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1. Comprehensive Association Analyses of Extraintestinal Manifestations in Inflammatory Bowel Disease

Author

Khrom, Michelle, Long, Millie, Dube, Shishir, Robbins, Lori, Botwin, Gregory J., Yang, Shaohong, Mengesha, Emebet, Li, Dalin, Naito, Takeo, Bonthala, Nirupama N., Ha, Christina, Melmed, Gil, Rabizadeh, Shervin, Syal, Gaurav, Vasiliauskas, Eric, Ziring, David, Brant, Steven R., Cho, Judy, Duerr, Richard H., Rioux, John, Schumm, Phil, Silverberg, Mark, Ananthakrishnan, Ashwin N., Faubion, William A., Jabri, Bana, Lira, Sergio A., Newberry, Rodney D., Sandler, Robert S., Xavier, Ramnik J., Kugathasan, Subra, Hercules, David, Targan, Stephan R., Sartor, R. Balfour, Haritunians, Talin, and McGovern, Dermot P.B.

Published
2024
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3. Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients

Author

Wu, Yiming, Gettler, Kyle, Kars, Meltem Ece, Giri, Mamta, Li, Dalin, Bayrak, Cigdem Sevim, Zhang, Peng, Jain, Aayushee, Maffucci, Patrick, Sabic, Ksenija, Van Vleck, Tielman, Nadkarni, Girish, Denson, Lee A., Ostrer, Harry, Levine, Adam P., Schiff, Elena R., Segal, Anthony W., Kugathasan, Subra, Stenson, Peter D., Cooper, David N., Philip Schumm, L., Snapper, Scott, Daly, Mark J., Haritunians, Talin, Duerr, Richard H., Silverberg, Mark S., Rioux, John D., Brant, Steven R., McGovern, Dermot P. B., Cho, Judy H., and Itan, Yuval

Published
2023
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5. After Surgically Induced Remission, Ileal and Colonic Mucosa-Associated Microbiota Predicts Crohn’s Disease Recurrence

Author

Hernández-Rocha, Cristian, Turpin, Williams, Borowski, Krzysztof, Stempak, Joanne M., Sabic, Ksenija, Gettler, Kyle, Tastad, Christopher, Chasteau, Colleen, Korie, Ujunwa, Hanna, Mary, Khan, Abdul, Mengesha, Emebet, Bitton, Alain, Schwartz, Marc B., Barrie, Arthur, Datta, Lisa W., Lazarev, Mark, Brant, Steven R., Rioux, John D., McGovern, Dermot P.B., Duerr, Richard H., Schumm, L. Phil, Cho, Judy H., and Silverberg, Mark S.

Published
2024
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6. HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis

