan, J. (Jubao), Gejman, P.V. (Pablo), Levinson, D.F. (Douglas), Sanders, A.R. (Alan), Shi, J. (Jianxin), Lips, E.H. (Esther), McKay, J.D. (James), Agudo, A. (Antonio), Barzan, L. (Luigi), Bencko, V. (Vladimir), Benhamou, S. (Simone), Castellsagué, X. (Xavier), Canova, C. (Cristina), Conway, D.I. (David), Fabianova, E. (Eleonora), Foretova, L. (Lenka), Janout, V. (Vladimir), Healy, C.M. (Claire), Holcátová, I. (Ivana), Kjaerheim, K. (Kristina), Lagiou, P., Lissowska, J. (Jolanta), Lowry, R. (Ray), MacFarlane, T.V. (Tatiana), Mates, D. (Dana), Richiardi, L. (Lorenzo), Rudnai, P. (Peter), Szeszenia-Dabrowska, N. (Neonilia), Zaridze, D., Znaor, A. (Ariana), Lathrop, M. (Mark), Brennan, P. (Paul), Bandinelli, S. (Stefania), Frayling, T.M. (Timothy), Guralnik, J.M. (Jack), Milaneschi, Y. (Yuri), Perry, J.R.B. (John), Altshuler, D. (David), Elosua, R. (Roberto), Kathiresan, S. (Sekar), Lucas, G. (Gavin), Melander, O. (Olle), O'Donnell, C.J. (Christopher), Schwartz, S.M. (Stephen), Voight, B.F. (Benjamin), Smith, A.V. (Davey), Geus, E.J.C. (Eco) de, Chanock, S.J. (Stephen), Gu, F. (Fangyi), Hankinson, S.E. (Susan), Hunter, D. (David), Chasman, D.I. (Daniel), Everett, B.M. (Brendan), Paré, G. (Guillaume), Ridker, P.M. (Paul), Li, M.D. (Ming), Maes, H.H. (Hermine), Audrain-Mcgovern, J. (Janet), Posthuma, D. (Danielle), Thornton, L.M. (Laura), Lerman, C. (Caryn), Rose, J.E. (Jed), Ioannidis, J.P.A. (John), Kraft, P. (Peter), Lin, D.Y. (Dan), Liu, J. (Jason), Muglia, P. (Pierandrea), Waterworth, D. (Dawn), Pillai, A.D. (Ajay), Middleton, L. (Lefkos), Berrettini, W. (Wade), Knouff, C.W. (Christopher), Yuan, X. (Xin), Waeber, G. (Gérard), Vollenweider, P. (Peter), Preisig, M. (Martin), Wareham, N.J. (Nick), Zhao, J.H. (Jing Hua), Loos, R.J.F. (Ruth), Barroso, I.E. (Inês), Khaw, K-T. (Kay-Tee), Grundy, S.M. (Scott), Barter, P. (Phil), Mahley, R. (Robert), Kesaniemi, Y.A. (Antero), McPherson, R. (Ruth), Vincent, J. (John), Strauss, J.S. (John S), Kennedy, J. (James), Farmer, A.E. (Anne