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2. Hospital-wide access to genomic data advanced pediatric rare disease research and clinical outcomes

Author

French, Courtney E., Andrews, Nancy C., Beggs, Alan H., Boone, Philip M., Brownstein, Catherine A., Chopra, Maya, Chou, Janet, Chung, Wendy K., D’Gama, Alissa M., Doan, Ryan N., Ebrahimi-Fakhari, Darius, Goldstein, Richard D., Irons, Mira, Jacobsen, Christina, Kenna, Margaret, Lee, Ted, Madden, Jill A., Majmundar, Amar J., Mann, Nina, Morton, Sarah U., Poduri, Annapurna, Randolph, Adrienne G., Roberts, Amy E., Roberts, Stephanie, Sampson, Matthew G., Shao, Diane D., Shao, Wanqing, Sharma, Aditi, Shearer, Eliot, Shimamura, Akiko, Snapper, Scott B., Srivastava, Siddharth, Thiagarajah, Jay R., Whitman, Mary C., Wojcik, Monica H., Rockowitz, Shira, and Sliz, Piotr

Published
2024
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3. Intestinal microbiome and metabolome signatures in patients with chronic granulomatous disease.

Author

Chandrasekaran, Prabha, Han, Yu, Zerbe, Christa, Heller, Theo, DeRavin, Suk, Kreuzberg, Samantha, Marciano, Beatriz, Siu, Yik, Jones, Drew, Abraham, Roshini, Stephens, Michael, Tsou, Amy, Snapper, Scott, Conlan, Sean, Subramanian, Poorani, Quinones, Mariam, Grou, Caroline, Calderon, Virginie, Deming, Clayton, Leiding, Jennifer, Arnold, Danielle, Logan, Brent, Griffith, Linda, Petrovic, Aleksandra, Mousallem, Talal, Kapoor, Neena, Heimall, Jennifer, Barnum, Jessie, Kapadia, Malika, Wright, Nicola, Rayes, Ahmad, Chandra, Sharat, Broglie, Larisa, Chellapandian, Deepak, Deal, Christin, Grunebaum, Eyal, Lim, Stephanie, Mallhi, Kanwaldeep, Marsh, Rebecca, Murguia-Favela, Luis, Parikh, Suhag, Touzot, Fabien, Cowan, Morton, Dvorak, Christopher, Haddad, Elie, Kohn, Donald, Notarangelo, Luigi, Pai, Sung-Yun, Puck, Jennifer, Pulsipher, Michael, Torgerson, Troy, Kang, Elizabeth, Malech, Harry, Segre, Julia, Bryant, Clare, Holland, Steven, and Falcone, Emilia

Subjects
CGD, Chronic granulomatous disease, IBD, NADPH oxidase, dysbiosis, inborn errors of immunity, inflammatory bowel disease, intestinal inflammation, metabolome, microbiome, primary immune deficiency, Humans, Granulomatous Disease, Chronic, Gastrointestinal Microbiome, NADPH Oxidases, Cross-Sectional Studies, Inflammatory Bowel Diseases
Abstract

BACKGROUND: Chronic granulomatous disease (CGD) is caused by defects in any 1 of the 6 subunits forming the nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2), leading to severely reduced or absent phagocyte-derived reactive oxygen species production. Almost 50% of patients with CGD have inflammatory bowel disease (CGD-IBD). While conventional IBD therapies can treat CGD-IBD, their benefits must be weighed against the risk of infection. Understanding the impact of NOX2 defects on the intestinal microbiota may lead to the identification of novel CGD-IBD treatments. OBJECTIVE: We sought to identify microbiome and metabolome signatures that can distinguish individuals with CGD and CGD-IBD. METHODS: We conducted a cross-sectional observational study of 79 patients with CGD, 8 pathogenic variant carriers, and 19 healthy controls followed at the National Institutes of Health Clinical Center. We profiled the intestinal microbiome (amplicon sequencing) and stool metabolome, and validated our findings in a second cohort of 36 patients with CGD recruited through the Primary Immune Deficiency Treatment Consortium. RESULTS: We identified distinct intestinal microbiome and metabolome profiles in patients with CGD compared to healthy individuals. We observed enrichment for Erysipelatoclostridium spp, Sellimonas spp, and Lachnoclostridium spp in CGD stool samples. Despite differences in bacterial alpha and beta diversity between the 2 cohorts, several taxa correlated significantly between both cohorts. We further demonstrated that patients with CGD-IBD have a distinct microbiome and metabolome profile compared to patients without CGD-IBD. CONCLUSION: Intestinal microbiome and metabolome signatures distinguished patients with CGD and CGD-IBD, and identified potential biomarkers and therapeutic targets.