Author

Akar, Alaa, Flemming, Cornelius, Felix, Flomm, Flosbach, Markus, Jäger, Julia, Jeromin, Niklas, Jung, Johannes, Ohms, Mareike, Reinshagen, Konrad, Rische, Johann, Sagebiel, Adrian, Sandfort, Deborah, Steinert, Fenja, Tomuschat, Christian, Wesche, Jasmin, Shifteh Abedian, Abraham, Clara, Achkar, Jean-Paul, Ahmad, Tariq, Alberts, Rudi, Alizadeh, Behrooz, Amininejad, Leila, Ananthakrishnan, Ashwin N., Andersen, Vibeke, Anderson, Carl A., Andrews, Jane M., Annese, Vito, Aumais, Guy, Baidoo, Leonard, Baldassano, Robert N., Bampton, Peter A., Barclay, Murray, Barrett, Jeffrey C., Bethge, Johannes, Bewshea, Claire, Bis, Joshua C., Bitton, Alain, BK, Thelma, Boucher, Gabrielle, Brain, Oliver, Brand, Stephan, Brant, Steven R., Cheon, Jae Hee, Chew, Angela, Cho, Judy H., Cleynen, Isabelle, Cohain, Ariella, Cooney, Rachel, Croft, Anthony, Daly, Mark J., D'Amato, Mauro, Danese, Silvio, Daryani, Naser Ebrahim, Datta, Lisa Wu, Degenhardt, Frauke, Denapiene, Goda, Denson, Lee A., Devaney, Kathy L., Dewit, Olivier, D'Inca, Renata, Drummond, Hazel E., Dubinsky, Marla, Duerr, Richard H., Edwards, Cathryn, Ellinghaus, David, Ellul, Pierre, Esaki, Motohiro, Essers, Jonah, Ferguson, Lynnette R., Festen, Eleonora A., Fleshner, Philip, Florin, Tim, Franchimont, Denis, Franke, Andre, Fuyuno, Yuta, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jürgen, Goyette, Philippe, Green, Todd, Griffiths, Anne M., Guthery, Stephen L., Hakonarson, Hakon, Halfvarson, Jonas, Hanigan, Katherine, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hayward, Nicholas K., Hedl, Matija, Henderson, Paul, Hold, Georgina L., Hong, Myhunghee, Hu, Xinli, Huang, Hailiang, Hugot, Jean-Pierre, Hui, Ken Y., Imielinski, Marcin, Jazayeri, Omid, Jonaitis, Laimas, Jostins, Luke, Juyal, Garima, Chandra Juyal, Ramesh, Kalla, Rahul, Karlsen, Tom H., Kennedy, Nicholas A., Khan, Mohammed Azam, Kim, Won Ho, Kitazono, Takanari, Kiudelis, Gediminas, Kubo, Michiaki, Kugathasan, Subra, Kupcinskas, Limas, Lamb, Christopher A., de Lange, Katrina M., Latiano, Anna, Laukens, Debby, Lawrance, Ian C., Lee, James C., Lees, Charlie W., Leja, Marcis, Lewis, Nina, Van Limbergen, Johan, Lionetti, Paolo, Liu, Jimmy Z., Louis, Edouard, Luo, Yang, Mahy, Gillian, Malekzadeh, Masoud Mohammad, Malekzadeh, Reza, Mansfield, John, Marriott, Suzie, Massey, Dunecan, Mathew, Christopher G., Matsui, Toshiyuki, McGovern, Dermot P.B., van der Meulen, Andrea, Midha, Vandana, Milgrom, Raquel, Mirzaei, Samaneh, Mitrovic, Mitja, Montgomery, Grant W., Mowat, Craig, Müller, Christoph, Newman, William G., Ng, Aylwin, Ng, Siew C., Evelyn Ng, Sok Meng, Nikolaus, Susanna, Ning, Kaida, Nöthen, Markus, Oikonomou, Ioannis, Okou, David, Orchard, Timothy R., Palmieri, Orazio, Parkes, Miles, Phillips, Anne, Ponsioen, Cyriel Y., Potocnik, Urõs, Poustchi, Hossein, Prescott, Natalie J., Proctor, Deborah D., Radford-Smith, Graham, Rahier, Jean- Francois, Regueiro, Miguel, Reinisch, Walter, Rieder, Florian, Rioux, John D., Roberts, Rebecca, Rogler, Gerhard, Russell, Richard K., Sanderson, Jeremy D., Sans, Miquel, Satsangi, Jack, Schadt, Eric E., Scharl, Michael, Schembri, John, Schreiber, Stefan, Schumm, L. Philip, Scott, Regan, Seielstad, Mark, Shah, Tejas, Sharma, Yashoda, Silverberg, Mark S., Simmons, Alison, Simms, Lisa A., Singh, Abhey, Skieceviciene, Jurgita, van Sommeren, Suzanne, Song, Kyuyoung, Sood, Ajit, Spain, Sarah L., Steinhart, A. Hillary, Stempak, Joanne M., Stronati, Laura, Sung, Joseph J.Y., Targan, Stephan R., Taylor, Kirstin M., Theatre, Emilie, Torkvist, Leif, Torres, Esther A., Tremelling, Mark, Uhlig, Holm H., Umeno, Junji, Vahedi, Homayon, Vasiliauskas, Eric, Velde, Anje ter, Ventham, Nicholas T., Vermeire, Severine, Verspaget, Hein W., De Vos, Martine, Walters, Thomas, Wang, Kai, Wang, Ming-Hsi, Weersma, Rinse K., Wei, Zhi, Whiteman, David, Wijmenga, Cisca, Wilson, David C., Winkelmann, Juliane, Wong, Sunny H., Xavier, Ramnik J., Yamazaki, Keiko, Yang, Suk-Kyun, Ye, Byong Duk, Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K., Zhang, Hu, Zhang, Wei, Zhao, Hongyu, Zhao, Zhen Z., Baumdick, Martin E., Niehrs, Annika, Schwerk, Maria, Hinrichs, Ole, Jordan-Paiz, Ana, Padoan, Benedetta, Wegner, Lucy H.M., Schloer, Sebastian, Zecher, Britta F., Malsy, Jakob, Joshi, Vinita R., Illig, Christin, Schröder-Schwarz, Jennifer, Möller, Kimberly J., Martin, Maureen P., Yuki, Yuko, Ozawa, Mikki, Sauter, Jürgen, Schmidt, Alexander H., Perez, Daniel, Giannou, Anastasios D., Carrington, Mary, Davis, Randall S., Schumacher, Udo, Sauter, Guido, Huber, Samuel, Puelles, Victor G., Melling, Nathaniel, Altfeld, Marcus, and Bunders, Madeleine J.

Published
2023
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7. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

Author

Sazonovs, Aleksejs, Stevens, Christine R., Venkataraman, Guhan R., Yuan, Kai, Avila, Brandon, Abreu, Maria T., Ahmad, Tariq, Allez, Matthieu, Ananthakrishnan, Ashwin N., Atzmon, Gil, Baras, Aris, Barrett, Jeffrey C., Barzilai, Nir, Beaugerie, Laurent, Beecham, Ashley, Bernstein, Charles N., Bitton, Alain, Bokemeyer, Bernd, Chan, Andrew, Chung, Daniel, Cleynen, Isabelle, Cosnes, Jacques, Cutler, David J., Daly, Allan, Damas, Oriana M., Datta, Lisa W., Dawany, Noor, Devoto, Marcella, Dodge, Sheila, Ellinghaus, Eva, Fachal, Laura, Farkkila, Martti, Faubion, William, Ferreira, Manuel, Franchimont, Denis, Gabriel, Stacey B., Ge, Tian, Georges, Michel, Gettler, Kyle, Giri, Mamta, Glaser, Benjamin, Goerg, Siegfried, Goyette, Philippe, Graham, Daniel, Hämäläinen, Eija, Haritunians, Talin, Heap, Graham A., Hiltunen, Mikko, Hoeppner, Marc, Horowitz, Julie E., Irving, Peter, Iyer, Vivek, Jalas, Chaim, Kelsen, Judith, Khalili, Hamed, Kirschner, Barbara S., Kontula, Kimmo, Koskela, Jukka T., Kugathasan, Subra, Kupcinskas, Juozas, Lamb, Christopher A., Laudes, Matthias, Lévesque, Chloé, Levine, Adam P., Lewis, James D., Liefferinckx, Claire, Loescher, Britt-Sabina, Louis, Edouard, Mansfield, John, May, Sandra, McCauley, Jacob L., Mengesha, Emebet, Mni, Myriam, Moayyedi, Paul, Moran, Christopher J., Newberry, Rodney D., O’Charoen, Sirimon, Okou, David T., Oldenburg, Bas, Ostrer, Harry, Palotie, Aarno, Paquette, Jean, Pekow, Joel, Peter, Inga, Pierik, Marieke J., Ponsioen, Cyriel Y., Pontikos, Nikolas, Prescott, Natalie, Pulver, Ann E., Rahmouni, Souad, Rice, Daniel L., Saavalainen, Päivi, Sands, Bruce, Sartor, R. Balfour, Schiff, Elena R., Schreiber, Stefan, Schumm, L. Philip, Segal, Anthony W., Seksik, Philippe, Shawky, Rasha, Sheikh, Shehzad Z., Silverberg, Mark S., Simmons, Alison, Skeiceviciene, Jurgita, Sokol, Harry, Solomonson, Matthew, Somineni, Hari, Sun, Dylan, Targan, Stephan, Turner, Dan, Uhlig, Holm H., van der Meulen, Andrea E., Vermeire, Séverine, Verstockt, Sare, Voskuil, Michiel D., Winter, Harland S., Young, Justine, Duerr, Richard H., Franke, Andre, Brant, Steven R., Cho, Judy, Weersma, Rinse K., Parkes, Miles, Xavier, Ramnik J., Rivas, Manuel A., Rioux, John D., McGovern, Dermot P. B., Huang, Hailiang, Anderson, Carl A., and Daly, Mark J.

