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51. The gut microbiome across the cardiovascular risk spectrum

Author

Cardiologie, Gezonde Vaten, Circulatory Health, Prins, Femke M., Collij, Valerie, Groot, Hilde E., Björk, Johannes R., Swarte, J. Casper, Andreu-Sánchez, Sergio, Jansen, Bernadien H., Fu, Jingyuan, Harmsen, Hermie J.M., Zhernakova, Alexandra, Lipsic, Erik, Van Der Harst, Pim, Weersma, Rinse K., Gacesa, Ranko, Cardiologie, Gezonde Vaten, Circulatory Health, Prins, Femke M., Collij, Valerie, Groot, Hilde E., Björk, Johannes R., Swarte, J. Casper, Andreu-Sánchez, Sergio, Jansen, Bernadien H., Fu, Jingyuan, Harmsen, Hermie J.M., Zhernakova, Alexandra, Lipsic, Erik, Van Der Harst, Pim, Weersma, Rinse K., and Gacesa, Ranko

Published
2024

52. Limited predictive value of the gut microbiome and metabolome for response to biological therapy in inflammatory bowel disease

Author

MS MDL 1, Cancer, Infection & Immunity, Prins, Femke M, Hidding, Iwan J, Klaassen, Marjolein A Y, Collij, Valerie, Schultheiss, Johannes P D, Uniken Venema, Werna T C, Bangma, Amber, Aardema, Jurne B, Jansen, Bernadien H, Mares, Wout G N, Witteman, Ben J M, Festen, Eleonora A M, Dijkstra, Gerard, Visschedijk, Marijn C, Fidder, Herma H, Vich Vila, Arnau, Oldenburg, Bas, Gacesa, Ranko, Weersma, Rinse K, MS MDL 1, Cancer, Infection & Immunity, Prins, Femke M, Hidding, Iwan J, Klaassen, Marjolein A Y, Collij, Valerie, Schultheiss, Johannes P D, Uniken Venema, Werna T C, Bangma, Amber, Aardema, Jurne B, Jansen, Bernadien H, Mares, Wout G N, Witteman, Ben J M, Festen, Eleonora A M, Dijkstra, Gerard, Visschedijk, Marijn C, Fidder, Herma H, Vich Vila, Arnau, Oldenburg, Bas, Gacesa, Ranko, and Weersma, Rinse K

Published
2024

54. Author Correction: Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch Microbiome Project

Author

Lopera-Maya, Esteban A., Kurilshikov, Alexander, van der Graaf, Adriaan, Hu, Shixian, Andreu-Sánchez, Sergio, Chen, Lianmin, Vila, Arnau Vich, Gacesa, Ranko, Sinha, Trishla, Collij, Valerie, Klaassen, Marjiolein A. Y., Bolte, Laura A., Gois, Milla F. Brandao, Neerincx, Pieter B. T., Swertz, Morris A., Harmsen, Hermie J. M., Wijmenga, Cisca, Fu, Jingyuan, Weersma, Rinse K., Zhernakova, Alexandra, and Sanna, Serena

Published
2022
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55. Crohn’s Disease–Associated Pathogenic Mutation in the Manganese Transporter ZIP8 Shifts the Ileal and Rectal Mucosal Microbiota Implicating Aberrant Bile Acid Metabolism

Author

Briggs, Kristi, primary, Tomar, Vartika, additional, Ollberding, Nicholas, additional, Haberman, Yael, additional, Bourgonje, Arno R, additional, Hu, Shixian, additional, Chaaban, Lara, additional, Sunuwar, Laxmi, additional, Weersma, Rinse K, additional, Denson, Lee A, additional, and Melia, Joanna M P, additional

Published
2024
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61. The gut microbiome across the cardiovascular risk spectrum

Author

Prins, Femke M, primary, Collij, Valerie, additional, Groot, Hilde E, additional, Björk, Johannes R, additional, Swarte, J Casper, additional, Andreu-Sánchez, Sergio, additional, Jansen, Bernadien H, additional, Fu, Jingyuan, additional, Harmsen, Hermie J M, additional, Zhernakova, Alexandra, additional, Lipsic, Erik, additional, van der Harst, Pim, additional, Weersma, Rinse K, additional, and Gacesa, Ranko, additional

Published
2023
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62. Multiomics Analyses to Deliver the Most Effective Treatment to Every Patient With Inflammatory Bowel Disease

Author

Weersma, R.K., Barrett, J.C., Vermeire, S., Xavier, R.J., Anderson, C.A., Wijmenga, C., Daly, M.J., Alm, E.J., Raes, J., Huttenhower, C., Stappenbeck, T., Netea, M., Kaser, A., Franke, A., McGovern, D.P., Colombel, J.F., van den Brink, G.R., Uhlig, H.H., Georges, M., Lees, C.W., Parkes, M., Giallourakis, C., Hart, A., Rioux, J.D., Sokol, H., Hurtado-Lorenzo, A., Yeretssian, G., Markus- de Kwaadsteniet, M.L., Festen, E.A., Rahmouni, S., Vieira-Silva, S., McIntyre, R.E., Moutsianas, L., Weersma, Rinse K., Xavier, Ramnik J., Vermeire, Severine, and Barrett, Jeffrey C.

Published
2018
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63. Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies

Author

Ellinghaus, David, Zhang, Hu, Zeissig, Sebastian, Lipinski, Simone, Till, Andreas, Jiang, Tao, Stade, Björn, Bromberg, Yana, Ellinghaus, Eva, Keller, Andreas, Rivas, Manuel A, Skieceviciene, Jurgita, Doncheva, Nadezhda T, Liu, Xiao, Liu, Qing, Jiang, Fuman, Forster, Michael, Mayr, Gabriele, Albrecht, Mario, Häsler, Robert, Boehm, Bernhard O, Goodall, Jane, Berzuini, Carlo R, Lee, James, Andersen, Vibeke, Vogel, Ulla, Kupcinskas, Limas, Kayser, Manfred, Krawczak, Michael, Nikolaus, Susanna, Weersma, Rinse K, Ponsioen, Cyriel Y, Sans, Miquel, Wijmenga, Cisca, Strachan, David P, McArdle, Wendy L, Vermeire, Séverine, Rutgeerts, Paul, Sanderson, Jeremy D, Mathew, Christopher G, Vatn, Morten H, Wang, Jun, Nöthen, Markus M, Duerr, Richard H, Büning, Carsten, Brand, Stephan, Glas, Jürgen, Winkelmann, Juliane, Illig, Thomas, Latiano, Anna, Annese, Vito, Halfvarson, Jonas, D'Amato, Mauro, Daly, Mark J, Nothnagel, Michael, Karlsen, Tom H, Subramani, Suresh, Rosenstiel, Philip, Schreiber, Stefan, Parkes, Miles, and Franke, Andre

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Nutrition and Dietetics, Human Genome, Genetics, Clinical Research, Crohn's Disease, Inflammatory Bowel Disease, Autoimmune Disease, Digestive Diseases, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Inflammatory and immune system, Adolescent, Adult, Case-Control Studies, Colitis, Ulcerative, Crohn Disease, Exome, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mutation, Missense, Nuclear Proteins, Polymorphism, Single Nucleotide, Positive Regulatory Domain I-Binding Factor 1, Quantitative Trait Loci, Repressor Proteins, Young Adult, Whole-Exome Sequencing, Complex Disease, CD, Crohn’s disease, GWAS, IBD, IFN, NF-κB, PBL, PBMC, SNP, SNV, TLR, Toll-like receptor, UC, WT, eQTL, expression quantitative trait locus, genome-wide association studies, inflammatory bowel disease, interferon, nuclear factor κB, peripheral blood lymphocyte, peripheral blood mononuclear cell, qRT-PCR, quantitative reverse-transcription polymerase chain reaction, single nucleotide polymorphism, single nucleotide variant, ulcerative colitis, wild-type, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsGenome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.MethodsWe sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.ResultsWe identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 × 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 × 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.ConclusionsWe have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.