E), Mcguffin, P. (Peter), Day, R.N. (Richard), Matthews, K. (Keith), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Lucae, S. (Susanne), Ising, M. (Marcus), Brueckl, T. (Tanja), Horstmann, S. (Sonja), Heinrich, J. (Joachim), Lamina, C. (Claudia), Polasek, O. (Ozren), Zgaga, L. (Lina), Huffman, J.E. (Jennifer), Campbell, S. (Susan), Kooner, J.S. (Jaspal), Chambers, J.C. (John), Burnett, M.S., Devaney, J. (Joseph), Pichard, A.D., Kent, K.M. (Kenneth), Satler, L.F., Lindsay, J.M. (Joseph), Waksman, R. (Ron), Epstein, S.E. (Stephen), Wilson, J.F. (James), Wild, S.H. (Sarah), Campbell, H. (Harry), Vitart, V. (Veronique), Reilly, M.P. (Muredach), Li, M. (Mingyao), Qu, L. (Liming), Wilensky, A. (Asaf), Matthai, W. (William), Hakonarson, H. (Hakon), Rader, D.J. (Daniel), Franke, A. (Andre), Wittig, M. (Michael), Schäfer, A. (Arne), Uda, M. (Manuela), Terracciano, A., Xiao, X. (Xiangjun), Busonero, F., Scheet, P. (Paul), Schlessinger, D., Clair, D.S., Rujescu, D. (Dan), Abecasis, G.R. (Gonçalo), Grabe, H.J. (Hans Jörgen), Teumer, A. (Alexander), Völzke, H. (Henry), Petersmann, A. (Astrid), John, U. (Ulrich), Rudan, I. (Igor), Hayward, C. (Caroline), Wright, A.F. (Alan), Kolcic, I. (Ivana), Wright, B.J. (Benjamin), Balmforth, A.J. (Anthony), Anderson, C. (Carl), Ahmed, T. (Tariq), Mathew, J. (Joseph), Parkes, M. (Miles), Satsangi, J. (Jack), Caulfield, M. (Mark), Munroe, P. (Patricia), Farrall, M. (Martin), Dominiczak, A. (Anna), Worthington, H. (Helen), Thomson, W. (Wendy), Eyre, D.S. (Dylan Samuel), Barton, A. (Anne), Mooser, V. (Vincent), and Francks, C. (Clyde)
Abstract: Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34 216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10-7). These findings replicate in a second large data set (N=127 274, thereof 76 242 smokers) for both SI (P=1.2 × 10-5) and CPD (P=9.3 × 10-5). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.
Published: 2013
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43. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.