Published
2022
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9. Type 1 Diabetes Risk in African-Ancestry Participants and Utility of an Ancestry-Specific Genetic Risk Score

Author

Onengut-Gumuscu, Suna, Chen, Wei-Min, Robertson, Catherine C, Bonnie, Jessica K, Farber, Emily, Zhu, Zhennan, Oksenberg, Jorge R, Brant, Steven R, Bridges, S Louis, Edberg, Jeffrey C, Kimberly, Robert P, Gregersen, Peter K, Rewers, Marian J, Steck, Andrea K, Black, Mary H, Dabelea, Dana, Pihoker, Catherine, Atkinson, Mark A, Wagenknecht, Lynne E, Divers, Jasmin, Bell, Ronny A, Youth, SEARCH for Diabetes in, Consortium, Type 1 Diabetes Genetics, Erlich, Henry A, Concannon, Patrick, and Rich, Stephen S

Subjects
Biomedical and Clinical Sciences, Genetics, Diabetes, Prevention, Human Genome, Clinical Research, Autoimmune Disease, Metabolic and endocrine, Alleles, Black People, Case-Control Studies, Diabetes Mellitus, Type 1, Female, Genetic Predisposition to Disease, Genetic Testing, Genome-Wide Association Study, HLA-D Antigens, HLA-DQ alpha-Chains, HLA-DQ beta-Chains, HLA-DRB1 Chains, Haplotypes, Humans, Male, Polymorphism, Single Nucleotide, Predictive Value of Tests, Research Design, Risk Factors, White People, SEARCH for Diabetes in Youth, Type 1 Diabetes Genetics Consortium, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences, Health sciences
Abstract

ObjectiveGenetic risk scores (GRS) have been developed that differentiate individuals with type 1 diabetes from those with other forms of diabetes and are starting to be used for population screening; however, most studies were conducted in European-ancestry populations. This study identifies novel genetic variants associated with type 1 diabetes risk in African-ancestry participants and develops an African-specific GRS.Research design and methodsWe generated single nucleotide polymorphism (SNP) data with the ImmunoChip on 1,021 African-ancestry participants with type 1 diabetes and 2,928 control participants. HLA class I and class II alleles were imputed using SNP2HLA. Logistic regression models were used to identify genome-wide significant (P < 5.0 × 10-8) SNPs associated with type 1 diabetes in the African-ancestry samples and validate SNPs associated with risk in known European-ancestry loci (P < 2.79 × 10-5).ResultsAfrican-specific (HLA-DQA1*03:01-HLA-DQB1*02:01) and known European-ancestry HLA haplotypes (HLA-DRB1*03:01-HLA-DQA1*05:01-HLA-DQB1*02:01, HLA-DRB1*04:01-HLA-DQA1*03:01-HLA-DQB1*03:02) were significantly associated with type 1 diabetes risk. Among European-ancestry defined non-HLA risk loci, six risk loci were significantly associated with type 1 diabetes in subjects of African ancestry. An African-specific GRS provided strong prediction of type 1 diabetes risk (area under the curve 0.871), performing significantly better than a European-based GRS and two polygenic risk scores in independent discovery and validation cohorts.ConclusionsGenetic risk of type 1 diabetes includes ancestry-specific, disease-associated variants. The GRS developed here provides improved prediction of type 1 diabetes in African-ancestry subjects and a means to identify groups of individuals who would benefit from immune monitoring for early detection of islet autoimmunity.

Published
2019

11. A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn’s Disease and Human Gut Microbiome Composition

Author

Li, Dalin, Achkar, Jean-Paul, Haritunians, Talin, Jacobs, Jonathan P, Hui, Ken Y, D'Amato, Mauro, Brand, Stephan, Radford-Smith, Graham, Halfvarson, Jonas, Niess, Jan-Hendrik, Kugathasan, Subra, Büning, Carsten, Schumm, L Philip, Klei, Lambertus, Ananthakrishnan, Ashwin, Aumais, Guy, Baidoo, Leonard, Dubinsky, Marla, Fiocchi, Claudio, Glas, Jürgen, Milgrom, Raquel, Proctor, Deborah D, Regueiro, Miguel, Simms, Lisa A, Stempak, Joanne M, Targan, Stephan R, Törkvist, Leif, Sharma, Yashoda, Devlin, Bernie, Borneman, James, Hakonarson, Hakon, Xavier, Ramnik J, Daly, Mark, Brant, Steven R, Rioux, John D, Silverberg, Mark S, Cho, Judy H, Braun, Jonathan, McGovern, Dermot PB, and Duerr, Richard H

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Nutrition and Dietetics, Genetics, Nutrition, Inflammatory Bowel Disease, Autoimmune Disease, Human Genome, Clinical Research, Digestive Diseases, Crohn's Disease, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Alleles, Case-Control Studies, Cation Transport Proteins, Colitis, Ulcerative, Crohn Disease, Female, Gastrointestinal Microbiome, Genetic Pleiotropy, Genotype, Humans, Male, Mutation, Missense, Risk Factors, Inflammatory Bowel Diseases, Microbiota, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsGenome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA).MethodsGenotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing.ResultsWe identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)).ConclusionsOur results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