Published
2013

64. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.

Author

Liu, Jimmy Z, Hov, Johannes Roksund, Folseraas, Trine, Ellinghaus, Eva, Rushbrook, Simon M, Doncheva, Nadezhda T, Andreassen, Ole A, Weersma, Rinse K, Weismüller, Tobias J, Eksteen, Bertus, Invernizzi, Pietro, Hirschfield, Gideon M, Gotthardt, Daniel Nils, Pares, Albert, Ellinghaus, David, Shah, Tejas, Juran, Brian D, Milkiewicz, Piotr, Rust, Christian, Schramm, Christoph, Müller, Tobias, Srivastava, Brijesh, Dalekos, Georgios, Nöthen, Markus M, Herms, Stefan, Winkelmann, Juliane, Mitrovic, Mitja, Braun, Felix, Ponsioen, Cyriel Y, Croucher, Peter JP, Sterneck, Martina, Teufel, Andreas, Mason, Andrew L, Saarela, Janna, Leppa, Virpi, Dorfman, Ruslan, Alvaro, Domenico, Floreani, Annarosa, Onengut-Gumuscu, Suna, Rich, Stephen S, Thompson, Wesley K, Schork, Andrew J, Næss, Sigrid, Thomsen, Ingo, Mayr, Gabriele, König, Inke R, Hveem, Kristian, Cleynen, Isabelle, Gutierrez-Achury, Javier, Ricaño-Ponce, Isis, van Heel, David, Björnsson, Einar, Sandford, Richard N, Durie, Peter R, Melum, Espen, Vatn, Morten H, Silverberg, Mark S, Duerr, Richard H, Padyukov, Leonid, Brand, Stephan, Sans, Miquel, Annese, Vito, Achkar, Jean-Paul, Boberg, Kirsten Muri, Marschall, Hanns-Ulrich, Chazouillères, Olivier, Bowlus, Christopher L, Wijmenga, Cisca, Schrumpf, Erik, Vermeire, Severine, Albrecht, Mario, UK-PSCSC Consortium, Rioux, John D, Alexander, Graeme, Bergquist, Annika, Cho, Judy, Schreiber, Stefan, Manns, Michael P, Färkkilä, Martti, Dale, Anders M, Chapman, Roger W, Lazaridis, Konstantinos N, International PSC Study Group, Franke, Andre, Anderson, Carl A, Karlsen, Tom H, and International IBD Genetics Consortium

Subjects
UK-PSCSC Consortium, International PSC Study Group, International IBD Genetics Consortium, Humans, Cholangitis, Sclerosing, Oligonucleotide Array Sequence Analysis, Risk Factors, Case-Control Studies, Gene Frequency, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci, Genetic Pleiotropy, Genotyping Techniques, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.

Published
2013

65. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Author

Jostins, Luke, Ripke, Stephan, Weersma, Rinse K, Duerr, Richard H, McGovern, Dermot P, Hui, Ken Y, Lee, James C, Philip Schumm, L, Sharma, Yashoda, Anderson, Carl A, Essers, Jonah, Mitrovic, Mitja, Ning, Kaida, Cleynen, Isabelle, Theatre, Emilie, Spain, Sarah L, Raychaudhuri, Soumya, Goyette, Philippe, Wei, Zhi, Abraham, Clara, Achkar, Jean-Paul, Ahmad, Tariq, Amininejad, Leila, Ananthakrishnan, Ashwin N, Andersen, Vibeke, Andrews, Jane M, Baidoo, Leonard, Balschun, Tobias, Bampton, Peter A, Bitton, Alain, Boucher, Gabrielle, Brand, Stephan, Büning, Carsten, Cohain, Ariella, Cichon, Sven, D’Amato, Mauro, De Jong, Dirk, Devaney, Kathy L, Dubinsky, Marla, Edwards, Cathryn, Ellinghaus, David, Ferguson, Lynnette R, Franchimont, Denis, Fransen, Karin, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jürgen, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hedl, Matija, Hu, Xinli, Karlsen, Tom H, Kupcinskas, Limas, Kugathasan, Subra, Latiano, Anna, Laukens, Debby, Lawrance, Ian C, Lees, Charlie W, Louis, Edouard, Mahy, Gillian, Mansfield, John, Morgan, Angharad R, Mowat, Craig, Newman, William, Palmieri, Orazio, Ponsioen, Cyriel Y, Potocnik, Uros, Prescott, Natalie J, Regueiro, Miguel, Rotter, Jerome I, Russell, Richard K, Sanderson, Jeremy D, Sans, Miquel, Satsangi, Jack, Schreiber, Stefan, Simms, Lisa A, Sventoraityte, Jurgita, Targan, Stephan R, Taylor, Kent D, Tremelling, Mark, Verspaget, Hein W, De Vos, Martine, Wijmenga, Cisca, Wilson, David C, Winkelmann, Juliane, Xavier, Ramnik J, Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K, Zhao, Hongyu, Silverberg, Mark S, Annese, Vito, Hakonarson, Hakon, Brant, Steven R, Radford-Smith, Graham, Mathew, Christopher G, Rioux, John D, and Schadt, Eric E

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Crohn's Disease, Human Genome, Autoimmune Disease, Inflammatory Bowel Disease, Digestive Diseases, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Colitis, Ulcerative, Crohn Disease, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Haplotypes, Host-Pathogen Interactions, Humans, Inflammatory Bowel Diseases, Mycobacterium, Mycobacterium Infections, Mycobacterium tuberculosis, Phenotype, Polymorphism, Single Nucleotide, Reproducibility of Results, International IBD Genetics Consortium, General Science & Technology
Abstract

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Published
2012

66. Unraveling the regulatory mechanisms underlying tissue-dependent genetic variation of gene expression.

Author

Fu, Jingyuan, Wolfs, Marcel GM, Deelen, Patrick, Westra, Harm-Jan, Fehrmann, Rudolf SN, Te Meerman, Gerard J, Buurman, Wim A, Rensen, Sander SM, Groen, Harry JM, Weersma, Rinse K, van den Berg, Leonard H, Veldink, Jan, Ophoff, Roel A, Snieder, Harold, van Heel, David, Jansen, Ritsert C, Hofker, Marten H, Wijmenga, Cisca, and Franke, Lude