Author: Jostins, L., Ripke, S., Weersma, R.K., Duerr, R.H., McGovern, D.P., Hui, K.Y., Lee, J.C., Schumm, L.P., Sharma, Y., Anderson, C.A., Essers, J., Mitrovic, M., Ning, K., Cleynen, I., Theatre, E., Spain, S.L., Raychaudhuri, S., Goyette, P., Wei, Z., Abraham, C., Achkar, J.P., Ahmad, T., Amininejad, L., Ananthakrishnan, A.N., Andersen, V., Andrews, J.M., Baidoo, L., Balschun, T., Bampton, P.A., Bitton, A., Boucher, G., Brand, S., Buning, C., Cohain, A., Cichon, S., D'Amato, M., Jong, D.J. de, Devaney, K.L., Dubinsky, M.C., Edwards, C., Ellinghaus, D., Ferguson, L.R., Franchimont, D., Fransen, K., Gearry, R.B., Georges, M., Gieger, C., Glas, J., Haritunians, T., Hart, A., Hawkey, C.J., Hedl, M., Hu, X., Karlsen, T.H., Kupcinskas, L., Kugathasan, S., Latiano, A., Laukens, D., Lawrance, I.C., Lees, C.W., Louis, E., Mahy, G., Mansfield, J., Morgan, A.R., Mowat, C., Newman, W.G., Palmieri, O., Ponsioen, C.Y., Potocnik, U., Prescott, N.J., Regueiro, M., Rotter, J.I., Russell, R.K., Sanderson, J.D., Sans, M., Satsangi, J., Schreiber, S., Simms, L.A., Sventoraityte, J., Targan, S.R., Taylor, K.D., Tremelling, M., Verspaget, H.W., Vos, M de, Wijmenga, C., Winkelmann, J., Wilson, D.C., Xavier, R.J., Zeissig, S., Zhang, B., Zhang, C.K., Zhao, H., Silverberg, M.S., Annesse, V., Hakonarson, H., Brant, S.R., Radford-Smith, G., Mathew, C.G., Rioux, J.D., Schadt, E.E., Daly, M.J., Franke, A., Parkes, M., Vermeire, S., Barrett, J.C., Cho, J.H., Donnelly, J.P., et al., Jostins, L., Ripke, S., Weersma, R.K., Duerr, R.H., McGovern, D.P., Hui, K.Y., Lee, J.C., Schumm, L.P., Sharma, Y., Anderson, C.A., Essers, J., Mitrovic, M., Ning, K., Cleynen, I., Theatre, E., Spain, S.L., Raychaudhuri, S., Goyette, P., Wei, Z., Abraham, C., Achkar, J.P., Ahmad, T., Amininejad, L., Ananthakrishnan, A.N., Andersen, V., Andrews, J.M., Baidoo, L., Balschun, T., Bampton, P.A., Bitton, A., Boucher, G., Brand, S., Buning, C., Cohain, A., Cichon, S., D'Amato, M., Jong, D.J. de, Devaney, K.L., Dubinsky, M.C., Edwards, C., Ellinghaus, D., Ferguson, L.R., Franchimont, D., Fransen, K., Gearry, R.B., Georges, M., Gieger, C., Glas, J., Haritunians, T., Hart, A., Hawkey, C.J., Hedl, M., Hu, X., Karlsen, T.H., Kupcinskas, L., Kugathasan, S., Latiano, A., Laukens, D., Lawrance, I.C., Lees, C.W., Louis, E., Mahy, G., Mansfield, J., Morgan, A.R., Mowat, C., Newman, W.G., Palmieri, O., Ponsioen, C.Y., Potocnik, U., Prescott, N.J., Regueiro, M., Rotter, J.I., Russell, R.K., Sanderson, J.D., Sans, M., Satsangi, J., Schreiber, S., Simms, L.A., Sventoraityte, J., Targan, S.R., Taylor, K.D., Tremelling, M., Verspaget, H.W., Vos, M de, Wijmenga, C., Winkelmann, J., Wilson, D.C., Xavier, R.J., Zeissig, S., Zhang, B., Zhang, C.K., Zhao, H., Silverberg, M.S., Annesse, V., Hakonarson, H., Brant, S.R., Radford-Smith, G., Mathew, C.G., Rioux, J.D., Schadt, E.E., Daly, M.J., Franke, A., Parkes, M., Vermeire, S., Barrett, J.C., Cho, J.H., Donnelly, J.P., and et al.
Abstract: Item does not contain fulltext
Published: 2012

44. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.

Author: Jostins, L., Ripke, S., Weersma, R.K., Duerr, R.H., McGovern, D.P., Hui, K.Y., Lee, J.C., Schumm, L.P., Sharma, Y., Anderson, C.A., Essers, J., Mitrovic, M., Ning, K., Cleynen, I., Theatre, E., Spain, S.L., Raychaudhuri, S., Goyette, P., Wei, Z., Abraham, C., Achkar, J.P., Ahmad, T., Amininejad, L., Ananthakrishnan, A.N., Andersen, V., Andrews, J.M., Baidoo, L., Balschun, T., Bampton, P.A., Bitton, A., Boucher, G., Brand, S., Buning, C., Cohain, A., Cichon, S., D'Amato, M., Jong, D.J. de, Devaney, K.L., Dubinsky, M.C., Edwards, C., Ellinghaus, D., Ferguson, L.R., Franchimont, D., Fransen, K., Gearry, R.B., Georges, M., Gieger, C., Glas, J., Haritunians, T., Hart, A., Hawkey, C.J., Hedl, M., Hu, X., Karlsen, T.H., Kupcinskas, L., Kugathasan, S., Latiano, A., Laukens, D., Lawrance, I.C., Lees, C.W., Louis, E., Mahy, G., Mansfield, J., Morgan, A.R., Mowat, C., Newman, W.G., Palmieri, O., Ponsioen, C.Y., Potocnik, U., Prescott, N.J., Regueiro, M., Rotter, J.I., Russell, R.K., Sanderson, J.D., Sans, M., Satsangi, J., Schreiber, S., Simms, L.A., Sventoraityte, J., Targan, S.R., Taylor, K.D., Tremelling, M., Verspaget, H.W., Vos, M de, Wijmenga, C., Winkelmann, J., Wilson, D.C., Xavier, R.J., Zeissig, S., Zhang, B., Zhang, C.K., Zhao, H., Silverberg, M.S., Annesse, V., Hakonarson, H., Brant, S.R., Radford-Smith, G., Mathew, C.G., Rioux, J.D., Schadt, E.E., Daly, M.J., Franke, A., Parkes, M., Vermeire, S., Barrett, J.C., Cho, J.H., Donnelly, J.P., et al., Jostins, L., Ripke, S., Weersma, R.K., Duerr, R.H., McGovern, D.P., Hui, K.Y., Lee, J.C., Schumm, L.P., Sharma, Y., Anderson, C.A., Essers, J., Mitrovic, M., Ning, K., Cleynen, I., Theatre, E., Spain, S.L., Raychaudhuri, S., Goyette, P., Wei, Z., Abraham, C., Achkar, J.P., Ahmad, T., Amininejad, L., Ananthakrishnan, A.N., Andersen, V., Andrews, J.M., Baidoo, L., Balschun, T., Bampton, P.A., Bitton, A., Boucher, G., Brand, S., Buning, C., Cohain, A., Cichon, S., D'Amato, M., Jong, D.J. de, Devaney, K.L., Dubinsky, M.C., Edwards, C., Ellinghaus, D., Ferguson, L.R., Franchimont, D., Fransen, K., Gearry, R.B., Georges, M., Gieger, C., Glas, J., Haritunians, T., Hart, A., Hawkey, C.J., Hedl, M., Hu, X., Karlsen, T.H., Kupcinskas, L., Kugathasan, S., Latiano, A., Laukens, D., Lawrance, I.C., Lees, C.W., Louis, E., Mahy, G., Mansfield, J., Morgan, A.R., Mowat, C., Newman, W.G., Palmieri, O., Ponsioen, C.Y., Potocnik, U., Prescott, N.J., Regueiro, M., Rotter, J.I., Russell, R.K., Sanderson, J.D., Sans, M., Satsangi, J., Schreiber, S., Simms, L.A., Sventoraityte, J., Targan, S.R., Taylor, K.D., Tremelling, M., Verspaget, H.W., Vos, M de, Wijmenga, C., Winkelmann, J., Wilson, D.C., Xavier, R.J., Zeissig, S., Zhang, B., Zhang, C.K., Zhao, H., Silverberg, M.S., Annesse, V., Hakonarson, H., Brant, S.R., Radford-Smith, G., Mathew, C.G., Rioux, J.D., Schadt, E.E., Daly, M.J., Franke, A., Parkes, M., Vermeire, S., Barrett, J.C., Cho, J.H., Donnelly, J.P., and et al.
Abstract: Item does not contain fulltext
Published: 2012

45. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Author: Anderson, CA, Boucher, G, Lees, CW, Franke, A, D'Amato, M, Taylor, KD, Lee, JC, Goyette, P, Imielinski, M, Latiano, A, Lagace, C, Scott, R, Amininejad, L, Bumpstead, S, Baidoo, L, Baldassano, RN, Barclay, M, Bayless, TM, Brand, S, Buening, C, Colombel, J-F, Denson, LA, De Vos, M, Dubinsky, M, Edwards, C, Ellinghaus, D, Fehrmann, RSN, Floyd, JAB, Florin, T, Franchimont, D, Franke, L, Georges, M, Glas, J, Glazer, NL, Guthery, SL, Haritunians, T, Hayward, NK, Hugot, J-P, Jobin, G, Laukens, D, Lawrance, I, Lemann, M, Levine, A, Libioulle, C, Louis, E, McGovern, DP, Milla, M, Montgomery, GW, Morley, KI, Mowat, C, Ng, A, Newman, W, Ophoff, RA, Papi, L, Palmieri, O, Peyrin-Biroulet, L, Panes, J, Phillips, A, Prescott, NJ, Proctor, DD, Roberts, R, Russell, R, Rutgeerts, P, Sanderson, J, Sans, M, Schumm, P, Seibold, F, Sharma, Y, Simms, LA, Seielstad, M, Steinhart, AH, Targan, SR, van den Berg, LH, Vatn, M, Verspaget, H, Walters, T, Wijmenga, C, Wilson, DC, Westra, H-J, Xavier, RJ, Zhao, ZZ, Ponsioen, CY, Andersen, V, Torkvist, L, Gazouli, M, Anagnou, NP, Karlsen, TH, Kupcinskas, L, Sventoraityte, J, Mansfield, JC, Kugathasan, S, Silverberg, MS, Halfvarson, J, Rotter, JI, Mathew, CG, Griffiths, AM, Gearry, R, Ahmad, T, Brant, SR, Chamaillard, M, Satsangi, J, Cho, JH, Schreiber, S, Daly, MJ, Barrett, JC, Parkes, M, Annese, V, Hakonarson, H, Radford-Smith, G, Duerr, RH, Vermeire, S, Weersma, RK, Rioux, JD, Anderson, CA, Boucher, G, Lees, CW, Franke, A, D'Amato, M, Taylor, KD, Lee, JC, Goyette, P, Imielinski, M, Latiano, A, Lagace, C, Scott, R, Amininejad, L, Bumpstead, S, Baidoo, L, Baldassano, RN, Barclay, M, Bayless, TM, Brand, S, Buening, C, Colombel, J-F, Denson, LA, De Vos, M, Dubinsky, M, Edwards, C, Ellinghaus, D, Fehrmann, RSN, Floyd, JAB, Florin, T, Franchimont, D, Franke, L, Georges, M, Glas, J, Glazer, NL, Guthery, SL, Haritunians, T, Hayward, NK, Hugot, J-P, Jobin, G, Laukens, D, Lawrance, I, Lemann, M, Levine, A, Libioulle, C, Louis, E, McGovern, DP, Milla, M, Montgomery, GW, Morley, KI, Mowat, C, Ng, A, Newman, W, Ophoff, RA, Papi, L, Palmieri, O, Peyrin-Biroulet, L, Panes, J, Phillips, A, Prescott, NJ, Proctor, DD, Roberts, R, Russell, R, Rutgeerts, P, Sanderson, J, Sans, M, Schumm, P, Seibold, F, Sharma, Y, Simms, LA, Seielstad, M, Steinhart, AH, Targan, SR, van den Berg, LH, Vatn, M, Verspaget, H, Walters, T, Wijmenga, C, Wilson, DC, Westra, H-J, Xavier, RJ, Zhao, ZZ, Ponsioen, CY, Andersen, V, Torkvist, L, Gazouli, M, Anagnou, NP, Karlsen, TH, Kupcinskas, L, Sventoraityte, J, Mansfield, JC, Kugathasan, S, Silverberg, MS, Halfvarson, J, Rotter, JI, Mathew, CG, Griffiths, AM, Gearry, R, Ahmad, T, Brant, SR, Chamaillard, M, Satsangi, J, Cho, JH, Schreiber, S, Daly, MJ, Barrett, JC, Parkes, M, Annese, V, Hakonarson, H, Radford-Smith, G, Duerr, RH, Vermeire, S, Weersma, RK, and Rioux, JD
Abstract: Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.
Published: 2011

46. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author: Craddock, N, Hurles, ME, Cardin, N, Pearson, RD, Plagnol, V, Robson, S, Vukcevic, D, Barnes, C, Conrad, DF, Giannoulatou, E, Holmes, C, Marchini, JL, Stirrups, K, Tobin, MD, Wain, LV, Yau, C, Aerts, J, Ahmad, T, Andrews, TD, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Clee, CM, Coffey, AJ, Connell, JMC, Cooper, JD, Dominiczak, AF, Downes, K, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Feuk, L, Fitzgerald, T, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Freathy, RM, Gibbs, P, Gilbert, P, Gokumen, O, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Onyiah, I, Ovington, NR, Owen, MJ, Palin, K, Parnell, K, Pernet, D, Perry, JRB, Phillips, A, Pinto, D, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Redon, R, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Russell, E, St Clair, D, Sambrook, JG, Sanderson, JD, Schuilenburg, H, Scott, CE, Scott, R, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stone, MA, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Travers, ME, Turnbull, C, Valsesia, A, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Young, AH, Zeggini, E, Carter, NP, Frayling, TM, Lee, C, McVean, G, Munroe, PB, Palotie, A, Sawcer, SJ, Scherer, SW, Strachan, DP, Tyler-Smith, C, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Deloukas, P, Duncanson, A, Kwiatkowski, DP, McCarthy, MI, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ, Donnelly, P, Craddock, N, Hurles, ME, Cardin, N, Pearson, RD, Plagnol, V, Robson, S, Vukcevic, D, Barnes, C, Conrad, DF, Giannoulatou, E, Holmes, C, Marchini, JL, Stirrups, K, Tobin, MD, Wain, LV, Yau, C, Aerts, J, Ahmad, T, Andrews, TD, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Clee, CM, Coffey, AJ, Connell, JMC, Cooper, JD, Dominiczak, AF, Downes, K, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Feuk, L, Fitzgerald, T, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Freathy, RM, Gibbs, P, Gilbert, P, Gokumen, O, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Onyiah, I, Ovington, NR, Owen, MJ, Palin, K, Parnell, K, Pernet, D, Perry, JRB, Phillips, A, Pinto, D, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Redon, R, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Russell, E, St Clair, D, Sambrook, JG, Sanderson, JD, Schuilenburg, H, Scott, CE, Scott, R, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stone, MA, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Travers, ME, Turnbull, C, Valsesia, A, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Young, AH, Zeggini, E, Carter, NP, Frayling, TM, Lee, C, McVean, G, Munroe, PB, Palotie, A, Sawcer, SJ, Scherer, SW, Strachan, DP, Tyler-Smith, C, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Deloukas, P, Duncanson, A, Kwiatkowski, DP, McCarthy, MI, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ, and Donnelly, P
Abstract: Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
Published: 2010

47. Effect of HLA class II genotype on T helper lymphocyte responses and viral control in hepatitis C virus infection

Author: Harcourt, G., Hellier, S., Bunce, M., Satsangi, J., Collier, J., Chapman, R., Phillips, R., Klenerman, P., Harcourt, G., Hellier, S., Bunce, M., Satsangi, J., Collier, J., Chapman, R., Phillips, R., and Klenerman, P.
Abstract: Hepatitis C virus (HCV) infection is very common worldwide, but has a broad range of outcomes. A minority of patients are able to clear infection spontaneously, and this is thought to be due to the emergence and maintenance of effective cell-mediated immunity, particularly CD4+ T lymphocyte responses. Furthermore, genetic studies have indicated that HLA class II genotype strongly influences the outcome of infection. We have therefore investigated the influence of the protective HLA class II haplotype (DQB1*0301, which is in tight linkage disequilibrium with DRB1*1101) on the CD4+ T lymphocyte responses to HCV. We observe a strong association between this genotype and maintenance of a multispecific CD4+ T helper response. The effect on T helper responses was also maintained after combination interferon-α/ribavirin therapy, although the latter influenced the pattern of viral antigens to which patients responded. This is the first disease in which an association of HLA genotype with clinical outcome has been linked to an alteration of the immunological phenotype. The selection of protective peptides in those with the favourable HLA class II genotype may point in the direction of suitable vaccine candidates.
Published: 2001

48. The genetics of inflammatory bowel disease

Author: Ahmad, T., Satsangi, J., Mcgovern, D., Bunce, M., Jewell, D.P., Ahmad, T., Satsangi, J., Mcgovern, D., Bunce, M., and Jewell, D.P.
Abstract: Recent epidemiological, clinical and molecular studies have provided strong evidence that inherited predisposition is important in the pathogenesis of chronic inflammatory bowel diseases. The model most consistent with the epidemiological data suggests that Crohn’s disease and ulcerative colitis are related polygenic diseases, sharing some but not all susceptibility genes. Investigators throughout the world have applied the complementary techniques of genome-wide scanning and candidate gene analysis. Four areas of linkage have been widely replicated on chromosomes 16 (IBD1), 12 (IBD2), 6 (IBD3—the HLA region), and most recently on chromosome 14. Fine mapping of these regions is underway. Of the ‘positional’ candidate genes, most attention has centred on the genes of the major histocompatibility complex. Genes within this region may determine disease susceptibility, behaviour, complications and response to therapy. Hope continues that studies of inflammatory bowel disease genetics will provide fresh insight into disease pathogenesis and soon deliver clinical applications.
Published: 2001