Published
2016

12. A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF

Author

Chuang, Ling-Shiang, Villaverde, Nicole, Hui, Ken Y, Mortha, Arthur, Rahman, Adeeb, Levine, Adam P, Haritunians, Talin, Ng, Sok Meng Evelyn, Zhang, Wei, Hsu, Nai-Yun, Facey, Jody-Ann, Luong, Tramy, Fernandez-Hernandez, Heriberto, Li, Dalin, Rivas, Manuel, Schiff, Elena R, Gusev, Alexander, Schumm, L Phillip, Bowen, Beatrice M, Sharma, Yashoda, Ning, Kaida, Remark, Romain, Gnjatic, Sacha, Legnani, Peter, George, James, Sands, Bruce E, Stempak, Joanne M, Datta, Lisa W, Lipka, Seth, Katz, Seymour, Cheifetz, Adam S, Barzilai, Nir, Pontikos, Nikolas, Abraham, Clara, Dubinsky, Marla J, Targan, Stephan, Taylor, Kent, Rotter, Jerome I, Scherl, Ellen J, Desnick, Robert J, Abreu, Maria T, Zhao, Hongyu, Atzmon, Gil, Pe’er, Itsik, Kugathasan, Subra, Hakonarson, Hakon, McCauley, Jacob L, Lencz, Todd, Darvasi, Ariel, Plagnol, Vincent, Silverberg, Mark S, Muise, Aleixo M, Brant, Steven R, Daly, Mark J, Segal, Anthony W, Duerr, Richard H, Merad, Miriam, McGovern, Dermot PB, Peter, Inga, and Cho, Judy H

Subjects
Clinical Research, Genetics, Inflammatory Bowel Disease, Digestive Diseases, Crohn's Disease, 2.1 Biological and endogenous factors, Aetiology, Case-Control Studies, Crohn Disease, Cytokine Receptor Common beta Subunit, Female, Frameshift Mutation, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Intestines, Jews, Male, Monocytes, Risk Factors, Signal Transduction, IBD, Risk Factor, Ethnic Variation, Clinical Sciences, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology
Abstract

Background & aimsCrohn's disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects.MethodsWe performed exome sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for frameshift mutations in the colony-stimulating factor 2-receptor β common subunit gene (CSF2RB). Intestinal tissues and blood samples were collected from patients with CD; lamina propria leukocytes were isolated and expression of CSF2RB and granulocyte-macrophage colony-stimulating factor-responsive cells were defined by adenomatous polyposis coli (APC) time-of-flight mass cytometry (CyTOF analysis). Variants of CSF2RB were transfected into HEK293 cells and the expression and functions of gene products were compared.ResultsIn the discovery cohort, we associated CD with a frameshift mutation in CSF2RB (P = 8.52 × 10(-4)); the finding was validated in the replication cohort (combined P = 3.42 × 10(-6)). Incubation of intestinal lamina propria leukocytes with granulocyte-macrophage colony-stimulating factor resulted in high levels of phosphorylation of signal transducer and activator of transcription (STAT5) and lesser increases in phosphorylation of extracellular signal-regulated kinase and AK straining transforming (AKT). Cells co-transfected with full-length and mutant forms of CSF2RB had reduced pSTAT5 after stimulation with granulocyte-macrophage colony-stimulating factor, compared with cells transfected with control CSF2RB, indicating a dominant-negative effect of the mutant gene. Monocytes from patients with CD who were heterozygous for the frameshift mutation (6% of CD cases analyzed) had reduced responses to granulocyte-macrophage colony-stimulating factor and markedly decreased activity of aldehyde dehydrogenase; activity of this enzyme has been associated with immune tolerance.ConclusionsIn a genetic analysis of Ashkenazi Jewish individuals, we associated CD with a frameshift mutation in CSF2RB. Intestinal monocytes from carriers of this mutation had reduced responses to granulocyte-macrophage colony-stimulating factor, providing an additional mechanism for alterations to the innate immune response in individuals with CD.

Published
2016

13. Characterization of Genetic Loci That Affect Susceptibility to Inflammatory Bowel Diseases in African Americans

Author

Huang, Chengrui, Haritunians, Talin, Okou, David T, Cutler, David J, Zwick, Michael E, Taylor, Kent D, Datta, Lisa W, Maranville, Joseph C, Liu, Zhenqiu, Ellis, Shannon, Chopra, Pankaj, Alexander, Jonathan S, Baldassano, Robert N, Cross, Raymond K, Dassopoulos, Themistocles, Dhere, Tanvi A, Duerr, Richard H, Hanson, John S, Hou, Jason K, Hussain, Sunny Z, Isaacs, Kim L, Kachelries, Kelly E, Kader, Howard, Kappelman, Michael D, Katz, Jeffrey, Kellermayer, Richard, Kirschner, Barbara S, Kuemmerle, John F, Kumar, Archana, Kwon, John H, Lazarev, Mark, Mannon, Peter, Moulton, Dedrick E, Osuntokun, Bankole O, Patel, Ashish, Rioux, John D, Rotter, Jerome I, Saeed, Shehzad, Scherl, Ellen J, Silverberg, Mark S, Silverman, Ann, Targan, Stephan R, Valentine, John F, Wang, Ming-Hsi, Simpson, Claire L, Bridges, S Louis, Kimberly, Robert P, Rich, Stephen S, Cho, Judy H, Di Rienzo, Anna, Kao, Linda WH, McGovern, Dermot PB, Brant, Steven R, and Kugathasan, Subra