Subjects
Muscle, Skeletal, Liver, Subcutaneous Tissue, Humans, Blood Proteins, Gene Expression Profiling, Organ Specificity, Gene Expression Regulation, Regulatory Sequences, Nucleic Acid, Genotype, Polymorphism, Single Nucleotide, Alleles, Quantitative Trait Loci, Genome, Human, Adolescent, Adult, Aged, Middle Aged, Female, Male, Intra-Abdominal Fat, Genome, Human, Muscle, Skeletal, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid, Genetics, Developmental Biology
Abstract

It is known that genetic variants can affect gene expression, but it is not yet completely clear through what mechanisms genetic variation mediate this expression. We therefore compared the cis-effect of single nucleotide polymorphisms (SNPs) on gene expression between blood samples from 1,240 human subjects and four primary non-blood tissues (liver, subcutaneous, and visceral adipose tissue and skeletal muscle) from 85 subjects. We characterized four different mechanisms for 2,072 probes that show tissue-dependent genetic regulation between blood and non-blood tissues: on average 33.2% only showed cis-regulation in non-blood tissues; 14.5% of the eQTL probes were regulated by different, independent SNPs depending on the tissue of investigation. 47.9% showed a different effect size although they were regulated by the same SNPs. Surprisingly, we observed that 4.4% were regulated by the same SNP but with opposite allelic direction. We show here that SNPs that are located in transcriptional regulatory elements are enriched for tissue-dependent regulation, including SNPs at 3' and 5' untranslated regions (P = 1.84×10(-5) and 4.7×10(-4), respectively) and SNPs that are synonymous-coding (P = 9.9×10(-4)). SNPs that are associated with complex traits more often exert a tissue-dependent effect on gene expression (P = 2.6×10(-10)). Our study yields new insights into the genetic basis of tissue-dependent expression and suggests that complex trait associated genetic variants have even more complex regulatory effects than previously anticipated.

Published
2012

67. Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA.

Author

Fehrmann, Rudolf SN, Jansen, Ritsert C, Veldink, Jan H, Westra, Harm-Jan, Arends, Danny, Bonder, Marc Jan, Fu, Jingyuan, Deelen, Patrick, Groen, Harry JM, Smolonska, Asia, Weersma, Rinse K, Hofstra, Robert MW, Buurman, Wim A, Rensen, Sander, Wolfs, Marcel GM, Platteel, Mathieu, Zhernakova, Alexandra, Elbers, Clara C, Festen, Eleanora M, Trynka, Gosia, Hofker, Marten H, Saris, Christiaan GJ, Ophoff, Roel A, van den Berg, Leonard H, van Heel, David A, Wijmenga, Cisca, Te Meerman, Gerard J, and Franke, Lude

Subjects
Monocytes, Humans, HLA Antigens, Chromosome Mapping, Gene Expression Profiling, Gene Expression Regulation, Genotype, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genetic Variation, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Genetics, Developmental Biology
Abstract

For many complex traits, genetic variants have been found associated. However, it is still mostly unclear through which downstream mechanism these variants cause these phenotypes. Knowledge of these intermediate steps is crucial to understand pathogenesis, while also providing leads for potential pharmacological intervention. Here we relied upon natural human genetic variation to identify effects of these variants on trans-gene expression (expression quantitative trait locus mapping, eQTL) in whole peripheral blood from 1,469 unrelated individuals. We looked at 1,167 published trait- or disease-associated SNPs and observed trans-eQTL effects on 113 different genes, of which we replicated 46 in monocytes of 1,490 different individuals and 18 in a smaller dataset that comprised subcutaneous adipose, visceral adipose, liver tissue, and muscle tissue. HLA single-nucleotide polymorphisms (SNPs) were 10-fold enriched for trans-eQTLs: 48% of the trans-acting SNPs map within the HLA, including ulcerative colitis susceptibility variants that affect plausible candidate genes AOAH and TRBV18 in trans. We identified 18 pairs of unlinked SNPs associated with the same phenotype and affecting expression of the same trans-gene (21 times more than expected, P

Published
2011

68. A meta-analysis of genome-wide association scans identifies IL18RAP, PTPN2, TAGAP, and PUS10 as shared risk loci for Crohn's disease and celiac disease.

Author

Festen, Eleonora AM, Goyette, Philippe, Green, Todd, Boucher, Gabrielle, Beauchamp, Claudine, Trynka, Gosia, Dubois, Patrick C, Lagacé, Caroline, Stokkers, Pieter CF, Hommes, Daan W, Barisani, Donatella, Palmieri, Orazio, Annese, Vito, van Heel, David A, Weersma, Rinse K, Daly, Mark J, Wijmenga, Cisca, and Rioux, John D

Subjects
Humans, Crohn Disease, Celiac Disease, Genetic Predisposition to Disease, Hydro-Lyases, GTPase-Activating Proteins, Data Interpretation, Statistical, Risk Factors, Interleukin-18 Receptor beta Subunit, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Genome-Wide Association Study, Data Interpretation, Statistical, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Genetics, Developmental Biology
Abstract

Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value

Published
2011

69. Farnesoid X receptor (FXR) activation and FXR genetic variation in inflammatory bowel disease.

Author

Nijmeijer, Rian M, Gadaleta, Raffaella M, van Mil, Saskia WC, van Bodegraven, Adriaan A, Crusius, J Bart A, Dijkstra, Gerard, Hommes, Daan W, de Jong, Dirk J, Stokkers, Pieter CF, Verspaget, Hein W, Weersma, Rinse K, van der Woude, C Janneke, Stapelbroek, Janneke M, Schipper, Marguerite EI, Wijmenga, Cisca, van Erpecum, Karel J, Oldenburg, Bas, and Dutch Initiative on Crohn, Colitis (ICC)

Subjects
Dutch Initiative on Crohn, Colitis, Colon, Ileum, Humans, Colitis, Ulcerative, Inflammatory Bowel Diseases, Receptors, Cytoplasmic and Nuclear, RNA, Messenger, Case-Control Studies, Gene Expression, Polymorphism, Single Nucleotide, Female, Male, Genetic Variation, General Science & Technology
Abstract

BackgroundWe previously showed that activation of the bile salt nuclear receptor Farnesoid X Receptor (FXR) protects against intestinal inflammation in mice. Reciprocally, these inflammatory mediators may decrease FXR activation. We investigated whether FXR activation is repressed in the ileum and colon of inflammatory bowel disease (IBD) patients in remission. Additionally, we evaluated whether genetic variation in FXR is associated with IBD.MethodsmRNA expression of FXR and FXR target gene SHP was determined in ileal and colonic biopsies of patients with Crohn's colitis (n = 15) and ulcerative colitis (UC; n = 12), all in clinical remission, and healthy controls (n = 17). Seven common tagging SNPs and two functional SNPs in FXR were genotyped in 2355 Dutch IBD patients (1162 Crohn's disease (CD) and 1193 UC) and in 853 healthy controls.ResultsmRNA expression of SHP in the ileum is reduced in patients with Crohn's colitis but not in patients with UC compared to controls. mRNA expression of villus marker Villin was correlated with FXR and SHP in healthy controls, a correlation that was weaker in UC patients and absent in CD patients. None of the SNPs was associated with IBD, UC or CD, nor with clinical subgroups of CD.ConclusionsFXR activation in the ileum is decreased in patients with Crohn's colitis. This may be secondary to altered enterohepatic circulation of bile salts or transrepression by inflammatory signals but does not seem to be caused by the studied SNPs in FXR. Increasing FXR activity by synthetic FXR agonists may have benefit in CD patients.