Published
2023

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

Author

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

Subjects
Adult, Humans, Jews, Exome, Inflammatory Bowel Diseases, Risk Assessment, Genetic Predisposition to Disease
Abstract

Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.

Published
2023

5. Development and Validation of an Integrative Risk Score for Future Risk of Crohn’s Disease in Healthy First-Degree Relatives: A Multicenter Prospective Cohort Study

Author

Lee, Sun-Ho, Turpin, Williams, Espin-Garcia, Osvaldo, Xu, Wei, Leibovitzh, Haim, Xue, Mingyue, Raygoza Garay, Juan Antonio, Graña-Miraglia, Lucía, Smith, Michelle I., Goethel, Ashleigh, Madsen, Karen L., Avni-Biron, Irit, Dotan, Iris, Weiss, Batia, Panaccione, Remo, Huynh, Hien, Jacobson, Kevan, Aumais, Guy, Mack, David, Griffiths, Anne M., Steinhart, A. Hillary, Silverberg, Mark S., Turner, Dan, Bernstein, Charles N., Feagan, Brian G., Moayyedi, Paul, Paterson, Andrew, Guttman, David S., Abreu, Maria, Beck, Paul, Dieleman, Leo, Kaplan, Gilaad, Krause, Denis O., Marshall, John, Ropeleski, Mark, Seidman, Ernest, Snapper, Scott, Stadnyk, Andy, Surette, Michael, Walters, Thomas, Vallance, Bruce, Bitton, Alain, Cino, Maria, Critch, Jeff, Denson, Lee, Deslandres, Colette, El-Matary, Wael, Herfarth, Hans, Higgins, Peter, Hyams, Jeff, McGrath, Jerry, Otley, Anthony, and Croitoru, Kenneth

Published
2025
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6. Healthy First-Degree Relatives From Multiplex Families vs Simplex Families Have Higher Subclinical Intestinal Inflammation, a Distinct Fecal Microbial Signature, and Harbor a Higher Risk of Developing Crohn’s Disease

Author

Abreu, Maria T., Beck, Paul, Bernstein, Charles, Croitoru, Kenneth, Dieleman, Levinus, Feagan, Brian, Griffiths, Anne, Guttman, David S., Jacobson, Kevan, Kaplan, Gilaad, Krause, Denis O., Madsen, Karen L., Marshall, John K., Moayyedi, Paul, Ropeleski, Mark, Seidman, Ernest, Silverberg, Mark S., Snapper, Scott, Stadnyk, Andy, Steinhart, A. Hillary, Surette, Michael, Turner, Dan, Walters, Thomas, Vallance, Bruce, Aumais, Guy, Bitton, Alain, Cino, Maria, Critch, Jeff, Denson, Lee, Deslandres, Colette, El-Matary, Wael, Herfarth, Hans, Higgins, Peter, Huynh, Hien Q., Hyams, Jeff, Mack, David R., McGrath, Jerry, Otley, Anthony, Panaccione, Remo, Olivera, Pablo A., Martinez-Lozano, Helena, Leibovitzh, Haim, Xue, Mingyue, Neustaeter, Anna, Espin-Garcia, Osvaldo, Xu, Wei, Bernstein, Charles N., Yerushalmi, Baruch, Hyams, Jeffrey S., Wrobel, Iwona, Panacionne, Remo, Dieleman, Levinus A., Griffiths, Anne M., Turpin, Williams, and Lee, Sun-Ho

Published
2025
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7. Precision medicine in monogenic inflammatory bowel disease: proposed mIBD REPORT standards

Author

Uhlig, Holm H., Booth, Claire, Cho, Judy, Dubinsky, Marla, Griffiths, Anne M., Grimbacher, Bodo, Hambleton, Sophie, Huang, Ying, Jones, Kelsey, Kammermeier, Jochen, Kanegane, Hirokazu, Koletzko, Sibylle, Kotlarz, Daniel, Klein, Christoph, Lenardo, Michael J., Lo, Bernice, McGovern, Dermot P. B., Özen, Ahmet, de Ridder, Lissy, Ruemmele, Frank, Shouval, Dror S., Snapper, Scott B., Travis, Simon P., Turner, Dan, Wilson, David C., and Muise, Aleixo M.