Subjects
Genetics, Clinical Research, Crohn's Disease, Digestive Diseases, Inflammatory Bowel Disease, Autoimmune Disease, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Good Health and Well Being, Adult, Black or African American, Aged, Colitis, Ulcerative, Crohn Disease, Female, Genetic Loci, Genetic Predisposition to Disease, Humans, Inflammatory Bowel Diseases, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, United States, White People, Young Adult, Race, Ethnicity, Genetic Variant, Intestinal Inflammation, Clinical Sciences, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology
Abstract

Background & aimsInflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci.MethodsWe recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed.ResultsThe strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10(-6)), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10(-6)), and IBD and KAT2A rs730086 (P = 2.3 × 10(-6)). Additional suggestive associations (P < 4.2 × 10(-5)) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10(-4)) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10(-4)) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate

Published
2015

14. Clinical Predictors of Early and Late Endoscopic Recurrence Following Ileocolonic Resection in Crohn's Disease.

Author

Hernández-Rocha, Cristian, Walshe, Margaret, Birch, Sondra, Sabic, Ksenija, Korie, Ujunwa, Chasteau, Colleen, Miladinova, Vessela M, Sabol, William B, Mengesha, Emebet, Hanna, Mary, Pozdnyakova, Valeriya, Datta, Lisa, Kohen, Rita, Milgrom, Raquel, Stempak, Joanne M, Bitton, Alain, Brant, Steven R, Rioux, John D, McGovern, Dermot P B, and Duerr, Richard H

Abstract

Background and Aims Multiple factors are suggested to place Crohn's disease patients at risk of recurrence after ileocolic resection with conflicting associations. We aimed to identify clinical predictors of recurrence at first [early] and further [late] postoperative colonoscopy. Methods Crohn's disease patients undergoing ileocolic resection were prospectively recruited at six North American centres. Clinical data were collected and endoscopic recurrence was defined as Rutgeerts score ≥i2. A multivariable model was fitted to analyse variables independently associated with recurrence. Results A total of 365 patients undergoing 674 postoperative colonoscopies were included with a median age of 32 years, 189 [51.8%] were male, and 37 [10.1%] were non-Whites. Postoperatively, 133 [36.4%] used anti-tumour necrosis factor [anti-TNF] and 30 [8.2%] were smokers. At first colonoscopy, 109 [29.9%] had recurrence. Male gender (odds ratio [OR] = 1.95, 95% confidence interval [CI] 1.12–3.40), non-White ethnicity [OR = 2.48, 95% CI 1.09–5.63], longer interval between surgery and colonoscopy [OR = 1.09, 95% CI 1.002–1.18], and postoperative smoking [OR = 2.78, 95% CI 1.16–6.67] were associated with recurrence, while prophylactic anti-TNF reduced the risk [OR = 0.28, 95% CI 0.14–0.55]. Postoperative anti-TNF prophylaxis had a protective effect on anti-TNF experienced patients but not on anti-TNF naïve patients. Among patients without recurrence at first colonoscopy, Rutgeerts score i1 was associated with subsequent recurrence [OR = 4.43, 95% CI 1.73–11.35]. Conclusions We identified independent clinical predictors of early and late Crohn's disease postoperative endoscopic recurrence. Clinical factors traditionally used for risk stratification failed to predict recurrence and need to be revised. [ABSTRACT FROM AUTHOR]

Published
2024
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15. Clinical Predictors of Early and Late Endoscopic Recurrence Following Ileocolonic Resection in Crohn’s Disease

Author

Hernández-Rocha, Cristian, primary, Walshe, Margaret, additional, Birch, Sondra, additional, Sabic, Ksenija, additional, Korie, Ujunwa, additional, Chasteau, Colleen, additional, Miladinova, Vessela M, additional, Sabol, William B, additional, Mengesha, Emebet, additional, Hanna, Mary, additional, Pozdnyakova, Valeriya, additional, Datta, Lisa, additional, Kohen, Rita, additional, Milgrom, Raquel, additional, Stempak, Joanne M, additional, Bitton, Alain, additional, Brant, Steven R, additional, Rioux, John D, additional, McGovern, Dermot P B, additional, Duerr, Richard H, additional, Cho, Judy H, additional, Schumm, Phil L, additional, Silverberg, Mark S, additional, and Lazarev, Mark, additional

Published
2023
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17. 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, Digestive Diseases, Human Genome, Inflammatory Bowel Disease, Biotechnology, Autoimmune Disease, Crohn's Disease, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, 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

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

Author

Anderson, Carl A, Boucher, Gabrielle, Lees, Charlie W, Franke, Andre, D'Amato, Mauro, Taylor, Kent D, Lee, James C, Goyette, Philippe, Imielinski, Marcin, Latiano, Anna, Lagacé, Caroline, Scott, Regan, Amininejad, Leila, Bumpstead, Suzannah, Baidoo, Leonard, Baldassano, Robert N, Barclay, Murray, Bayless, Theodore M, Brand, Stephan, Büning, Carsten, Colombel, Jean-Frédéric, Denson, Lee A, De Vos, Martine, Dubinsky, Marla, Edwards, Cathryn, Ellinghaus, David, Fehrmann, Rudolf SN, Floyd, James AB, Florin, Timothy, Franchimont, Denis, Franke, Lude, Georges, Michel, Glas, Jürgen, Glazer, Nicole L, Guthery, Stephen L, Haritunians, Talin, Hayward, Nicholas K, Hugot, Jean-Pierre, Jobin, Gilles, Laukens, Debby, Lawrance, Ian, Lémann, Marc, Levine, Arie, Libioulle, Cecile, Louis, Edouard, McGovern, Dermot P, Milla, Monica, Montgomery, Grant W, Morley, Katherine I, Mowat, Craig, Ng, Aylwin, Newman, William, Ophoff, Roel A, Papi, Laura, Palmieri, Orazio, Peyrin-Biroulet, Laurent, Panés, Julián, Phillips, Anne, Prescott, Natalie J, Proctor, Deborah D, Roberts, Rebecca, Russell, Richard, Rutgeerts, Paul, Sanderson, Jeremy, Sans, Miquel, Schumm, Philip, Seibold, Frank, Sharma, Yashoda, Simms, Lisa A, Seielstad, Mark, Steinhart, A Hillary, Targan, Stephan R, van den Berg, Leonard H, Vatn, Morten, Verspaget, Hein, Walters, Thomas, Wijmenga, Cisca, Wilson, David C, Westra, Harm-Jan, Xavier, Ramnik J, Zhao, Zhen Z, Ponsioen, Cyriel Y, Andersen, Vibeke, Torkvist, Leif, Gazouli, Maria, Anagnou, Nicholas P, Karlsen, Tom H, Kupcinskas, Limas, Sventoraityte, Jurgita, Mansfield, John C, Kugathasan, Subra, Silverberg, Mark S, Halfvarson, Jonas, Rotter, Jerome I, Mathew, Christopher G, Griffiths, Anne M, Gearry, Richard, Ahmad, Tariq, Brant, Steven R, and Chamaillard, Mathias