Published
2011

70. Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction

Author

Sotoodehnia, Nona, Isaacs, Aaron, de Bakker, Paul IW, Dörr, Marcus, Newton-Cheh, Christopher, Nolte, Ilja M, van der Harst, Pim, Müller, Martina, Eijgelsheim, Mark, Alonso, Alvaro, Hicks, Andrew A, Padmanabhan, Sandosh, Hayward, Caroline, Smith, Albert Vernon, Polasek, Ozren, Giovannone, Steven, Fu, Jingyuan, Magnani, Jared W, Marciante, Kristin D, Pfeufer, Arne, Gharib, Sina A, Teumer, Alexander, Li, Man, Bis, Joshua C, Rivadeneira, Fernando, Aspelund, Thor, Köttgen, Anna, Johnson, Toby, Rice, Kenneth, Sie, Mark PS, Wang, Ying A, Klopp, Norman, Fuchsberger, Christian, Wild, Sarah H, Leach, Irene Mateo, Estrada, Karol, Völker, Uwe, Wright, Alan F, Asselbergs, Folkert W, Qu, Jiaxiang, Chakravarti, Aravinda, Sinner, Moritz F, Kors, Jan A, Petersmann, Astrid, Harris, Tamara B, Soliman, Elsayed Z, Munroe, Patricia B, Psaty, Bruce M, Oostra, Ben A, Cupples, L Adrienne, Perz, Siegfried, de Boer, Rudolf A, Uitterlinden, André G, Völzke, Henry, Spector, Timothy D, Liu, Fang-Yu, Boerwinkle, Eric, Dominiczak, Anna F, Rotter, Jerome I, van Herpen, Gé, Levy, Daniel, Wichmann, H-Erich, van Gilst, Wiek H, Witteman, Jacqueline CM, Kroemer, Heyo K, Kao, WH Linda, Heckbert, Susan R, Meitinger, Thomas, Hofman, Albert, Campbell, Harry, Folsom, Aaron R, van Veldhuisen, Dirk J, Schwienbacher, Christine, O'Donnell, Christopher J, Volpato, Claudia Beu, Caulfield, Mark J, Connell, John M, Launer, Lenore, Lu, Xiaowen, Franke, Lude, Fehrmann, Rudolf SN, te Meerman, Gerard, Groen, Harry JM, Weersma, Rinse K, van den Berg, Leonard H, Wijmenga, Cisca, Ophoff, Roel A, Navis, Gerjan, Rudan, Igor, Snieder, Harold, Wilson, James F, Pramstaller, Peter P, Siscovick, David S, Wang, Thomas J, Gudnason, Vilmundur, van Duijn, Cornelia M, Felix, Stephan B, Fishman, Glenn I, Jamshidi, Yalda, and Ch Stricker, Bruno H

Subjects
Biological Sciences, Genetics, Human Genome, Heart Disease, Cardiovascular, Animals, Animals, Newborn, Chromosomes, Human, Computational Biology, Electrocardiography, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Humans, Mice, Mice, Transgenic, Models, Animal, Myocytes, Cardiac, NAV1.8 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Sodium Channels, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

Published
2010

71. Multiple common variants for celiac disease influencing immune gene expression

Author

Dubois, Patrick CA, Trynka, Gosia, Franke, Lude, Hunt, Karen A, Romanos, Jihane, Curtotti, Alessandra, Zhernakova, Alexandra, Heap, Graham AR, Ádány, Róza, Aromaa, Arpo, Bardella, Maria Teresa, van den Berg, Leonard H, Bockett, Nicholas A, de la Concha, Emilio G, Dema, Bárbara, Fehrmann, Rudolf SN, Fernández-Arquero, Miguel, Fiatal, Szilvia, Grandone, Elvira, Green, Peter M, Groen, Harry JM, Gwilliam, Rhian, Houwen, Roderick HJ, Hunt, Sarah E, Kaukinen, Katri, Kelleher, Dermot, Korponay-Szabo, Ilma, Kurppa, Kalle, MacMathuna, Padraic, Mäki, Markku, Mazzilli, Maria Cristina, McCann, Owen T, Mearin, M Luisa, Mein, Charles A, Mirza, Muddassar M, Mistry, Vanisha, Mora, Barbara, Morley, Katherine I, Mulder, Chris J, Murray, Joseph A, Núñez, Concepción, Oosterom, Elvira, Ophoff, Roel A, Polanco, Isabel, Peltonen, Leena, Platteel, Mathieu, Rybak, Anna, Salomaa, Veikko, Schweizer, Joachim J, Sperandeo, Maria Pia, Tack, Greetje J, Turner, Graham, Veldink, Jan H, Verbeek, Wieke HM, Weersma, Rinse K, Wolters, Victorien M, Urcelay, Elena, Cukrowska, Bozena, Greco, Luigi, Neuhausen, Susan L, McManus, Ross, Barisani, Donatella, Deloukas, Panos, Barrett, Jeffrey C, Saavalainen, Paivi, Wijmenga, Cisca, and van Heel, David A

Subjects
Biotechnology, Human Genome, Genetics, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Case-Control Studies, Celiac Disease, Gene Expression, Gene Expression Profiling, Genes, MHC Class I, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Risk, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.

Published
2010

72. The Gut Microbiome in End-stage Lung Disease and Lung Transplantation

Author

Zhang, Shuyan, primary, Swarte, J. Casper, additional, Gacesa, Ranko, additional, Knobbe, Tim J., additional, Kremer, Daan, additional, Jansen, Bernadien H., additional, Borst, Martin H., additional, Harmsen, Hermie J.M., additional, Erasmus, Michiel E., additional, Verschuuren, Erik A.M., additional, Bakker, Stephan J.L., additional, Gan, C. Tji, additional, Weersma, Rinse K., additional, and Björk, Johannes R., additional

Published
2023
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73. Response to immune checkpoint inhibition is associated with the gut microbiome in advanced KRAS-mutated non-small cell lung cancer

Author

Hiddinga, Birgitta I, primary, Bolte, Laura A, additional, van der Leest, Paul, additional, Hijmering-Kappelle, Lucie BM, additional, van der Wekken, Anthonie J, additional, Schuuring, Ed, additional, Gacesa, Ranko, additional, Hospers, Geke AP, additional, Weersma, Rinse K, additional, Bjork, Johannes R, additional, and Hiltermann, T Jeroen N, additional

Published
2023
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74. Gut microbial co-abundance networks show specificity in inflammatory bowel disease and obesity

Author

Chen, Lianmin, Collij, Valerie, Jaeger, Martin, van den Munckhof, Inge C. L., Vich Vila, Arnau, Kurilshikov, Alexander, Gacesa, Ranko, Sinha, Trishla, Oosting, Marije, Joosten, Leo A. B., Rutten, Joost H. W., Riksen, Niels P., Xavier, Ramnik J., Kuipers, Folkert, Wijmenga, Cisca, Zhernakova, Alexandra, Netea, Mihai G., Weersma, Rinse K., and Fu, Jingyuan

Published
2020
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75. Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes.