49. The genetics of inflammatory bowel disease

Author: Ahmad, T., Satsangi, J., Mcgovern, D., Bunce, M., Jewell, D.P., Ahmad, T., Satsangi, J., Mcgovern, D., Bunce, M., and Jewell, D.P.
Abstract: Recent epidemiological, clinical and molecular studies have provided strong evidence that inherited predisposition is important in the pathogenesis of chronic inflammatory bowel diseases. The model most consistent with the epidemiological data suggests that Crohn’s disease and ulcerative colitis are related polygenic diseases, sharing some but not all susceptibility genes. Investigators throughout the world have applied the complementary techniques of genome-wide scanning and candidate gene analysis. Four areas of linkage have been widely replicated on chromosomes 16 (IBD1), 12 (IBD2), 6 (IBD3—the HLA region), and most recently on chromosome 14. Fine mapping of these regions is underway. Of the ‘positional’ candidate genes, most attention has centred on the genes of the major histocompatibility complex. Genes within this region may determine disease susceptibility, behaviour, complications and response to therapy. Hope continues that studies of inflammatory bowel disease genetics will provide fresh insight into disease pathogenesis and soon deliver clinical applications.
Published: 2001

50. Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease

Author: Satsangi, J., Farrant, J., Jewell, D.P., Bell, J.I., Welsh, K.I., Bunce, M., Julier, C., Satsangi, J., Farrant, J., Jewell, D.P., Bell, J.I., Welsh, K.I., Bunce, M., and Julier, C.
Abstract: Background Despite strong evidence implicating immune dysfunction and genetic predisposition in the pathogenesis of the chronic inflammatory bowel diseases Crohn's disease and ulcerative colitis, the importance of the genes of the major histocompatibility complex remains uncertain. We have investigated the contribution of HLA DRB1 and DQB genes by the strategies of non-parametric linkage analysis (affected sibling pair method) as well as association study. The relation between genotype and phenotype was examined in detail. Methods For linkage analysis 74 families in whom two or more siblings had inflammatory bowel disease were studied. A total of 83 affected sibling pairs were involved: in 42 pairs both siblings had Crohn's disease; in 29 both had ulcerative colitis; in 12 one sibling had Crohn's disease, the other ulcerative colitis. For the association study there were 175 patients with ulcerative colitis, 173 with Crohn's disease, and 472 controls. Details of sex, age of onset, disease extent, and family history were analysed. 24 patients with ulcerative colitis and 92 with Crohn's disease required surgery for refractory disease. HLA DRB1 and DQB1 gene-typing was performed by polymerase chain reaction with sequence-specific primers. Findings In ulcerative colitis, the sharing of alleles among affected sibling pairs provided evidence for linkage with DRB1 locus (p=0•017, X2=5•32). Of 29 affected sibling pairs studied, only one pair shared no DRB1 DQB haplotypes. 15 shared two DRB DQB haplotypes. In contrast, no linkage was noted for Crohn's disease (42 sibling pairs; p=0•30, X2=0•16) or for inflammatory bowel disease overall (83 sibling pairs, p=0•16, X2=2•28). In the association study the rare DRB1*103 (8•3% vs 3•2% in controls) and DRB1*12 (8•6% vs 2•1% in controls) alleles were associated with ulcerative colitis (p=0•0074, X2=7•22, odds ratio OR=2•9 [95% Cl 1•3-6•4] and p=0•0056, X2=12•63, OR=4•33 [1•8-11•0] respectively). No association with alleles representi
Published: 1996

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