Subjects
Biological Sciences, Genetics, Autoimmune Disease, Human Genome, Crohn's Disease, Digestive Diseases, Nutrition, Inflammatory Bowel Disease, Prevention, Oral and gastrointestinal, Colitis, Ulcerative, Crohn Disease, Genome-Wide Association Study, Humans, Risk, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
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

19. Ulcerative colitis–risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study

Author

Silverberg, Mark S, Cho, Judy H, Rioux, John D, McGovern, Dermot PB, Wu, Jing, Annese, Vito, Achkar, Jean-Paul, Goyette, Philippe, Scott, Regan, Xu, Wei, Barmada, M Michael, Klei, Lambertus, Daly, Mark J, Abraham, Clara, Bayless, Theodore M, Bossa, Fabrizio, Griffiths, Anne M, Ippoliti, Andrew F, Lahaie, Raymond G, Latiano, Anna, Paré, Pierre, Proctor, Deborah D, Regueiro, Miguel D, Steinhart, A Hillary, Targan, Stephan R, Schumm, L Philip, Kistner, Emily O, Lee, Annette T, Gregersen, Peter K, Rotter, Jerome I, Brant, Steven R, Taylor, Kent D, Roeder, Kathryn, and Duerr, Richard H

Subjects
Biological Sciences, Genetics, Butyrophilins, Case-Control Studies, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 6, Colitis, Ulcerative, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, HLA-DQ Antigens, HLA-DQ beta-Chains, Humans, Male, Membrane Glycoproteins, Polymorphism, Single Nucleotide, Receptors, Interleukin, Recombination, Genetic, Risk Factors, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 x 10(-13), combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 x 10(-12), combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 x 10(-16), combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 x 10(-8), combined OR = 0.56; rs10889677, combined P = 1.3 x 10(-8), combined OR = 1.29).

Published
2009

23. 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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24. Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

Author

Hui, Ken Y., Fernandez-Hernandez, Heriberto, Hu, Jianzhong, Schaffner, Adam, Pankratz, Nathan, Hsu, Nai-Yun, Chuang, Ling-Shiang, Carmi, Shai, Villaverde, Nicole, Li, Xianting, Rivas, Manual, Levine, Adam P., Bao, Xiuliang, Labrias, Philippe R., Haritunians, Talin, Ruane, Darren, Gettler, Kyle, Chen, Ernie, Li, Dalin, Schiff, Elena R., Pontikos, Nikolas, Barzilai, Nir, Brant, Steven R., Bressman, Susan, Cheifetz, Adam S., Clark, Lorraine N., Daly, Mark J., Desnick, Robert J., Duerr, Richard H., Katz, Seymour, Lencz, Todd, Myers, Richard H., Ostrer, Harry, Ozelius, Laurie, Payami, Haydeh, Peter, Yakov, Rioux, John D., Segal, Anthony W., Scott, William K., Silverberg, Mark S., Vance, Jeffery M., Ubarretxena-Belandia, Iban, Foroud, Tatiana, Atzmon, Gil, Pe’er, Itsik, Ioannou, Yiannis, McGovern, Dermot P. B., Yue, Zhenyu, Schadt, Eric E., Cho, Judy H., and Peter, Inga

Published
2018
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26. Inflammatory Bowel Diseases Before and After 1990

Author

Truta, Brindusa, primary, Begum, Ferdouse, additional, Datta, Lisa Wu, additional, Brant, Steven R., additional, Cho, Judy H., additional, Duerr, Richard H., additional, McGovern, Dermot B.P., additional, Rioux, John R., additional, and Silverberg, Mark S., additional

Published
2023
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27. Defects in Nicotinamide-adenine Dinucleotide Phosphate Oxidase Genes NOX1 and DUOX2 in Very Early Onset Inflammatory Bowel Disease

Author

Hayes, Patti, Dhillon, Sandeep, O’Neill, Kim, Thoeni, Cornelia, Hui, Ken Y., Elkadri, Abdul, Guo, Conghui H., Kovacic, Lidija, Aviello, Gabriella, Alvarez, Luis A., Griffiths, Anne M., Snapper, Scott B., Brant, Steven R., Doroshow, James H., Silverberg, Mark S., Peter, Inga, McGovern, Dermot P.B., Cho, Judy, Brumell, John H., Uhlig, Holm H., Bourke, Billy, Muise, Aleixo M., and Knaus, Ulla G.