Author

Zheng, Tenghao, Roda, Giulia, Zabana, Yamile, Escudero-Hernández, Celia, Liu, Xingrong, Chen, Ye, Tavares, Leticia Camargo, Bonfiglio, Ferdinando, Mellander, Marie-Rose, Janczewska, Izabella, Vigren, Lina, Sjöberg, Klas, Ohlsson, Bodil, Almer, Sven, Halfvarson, Jonas, Miehlke, Stephan, Madisch, Ahmed, Lieb, Wolfgang, Kupčinskas, Juozas, and Weersma, Rinse K

Abstract

Background and Aims Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. Methods We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. Results We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p  = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p  = 0.048] and oesophageal diseases [rg = 0.45, p  = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p  = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. Conclusion Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions. [ABSTRACT FROM AUTHOR]

Published
2024
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77. Gut microbiome structure and metabolic activity in inflammatory bowel disease

Author

Franzosa, Eric A., Sirota-Madi, Alexandra, Avila-Pacheco, Julian, Fornelos, Nadine, Haiser, Henry J., Reinker, Stefan, Vatanen, Tommi, Hall, A. Brantley, Mallick, Himel, McIver, Lauren J., Sauk, Jenny S., Wilson, Robin G., Stevens, Betsy W., Scott, Justin M., Pierce, Kerry, Deik, Amy A., Bullock, Kevin, Imhann, Floris, Porter, Jeffrey A., Zhernakova, Alexandra, Fu, Jingyuan, Weersma, Rinse K., Wijmenga, Cisca, Clish, Clary B., Vlamakis, Hera, Huttenhower, Curtis, and Xavier, Ramnik J.

Published
2019
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80. Impact of occupational pesticide exposure on the human gut microbiome

Author

Gois, Milla F. Brandao, primary, Fernández-Pato, Asier, additional, Huss, Anke, additional, Gacesa, Ranko, additional, Wijmenga, Cisca, additional, Weersma, Rinse K., additional, Fu, Jingyuan, additional, Vermeulen, Roel C. H., additional, Zhernakova, Alexandra, additional, Lenters, Virissa C., additional, and Kurilshikov, Alexander, additional

Published
2023
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81. Proton Pump Inhibitor Use, Fatigue, and Health-Related Quality of Life in Kidney Transplant Recipients: Results From the TransplantLines Biobank and Cohort Study

Author

Knobbe, Tim J., primary, Kremer, Daan, additional, Douwes, Rianne M., additional, Eisenga, Michele F., additional, Gomes-Neto, António W., additional, Annema, Coby, additional, Swarte, J. Casper, additional, Klont, Frank, additional, Navis, Gerjan, additional, Berger, Stefan P., additional, Bakker, Stephan J.L., additional, Blokzijl, Hans, additional, Bodewes, Frank A.J.A., additional, de Boer, Marieke T., additional, Damman, Kevin, additional, de Borst, Martin H., additional, Diepstra, Arjan, additional, Dijkstra, Gerard, additional, Doorenbos, Caecilia S.E., additional, Erasmus, Michiel E., additional, Gan, C. Tji, additional, Hak, Eelko, additional, Hepkema, Bouke G., additional, Leuvenink, Henri G.D., additional, Lexmond, Willem S., additional, de Meijer, Vincent E., additional, Niesters, Hubert G.M., additional, van Pelt, L. Joost, additional, Pol, Robert A., additional, Porte, Robert J., additional, Ranchor, Adelta V., additional, Sanders, Jan Stephan F., additional, Siebelink, Marion J., additional, Slart, Riemer J.H.J.A., additional, Touw, Daan J., additional, van den Heuvel, Marius C., additional, van Leer-Buter, Coretta, additional, van Londen, Marco, additional, Verschuuren, Erik A.M., additional, Vos, Michel J., additional, and Weersma, Rinse K., additional

Published
2023
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82. Gut dysbiosis associates with cytokine production capacity in viral-suppressed people living with HIV

Author

Zhang, Yue, primary, Andreu-Sánchez, Sergio, additional, Vadaq, Nadira, additional, Wang, Daoming, additional, Matzaraki, Vasiliki, additional, van der Heijden, Wouter A., additional, Gacesa, Ranko, additional, Weersma, Rinse K., additional, Zhernakova, Alexandra, additional, Vandekerckhove, Linos, additional, de Mast, Quirijn, additional, Joosten, Leo A. B., additional, Netea, Mihai G., additional, van der Ven, André J. A. M., additional, and Fu, Jingyuan, additional

Published
2023
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85. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity

Author

Zhernakova, Alexandra, Kurilshikov, Alexander, Bonder, Marc Jan, Tigchelaar, Ettje F., Schirmer, Melanie, Vatanen, Tommi, Mujagic, Zlatan, Vila, Arnau Vich, Falony, Gwen, Vieira-Silva, Sara, Wang, Jun, Imhann, Floris, Brandsma, Eelke, Jankipersadsing, Soesma A., Joossens, Marie, Cenit, Maria Carmen, Deelen, Patrick, Swertz, Morris A., study, LifeLines cohort, Weersma, Rinse K., Feskens, Edith J. M., Netea, Mihai G., Gevers, Dirk, Jonkers, Daisy, Franke, Lude, Aulchenko, Yurii S., Huttenhower, Curtis, Raes, Jeroen, Hofker, Marten H., Xavier, Ramnik J., Wijmenga, Cisca, and Fu, Jingyuan

Published
2016

86. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

Author

Cleynen, Isabelle, Boucher, Gabrielle, Jostins, Luke, Schumm, L Philip, Zeissig, Sebastian, Ahmad, Tariq, Andersen, Vibeke, Andrews, Jane M, Annese, Vito, Brand, Stephan, Brant, Steven R, Cho, Judy H, Daly, Mark J, Dubinsky, Marla, Duerr, Richard H, Ferguson, Lynnette R, Franke, Andre, Gearry, Richard B, Goyette, Philippe, Hakonarson, Hakon, Halfvarson, Jonas, Hov, Johannes R, Huang, Hailang, Kennedy, Nicholas A, Kupcinskas, Limas, Lawrance, Ian C, Lee, James C, Satsangi, Jack, Schreiber, Stephan, Théâtre, Emilie, van der Meulen-de Jong, Andrea E, Weersma, Rinse K, Wilson, David C, Parkes, Miles, Vermeire, Severine, Rioux, John D, Mansfield, John, Silverberg, Mark S, Radford-Smith, Graham, McGovern, Dermot P B, Barrett, Jeffrey C, and Lees, Charlie W