Published
2015
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30. A Systematic Review of Crohn’s Disease Case Definitions in Administrative or Claims Databases

Author

Hutfless, Susan, primary, Jasper, Ryan A, additional, Tilak, Aman, additional, Ghosh, Tamoghna, additional, Kedia, Saurabh, additional, Liu, Simon, additional, Urrunaga, Nathalie H, additional, Josephson, Matthew, additional, Narang, Arshit, additional, Miller, Steve, additional, Chen, Po-Hung, additional, Joseph, Shelly, additional, and Brant, Steven R, additional

Published
2022
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34. Su1017: MALE GENDER AND NON-CAUCASIAN ETHNICITY ARE ASSOCIATED WITH HIGHER RISK OF POSTOPERATIVE RECURRENCE OF CROHN'S DISEASE INDEPENDENT OF KNOWN CLINICAL RISK FACTORS

Author

Hernandez-Rocha, Cristian, primary, Schumm, L. Philip, additional, Birch, Sondra, additional, Walshe, Margaret, additional, Mcgovern, Dermot P.B., additional, Brant, Steven R., additional, Rioux, John D., additional, Duerr, Richard H., additional, Cho, Judy H., additional, Silverberg, Mark S., additional, and Lazarev, Mark, additional

Published
2022
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35. 555: MUCOSAL MICROBIAL PROFILES AT THE NEO-TERMINAL ILEUM ARE ASSOCIATED WITH FUTURE DEVELOPMENT OF POSTOPERATIVE ENDOSCOPIC RECURRENCE IN CROHN'S DISEASE PATIENTS.

Author

Hernandez-Rocha, Cristian, primary, Turpin, Williams, additional, Nayeri, Shadi, additional, Borowski, Krzysztof, additional, Stempak, Joanne M., additional, Schumm, L. Philip, additional, Brant, Steven R., additional, Lazarev, Mark, additional, Rioux, John D., additional, Mcgovern, Dermot P.B., additional, Duerr, Richard H., additional, Cho, Judy H., additional, and Silverberg, Mark S., additional

Published
2022
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37. Molecular Studies of Members of the Mammalian Na+/H+ Exchanger Gene Family

Author

Donowitz, Mark, Levine, Susan A., Chris Yun, C. H., Brant, Steven R., Nath, Samir, Yip, Jeannie, Hoogerwerf, Sandra, Pouysségur, Jacques, Tse, Chung-Ming, Schultz, Stanley G., editor, Andreoli, Thomas E., editor, Brown, Arthur M., editor, Fambrough, Douglas M., editor, Hoffman, Joseph F., editor, and Welsh, Michael J., editor

Published
1996
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38. A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene

Author

Duerr, Richard H., Taylor, Kent D., Brant, Steven R., Rioux, John D., Silverberg, Mark S., Daly, Mark J., Steinhart, A. Hillary, Abraham, Clara, Regueiro, Miguel, Griffiths, Anne, Dassopoulos, Themistocles, Bitton, Alain, Yang, Huiying, Targan, Stephan, Datta, Lisa Wu, Kistner, Emily O., Schumm, L. Philip, Lee, Annette T., Gregersen, Peter K., Barmada, M. Michael, Rotter, Jerome I., Nicolae, Dan L., and Cho, Judy H.

Published
2006
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41. Ocular Manifestations in Inflammatory Bowel Disease Are Associated with Other Extra-intestinal Manifestations, Gender, and Genes Implicated in Other Immune-related Traits

Author

Taleban, Sasha, Li, Dalin, Targan, Stephan R., Ippoliti, Andrew, Brant, Steven R., Cho, Judy H., Duerr, Richard H., Rioux, John D., Silverberg, Mark S., Vasiliauskas, Eric A., Rotter, Jerome I., Haritunians, Talin, Shih, David Q., Dubinsky, Marla, Melmed, Gil Y., and McGovern, Dermot P.B

Published
2016
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42. Genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohn’s disease and leads to impaired CFB cleavage and phagocytosis

Author

Akhlaghpour, Marzieh, Haritunians, Talin, More, Shyam K, Thomas, Lisa S, Stamps, Dalton T, Dube, Shishir, Li, Dalin, Yang, Shaohong, Landers, Carol J, Mengesha, Emebet, Hamade, Hussein, Murali, Ramachandran, Potdar, Alka A, Wolf, Andrea J, Botwin, Gregory J, Khrom, Michelle, Ananthakrishnan, Ashwin N, Faubion, William A, Jabri, Bana, Lira, Sergio A, Newberry, Rodney D, Sandler, Robert S, Sartor, R Balfour, Xavier, Ramnik J, Brant, Steven R, Cho, Judy H, Duerr, Richard H, Lazarev, Mark G, Rioux, John D, Schumm, L Philip, Silverberg, Mark S, Zaghiyan, Karen, Fleshner, Phillip, Melmed, Gil Y, Vasiliauskas, Eric A, Ha, Christina, Rabizadeh, Shervin, Syal, Gaurav, Bonthala, Nirupama N, Ziring, David A, Targan, Stephan R, Long, Millie D, McGovern, Dermot P B, and Michelsen, Kathrin S

Abstract

ObjectivePerianal Crohn’s disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in Complement Factor B(CFB).DesignImmunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum from CFBrisk, or protective CD or healthy subjects was assessed by flow cytometry.ResultsPerianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) in CFB, in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum.ConclusionpCD-associated rs4151651 in CFBis a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD aetiology.