Published
2016
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89. Impact of occupational pesticide exposure on the human gut microbiome

Author

Gois, Milla F Brandao, Fernández-Pato, Asier, Huss, Anke, Gacesa, Ranko, Wijmenga, Cisca, Weersma, Rinse K, Fu, Jingyuan, Vermeulen, Roel C H, Zhernakova, Alexandra, Lenters, Virissa C, Kurilshikov, Alexander, Gois, Milla F Brandao, Fernández-Pato, Asier, Huss, Anke, Gacesa, Ranko, Wijmenga, Cisca, Weersma, Rinse K, Fu, Jingyuan, Vermeulen, Roel C H, Zhernakova, Alexandra, Lenters, Virissa C, and Kurilshikov, Alexander

Abstract

The rising use of pesticides in modern agriculture has led to a shift in disease burden in which exposure to these chemicals plays an increasingly important role. The human gut microbiome, which is partially responsible for the biotransformation of xenobiotics, is also known to promote biotransformation of environmental pollutants. Understanding the effects of occupational pesticide exposure on the gut microbiome can thus provide valuable insights into the mechanisms underlying the impact of pesticide exposure on health. Here we investigate the impact of occupational pesticide exposure on human gut microbiome composition in 7198 participants from the Dutch Microbiome Project of the Lifelines Study. We used job-exposure matrices in combination with occupational codes to retrieve categorical and cumulative estimates of occupational exposures to general pesticides, herbicides, insecticides and fungicides. Approximately 4% of our cohort was occupationally exposed to at least one class of pesticides, with predominant exposure to multiple pesticide classes. Most participants reported long-term employment, suggesting a cumulative profile of exposure. We demonstrate that contact with insecticides, fungicides and a general "all pesticides" class was consistently associated with changes in the gut microbiome, showing significant associations with decreased alpha diversity and a differing beta diversity. We also report changes in the abundance of 39 different bacterial taxa upon exposure to the different pesticide classes included in this study. Together, the extent of statistically relevant associations between gut microbial changes and pesticide exposure in our findings highlights the impact of these compounds on the human gut microbiome.

Published
2023

90. Disease burden in primary sclerosing cholangitis in the Netherlands: A long-term follow-up study

Author

Cancer, Infection & Immunity, MS MDL 1, van Munster, Kim N., Mol, Bregje, Goet, Jorn C., van Munster, Sanne N., Weersma, Rinse K., de Vries, Annemarie C., van der Meer, Adriaan J., Inderson, Akin, Drenth, Joost P., van Erpecum, Karel J., Boonstra, Kirsten, Beuers, Ulrich, Dijkgraaf, Marcel G.W., Ponsioen, Cyriel Y., the EpiPSC2 Study Group, Cancer, Infection & Immunity, MS MDL 1, van Munster, Kim N., Mol, Bregje, Goet, Jorn C., van Munster, Sanne N., Weersma, Rinse K., de Vries, Annemarie C., van der Meer, Adriaan J., Inderson, Akin, Drenth, Joost P., van Erpecum, Karel J., Boonstra, Kirsten, Beuers, Ulrich, Dijkgraaf, Marcel G.W., Ponsioen, Cyriel Y., and the EpiPSC2 Study Group

Published
2023

91. Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes

Author

Zheng, Tenghao, Roda, Giulia, Zabana, Yamile, Escudero-Hernández, Celia, Liu, Xingrong, Chen, Ye, Camargo Tavares, Leticia, Bonfiglio, Ferdinando, Mellander, Marie-Rose, Janczewska, Izabella, Vigren, Lina, Sjoberg, Klas, Ohlsson, Bodil, Almer, Sven, Halfvarson, Jonas, Miehlke, Stephan, Madisch, Ahmed, Lieb, Wolfgang, Kupcinskas, Juozas, Weersma, Rinse K., Bujanda, Luis, Julia, Antonio, Marsal, Sara, Esteve, Maria, Guagnozzi, Danila, Fernandez-Banares, Fernando, Ferrer, Carmen, Peter, Inga, Ludvigsson, Jonas F., Pardi, Darrell, Verhaegh, Bas, Jonkers, Daisy, Pierik, Marieke, Münch, Andreas, Franke, Andre, Bresso, Francesca, Khalili, Hamed, Colombel, Jean-Frederic, DAmato, Mauro, MC-Europe GETECCU GWAS group, Zheng, Tenghao, Roda, Giulia, Zabana, Yamile, Escudero-Hernández, Celia, Liu, Xingrong, Chen, Ye, Camargo Tavares, Leticia, Bonfiglio, Ferdinando, Mellander, Marie-Rose, Janczewska, Izabella, Vigren, Lina, Sjoberg, Klas, Ohlsson, Bodil, Almer, Sven, Halfvarson, Jonas, Miehlke, Stephan, Madisch, Ahmed, Lieb, Wolfgang, Kupcinskas, Juozas, Weersma, Rinse K., Bujanda, Luis, Julia, Antonio, Marsal, Sara, Esteve, Maria, Guagnozzi, Danila, Fernandez-Banares, Fernando, Ferrer, Carmen, Peter, Inga, Ludvigsson, Jonas F., Pardi, Darrell, Verhaegh, Bas, Jonkers, Daisy, Pierik, Marieke, Münch, Andreas, Franke, Andre, Bresso, Francesca, Khalili, Hamed, Colombel, Jean-Frederic, DAmato, Mauro, and MC-Europe GETECCU GWAS group

Abstract

Background and Aims: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies.Methods: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied.Results: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 x 10(-23), odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [r(g) = 0.77; p = 0.048] and oesophageal diseases [r(g) = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 x 10(-8), OR = 1.31]. No significant association was detected for LC.Conclusion: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions., Funding Agencies|Swedish Research Council [VR 2017-02403]

Published
2023
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92. Proton Pump Inhibitor Use, Fatigue, and Health-Related Quality of Life in Kidney Transplant Recipients:Results From the TransplantLines Biobank and Cohort Study

Author

Knobbe, Tim J., Kremer, Daan, Douwes, Rianne M., Eisenga, Michele F., Gomes-Neto, António W., Annema, Coby, Swarte, J. Casper, Klont, Frank, Navis, Gerjan, Berger, Stefan P., Bakker, Stephan J.L., Blokzijl, Hans, Bodewes, Frank A.J.A., de Boer, Marieke T., Damman, Kevin, de Borst, Martin H., Diepstra, Arjan, Dijkstra, Gerard, Doorenbos, Caecilia S.E., Erasmus, Michiel E., Gan, C. Tji, Hak, Eelko, Hepkema, Bouke G., Leuvenink, Henri G.D., Lexmond, Willem S., de Meijer, Vincent E., Niesters, Hubert G.M., van Pelt, L. Joost, Pol, Robert A., Porte, Robert J., Ranchor, Adelta V., Sanders, Jan Stephan F., Siebelink, Marion J., Slart, Riemer J.H.J.A., Touw, Daan J., van den Heuvel, Marius C., van Leer-Buter, Coretta, van Londen, Marco, Verschuuren, Erik A.M., Vos, Michel J., Weersma, Rinse K., Knobbe, Tim J., Kremer, Daan, Douwes, Rianne M., Eisenga, Michele F., Gomes-Neto, António W., Annema, Coby, Swarte, J. Casper, Klont, Frank, Navis, Gerjan, Berger, Stefan P., Bakker, Stephan J.L., Blokzijl, Hans, Bodewes, Frank A.J.A., de Boer, Marieke T., Damman, Kevin, de Borst, Martin H., Diepstra, Arjan, Dijkstra, Gerard, Doorenbos, Caecilia S.E., Erasmus, Michiel E., Gan, C. Tji, Hak, Eelko, Hepkema, Bouke G., Leuvenink, Henri G.D., Lexmond, Willem S., de Meijer, Vincent E., Niesters, Hubert G.M., van Pelt, L. Joost, Pol, Robert A., Porte, Robert J., Ranchor, Adelta V., Sanders, Jan Stephan F., Siebelink, Marion J., Slart, Riemer J.H.J.A., Touw, Daan J., van den Heuvel, Marius C., van Leer-Buter, Coretta, van Londen, Marco, Verschuuren, Erik A.M., Vos, Michel J., and Weersma, Rinse K.

Abstract

Rationale & Objective: Prior studies report that the use of proton pump inhibitors (PPIs) can adversely affect gut microbiota and gastrointestinal uptake of micronutrients, in particular iron and magnesium, and are used frequently by kidney transplant recipients. Altered gut microbiota, iron deficiency, and magnesium deficiency have been implicated in the pathogenesis of chronic fatigue. Therefore, we hypothesized that PPI use may be an important and underappreciated cause of fatigue and reduced health-related quality of life (HRQoL) in this population. Study Design: Cross-sectional study. Setting & Participants: Kidney transplant recipients (≥1 year after transplantation) enrolled in the TransplantLines Biobank and Cohort Study. Exposure: PPI use, PPI type, PPI dosage, and duration of PPI use. Outcome: Fatigue and HRQoL, assessed using the validated Checklist Individual Strength 20 Revised questionnaire and Short Form-36 questionnaire. Analytical Approach: Logistic and linear regression. Results: We included 937 kidney transplant recipients (mean age 56 ± 13 years, 39% female) at a median of 3 (1-10) years after transplantation. PPI use was associated with fatigue severity (regression coefficient 4.02, 95% CI, 2.18 to 5.85, P < 0.001), a higher risk of severe fatigue (OR 2.05, 95% CI, 1.48 to 2.84, P < 0.001), lower physical HRQoL (regression coefficient −8.54, 95% CI, −11.54 to −5.54, P < 0.001), and lower mental HRQoL (regression coefficient −4.66, 95% CI, −7.15 to −2.17, P < 0.001). These associations were independent of potential confounders including age, time since transplantation, history of upper gastrointestinal disease, antiplatelet therapy, and the total number of medications. They were present among all individually assessed PPI types and were dose dependent. Duration of PPI exposure was only associated with fatigue severity. Limitations: Residual confounding and inability to assess causal relationships. Conclusions: PPI use is in

Published
2023

93. Impact of occupational pesticide exposure on the human gut microbiome

Author

IRAS OH Epidemiology Chemical Agents, IRAS – One Health Chemical, Gois, Milla F Brandao, Fernández-Pato, Asier, Huss, Anke, Gacesa, Ranko, Wijmenga, Cisca, Weersma, Rinse K, Fu, Jingyuan, Vermeulen, Roel C H, Zhernakova, Alexandra, Lenters, Virissa C, Kurilshikov, Alexander, IRAS OH Epidemiology Chemical Agents, IRAS – One Health Chemical, Gois, Milla F Brandao, Fernández-Pato, Asier, Huss, Anke, Gacesa, Ranko, Wijmenga, Cisca, Weersma, Rinse K, Fu, Jingyuan, Vermeulen, Roel C H, Zhernakova, Alexandra, Lenters, Virissa C, and Kurilshikov, Alexander

Published
2023

94. Disease burden in primary sclerosing cholangitis in the Netherlands:A long-term follow-up study

Author

van Munster, Kim N., Mol, Bregje, Goet, Jorn C., van Munster, Sanne N., Weersma, Rinse K., de Vries, Annemarie C., van der Meer, Adriaan J., Inderson, Akin, Drenth, Joost P., van Erpecum, Karel J., Boonstra, Kirsten, Beuers, Ulrich, Dijkgraaf, Marcel G.W., Ponsioen, Cyriel Y., van Munster, Kim N., Mol, Bregje, Goet, Jorn C., van Munster, Sanne N., Weersma, Rinse K., de Vries, Annemarie C., van der Meer, Adriaan J., Inderson, Akin, Drenth, Joost P., van Erpecum, Karel J., Boonstra, Kirsten, Beuers, Ulrich, Dijkgraaf, Marcel G.W., and Ponsioen, Cyriel Y.

Abstract

Background & Aims: Primary sclerosing cholangitis (PSC) is a progressive, cholestatic liver disease which greatly impacts the lives of individuals. Burden of disease due to shortened life expectancy and impaired quality of life is ill-described. The aim of this study was to assess long-term disease burden in a large population-based registry with regard to survival, clinical course, quality adjusted life years (QALYs), medical consumption and work productivity loss. Methods: All PSC patients living in a geographically defined area covering ~50% of the Netherlands were included, together with patients from the three liver transplant centres. Survival was estimated by competing risk analysis. Proportional shortfall of QALYs during disease course was measured relative to a matched reference cohort using validated questionnaires. Work productivity loss and medical consumption were evaluated over time. Results: A total of 1208 patients were included with a median follow-up of 11.2 year. Median liver transplant-free survival was 21.0 years. Proportional shortfall of QALYs increased to 48% >25 years after diagnosis. Patients had on average 12.4 hospital contact days among which 3.17 admission days per year, annual medical costs were €12 169 and mean work productivity loss was 25%. Conclusions: Our data quantify for the first time disease burden in terms of QALYs lost, clinical events, medical consumption, costs as well as work productivity loss, and show that all these are substantial and increase over time.