Published
2023
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43. Sa482 MEGA-ANALYSIS REVEALS CLINICAL SEROLOGICAL AND GENETIC ASSOCIATIONS WITH EXTRAINTESTINAL MANIFESTATIONS IN IBD

Author

Khrom, Michelle, primary, Long, Millie D., additional, Dube, Shishir, additional, Botwin, Gregory J., additional, Yang, Shaohong, additional, Mengesha, Emebet, additional, Li, Dalin, additional, Bonthala, Nirupama, additional, Ha, Christina, additional, Melmed, Gil, additional, Rabizadeh, Shervin, additional, Syal, Gaurav, additional, Vasiliauskas, Eric, additional, Ziring, David, additional, Brant, Steven R., additional, Cho, Judy H., additional, Duerr, Richard H., additional, Rioux, John D., additional, Schumm, L. Philip, additional, Silverberg, Mark S., additional, Ananthakrishnan, Ashwin, additional, Faubion, William, additional, Jabri, Bana, additional, Lira, Sergio A., additional, Newberry, Rodney D., additional, Sandler, Robert, additional, Xavier, Ramnik, additional, Kugathasan, Subra, additional, Hercules, David, additional, Targan, Stephan R., additional, Sartor, R. Balfour, additional, Mcgovern, Dermot P.B., additional, and Haritunians, Talin, additional

Published
2021
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44. Sa449 SERUM ANALYTE PROFILES ASSOCIATED WITH CROHN'S DISEASE AND DISEASE LOCATION

Author

Boucher, Gabrielle, primary, Paradis, Alexandre, additional, Chabot-Roy, Geneviève, additional, Coderre, Lise, additional, Hillhouse, Erin E., additional, Bitton, Alain, additional, Rosiers, Christine Des, additional, Levings, Megan K., additional, Schumm, L. Philip, additional, Lazarev, Mark, additional, Brant, Steven R., additional, Duerr, Richard H., additional, Mcgovern, Dermot P.B., additional, Silverberg, Mark S., additional, Cho, Judy H., additional, Lesage, Sylvie, additional, and Rioux, John D., additional

Published
2021
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45. 374 INFLAMED ULCERATIVE COLITIS REGIONS ASSOCIATED TO MRGPRX2-MEDIATED MAST CELL DEGRANULATION AND CELL ACTIVATION MODULES, DEFINING A NEW THERAPEUTIC TARGET

Author

Chuang, Ling-shiang F., primary, Chen, Ernie, additional, Giri, Mamta, additional, Villaverde, Nicole, additional, Hsu, Nai-yun, additional, Sabic, Ksenija, additional, Joshowitz, Sari, additional, Gettler, Kyle, additional, Nayar, Shikha, additional, Chai, Zhi, additional, Alter, Isaac, additional, Chasteau, Colleen, additional, Korie, Ujunwa, additional, Dzedzik, Siarhei, additional, Thin, Tin Htwe, additional, Jain, Aayushee, additional, Moscati, Arden, additional, Bongers, Gerold, additional, Duerr, Richard H., additional, Silverberg, Mark S., additional, Brant, Steven R., additional, Rioux, John D., additional, Peter, Inga, additional, Schumm, L. Philip, additional, Haritunians, Talin, additional, Mcgovern, Dermot P.B., additional, Itan, Yuval, additional, and Cho, Judy H., additional

Published
2021
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46. 168 GENE EXPRESSION ANALYSES IN THE PERIOPERATIVE ILEAL RESECTION PERIOD ILLUMINATE PATHOGENIC AND PROTECTIVE CROHN'S DISEASE CELL SUBSETS

Author

Gettler, Kyle, primary, Sabic, Ksenija, additional, Giri, Mamta, additional, Schumm, L. Philip, additional, Haritunians, Talin, additional, Lazarev, Mark, additional, Mcgovern, Dermot P.B., additional, Duerr, Richard H., additional, Rioux, John D., additional, Brant, Steven R., additional, Silverberg, Mark S., additional, and Cho, Judy H., additional

Published
2021
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47. 776 IDENTIFYING NOVEL HIGH-IMPACT RARE DISEASE-CAUSING MUTATIONS, GENES AND PATHWAYS IN EXOMES OF ASHKENAZI JEWISH INFLAMMATORY BOWEL DISEASE PATIENT

Author

Wu, Yiming, primary, Gettler, Kyle, additional, Giri, Mamta, additional, Sabic, Ksenija, additional, Schumm, L. Philip, additional, Daly, Mark J., additional, Duerr, Richard H., additional, Silverberg, Mark S., additional, Rioux, John D., additional, Brant, Steven R., additional, Mcgovern, Dermot P.B., additional, Cho, Judy H., additional, and Itan, Yuval, additional

Published
2021
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48. Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort

Author

Gettler, Kyle, primary, Levantovsky, Rachel, additional, Moscati, Arden, additional, Giri, Mamta, additional, Wu, Yiming, additional, Hsu, Nai-Yun, additional, Chuang, Ling-Shiang, additional, Sazonovs, Aleksejs, additional, Venkateswaran, Suresh, additional, Korie, Ujunwa, additional, Chasteau, Colleen, additional, Duerr, Richard H., additional, Silverberg, Mark S., additional, Snapper, Scott B., additional, Daly, Mark J., additional, McGovern, Dermot P., additional, Brant, Steven R., additional, Rioux, John D., additional, Kugathasan, Subra, additional, Anderson, Carl A., additional, Itan, Yuval, additional, and Cho, Judy H., additional

Published
2021
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49. Inflamed Ulcerative Colitis Regions Associated With MRGPRX2-Mediated Mast Cell Degranulation and Cell Activation Modules, Defining a New Therapeutic Target

Author

Chen, Ernie, primary, Chuang, Ling-shiang, additional, Giri, Mamta, additional, Villaverde, Nicole, additional, Hsu, Nai-yun, additional, Sabic, Ksenija, additional, Joshowitz, Sari, additional, Gettler, Kyle, additional, Nayar, Shikha, additional, Chai, Zhi, additional, Alter, Isaac L., additional, Chasteau, Colleen C., additional, Korie, Ujunwa M., additional, Dzedzik, Siarhei, additional, Thin, Tin Htwe, additional, Jain, Aayushee, additional, Moscati, Arden, additional, Bongers, Gerardus, additional, Duerr, Richard H., additional, Silverberg, Mark S., additional, Brant, Steven R., additional, Rioux, John D., additional, Peter, Inga, additional, Schumm, L. Philip, additional, Haritunians, Talin, additional, McGovern, Dermot P., additional, Itan, Yuval, additional, and Cho, Judy H., additional

Published
2021
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