Published
2023

95. Faecal metabolome and its determinants in inflammatory bowel disease

Author

Vich Vila, Arnau, primary, Hu, Shixian, additional, Andreu-Sánchez, Sergio, additional, Collij, Valerie, additional, Jansen, Bernadien H, additional, Augustijn, Hannah E, additional, Bolte, Laura A, additional, Ruigrok, Renate A A A, additional, Abu-Ali, Galeb, additional, Giallourakis, Cosmas, additional, Schneider, Jessica, additional, Parkinson, John, additional, Al-Garawi, Amal, additional, Zhernakova, Alexandra, additional, Gacesa, Ranko, additional, Fu, Jingyuan, additional, and Weersma, Rinse K, additional

Published
2023
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96. Disease burden in primary sclerosing cholangitis in the Netherlands: A long-term follow-up study

Author

van Munster, Kim N., Mol, Bregje, Goet, Jorn C., van Munster, Sanne N., Weersma, Rinse K., de Vries, Annemarie C., van der Meer, Adriaan J., Inderson, Akin, Drenth, Joost P., van Erpecum, Karel J., Boonstra, Kirsten, Beuers, Ulrich, Dijkgraaf, Marcel G.W., Ponsioen, Cyriel Y., Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Gastroenterology & Hepatology

Subjects
disease burden, QALY, SDG 3 - Good Health and Well-being, PSC, work productivity loss, survival, medical costs
Abstract

Background & Aims: Primary sclerosing cholangitis (PSC) is a progressive, cholestatic liver disease which greatly impacts the lives of individuals. Burden of disease due to shortened life expectancy and impaired quality of life is ill-described. The aim of this study was to assess long-term disease burden in a large population-based registry with regard to survival, clinical course, quality adjusted life years (QALYs), medical consumption and work productivity loss. Methods: All PSC patients living in a geographically defined area covering ~50% of the Netherlands were included, together with patients from the three liver transplant centres. Survival was estimated by competing risk analysis. Proportional shortfall of QALYs during disease course was measured relative to a matched reference cohort using validated questionnaires. Work productivity loss and medical consumption were evaluated over time. Results: A total of 1208 patients were included with a median follow-up of 11.2 year. Median liver transplant-free survival was 21.0 years. Proportional shortfall of QALYs increased to 48% >25 years after diagnosis. Patients had on average 12.4 hospital contact days among which 3.17 admission days per year, annual medical costs were €12 169 and mean work productivity loss was 25%. Conclusions: Our data quantify for the first time disease burden in terms of QALYs lost, clinical events, medical consumption, costs as well as work productivity loss, and show that all these are substantial and increase over time.

Published
2023

97. Health-related quality of life in patients with primary sclerosing cholangitis

Author

Mol, Bregje, van Munster, Kim N., Bogaards, Johannes A., Weersma, Rinse K., Inderson, Akin, de Groof, E. Joline, Rossen, Noortje G.M., Ponsioen, Willemijn, Turkenburg, Maud, van Erpecum, Karel J., Poen, Alexander C., Spanier, B. W.Marcel, Beuers, Ulrich H.W., Ponsioen, Cyriel Y., Epidemiology and Data Science, AII - Infectious diseases, APH - Methodology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Gastroenterology and Hepatology, Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Surgery, Tytgat Institute for Liver and Intestinal Research, CCA - Cancer Treatment and Quality of Life, and CCA - Cancer biology and immunology

Subjects
health-related quality of life, Hepatology, inflammatory bowel disease, post-transplant, primary sclerosing cholangitis, population-based cohort, repeated measurements
Abstract

Background & Aims: Data regarding health-related quality of life (HRQoL) in primary sclerosing cholangitis (PSC) are sparse and have only been studied cross-sectionally in a disease which runs a fluctuating and unpredictable course. We aim to describe HRQoL longitudinally by using repeated measurements in a population-based cohort. Methods: Every 3 months from May 2017 up to August 2020, patients received digital questionnaires at home. These included the EQ-5D, 5-D Itch, patient-based SCCAI and patient-based HBI. The SF-36, measuring HRQoL over eight dimensions as well as a physical component summary (PCS) and mental component summary (MCS) score, was sent annually. Data were compared with Dutch reference data and a matched IBD disease control from the population-based POBASIC cohort. Mixed-effects modelling was performed to identify factors associated with HRQoL. Results: Three hundred twenty-eight patients completed 2576 questionnaires. A significant reduction of small clinical relevance in several mean HRQoL scores was found compared with the Dutch reference population: 46.4 versus 48.0, p =.018 for PCS and 47.5 versus 50.5, p =.004 for MCS scores. HRQoL outcomes were significantly negatively associated with coexisting active IBD (PCS −12.2, p

Published
2023
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98. Additional file 1 of Total serum N-glycans associate with response to immune checkpoint inhibition therapy and survival in patients with advanced melanoma

Author

Visconti, Alessia, Rossi, Niccolò, Deriš, Helena, Lee, Karla A, Hanić, Maja, Trbojević-Akmačić, Irena, Thomas, Andrew M., Bolte, Laura A., Björk, Johannes R., Hooiveld-Noeken, Jahlisa S., Board, Ruth, Harland, Mark, Newton-Bishop, Julia, Harries, Mark, Sacco, Joseph J., Lorigan, Paul, Shaw, Heather M., de Vries, Elisabeth G.E., Fehrmann, Rudolf S.N., Weersma, Rinse K., Spector, Tim D., Nathan, Paul, Hospers, Geke A. P., Sasieni, Peter, Bataille, Veronique, Lauc, Gordan, and Falchi, Mario

Abstract

Additional file 1: Figure 1. Representative chromatogram of total human plasma/serum N-glycome separated byHILIC-UPLC into 39 N-glycan peaks (GP1-GP39). Figure 2. Swimmer plot for the 88 patients with advanced melanoma included in this study. Figure 3. Pearson's correlation among the measured N-glycan and derived traits associated with overall response rate in 88 patients with advanced melanoma. Figure 4. Significant association between directly measured serum N-glycans and overall response rate. Figure 5. Kaplan-Meier progression-free survival curves in 88 patients with advanced melanoma (directly measured N-glycans). Figure 6. Diagnostic plots for Cox proportional hazards regression model of survival time on sex, age at diagnosis of advanced melanoma, BMI, dichotomized LDH levels, and ECOG performance-status. Figure 7. Kaplan-Meier overall survival curves in 88 patients with advanced melanoma (directly measured N-glycans).

Published
2023
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99. Association of a Mediterranean Diet With Outcomes for Patients Treated With Immune Checkpoint Blockade for Advanced Melanoma

Author

Bolte, Laura A., primary, Lee, Karla A., additional, Björk, Johannes R., additional, Leeming, Emily R., additional, Campmans-Kuijpers, Marjo J. E., additional, de Haan, Jacco J., additional, Vila, Arnau Vich, additional, Maltez-Thomas, Andrew, additional, Segata, Nicola, additional, Board, Ruth, additional, Harries, Mark, additional, Lorigan, Paul, additional, de Vries, Elisabeth G. E., additional, Nathan, Paul, additional, Fehrmann, Rudolf, additional, Bataille, Véronique, additional, Spector, Tim D., additional, Hospers, Geke A. P., additional, and Weersma, Rinse K., additional

Published
2023
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100. Hepcidin and Iron Status in Patients With Inflammatory Bowel Disease Undergoing Induction Therapy With Vedolizumab or Infliximab

Author

Loveikyte, Roberta, primary, Bourgonje, Arno R, additional, van der Reijden, Johannes J, additional, Bulthuis, Marian L C, additional, Hawinkels, Lukas J A C, additional, Visschedijk, Marijn C, additional, Festen, Eleonora A M, additional, van Dullemen, Hendrik M, additional, Weersma, Rinse K, additional, van Goor, Harry, additional, van der Meulen-de Jong, Andrea E, additional, and Dijkstra, Gerard, additional

Published
2023
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