Published
2023
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8. Environmental Factors Associated With Risk of Crohn’s Disease Development in the Crohn’s and Colitis Canada - Genetic, Environmental, Microbial Project

Author

Abreu, Maria, Beck, Paul, Bernstein, Charles, Croitoru, Kenneth, Dieleman, Levinus A., Feagan, Brian, Griffiths, Anne, Guttman, David, Jacobson, Kevan, Kaplan, Gilaad, Krause, Denis O., Madsen, Karen, Marshall, John, Moayyedi, Paul, Ropeleski, Mark, Seidman, Ernest, Silverberg, Mark, Snapper, Scott, Stadnyk, Andy, Steinhart, Hillary, Surette, Michael, Turner, Dan, Walters, Thomas, Vallance, Bruce, Aumais, Guy, Bitton, Alain, Cino, Maria, Critch, Jeff, Denson, Lee, Deslandres, Colette, El-Matary, Wael, Herfarth, Hans, Higgins, Peter, Huynh, Hien, Hyams, Jeffrey S., Mack, David, McGrath, Jerry, Otley, Anthony, Panancionne, Remo, Xue, Mingyue, Leibovitzh, Haim, Jingcheng, Shao, Neustaeter, Anna, Dong, Mei, Xu, Wei, Espin-Garcia, Osvaldo, Griffiths, Anne M., Steinhart, A. Hillary, Huynh, Hien Q., Panaccione, Remo, Bressler, Brian, Murthy, Sanjay, Marshall, John K., Bernstein, Charles N., Fich, Alexander, Denson, Lee A., Ropeleski, Mark J., Abreu, Maria T., Avni-Biron, Irit, Lee, Sun-Ho, and Turpin, Williams

Published
2024
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9. Association of Baseline Luminal Narrowing With Ileal Microbial Shifts and Gene Expression Programs and Subsequent Transmural Healing in Pediatric Crohn Disease

Author

Ta, Allison D, Ollberding, Nicholas J, Karns, Rebekah, Haberman, Yael, Alazraki, Adina L, Hercules, David, Baldassano, Robert, Markowitz, James, Heyman, Melvin B, Kim, Sandra, Kirschner, Barbara, Shapiro, Jason M, Noe, Joshua, Oliva-Hemker, Maria, Otley, Anthony, Pfefferkorn, Marian, Kellermayer, Richard, Snapper, Scott, Rabizadeh, Shervin, Xavier, Ramnik, Dubinsky, Marla, Hyams, Jeffrey, Kugathasan, Subra, Jegga, Anil G, Dillman, Jonathan R, and Denson, Lee A

Subjects
Pediatric, Inflammatory Bowel Disease, Digestive Diseases, Genetics, Autoimmune Disease, Oral and gastrointestinal, Child, Cohort Studies, Constriction, Pathologic, Crohn Disease, Gene Expression, Humans, RNA, Ribosomal, 16S, Wound Healing, microbiome, gene expression, luminal narrowing, magnetic resonance enterography, transmural healing, Clinical Sciences, Gastroenterology & Hepatology
Abstract

BackgroundTransmural healing (TH) is associated with better long-term outcomes in Crohn disease (CD), whereas pretreatment ileal gene signatures encoding myeloid inflammatory responses and extracellular matrix production are associated with stricturing. We aimed to develop a predictive model for ileal TH and to identify ileal genes and microbes associated with baseline luminal narrowing (LN), a precursor to strictures.Materials and methodsBaseline small bowel imaging obtained in the RISK pediatric CD cohort study was graded for LN. Ileal gene expression was determined by RNASeq, and the ileal microbial community composition was characterized using 16S rRNA amplicon sequencing. Clinical, demographic, radiologic, and genomic variables were tested for association with baseline LN and future TH.ResultsAfter controlling for ileal location, baseline ileal LN (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-0.8), increasing serum albumin (OR, 4; 95% CI, 1.3-12.3), and anti-Saccharomyces cerevisiae antibodies IgG serology (OR, 0.97; 95% CI, 0.95-1) were associated with subsequent TH. A multivariable regression model including these factors had excellent discriminant power for TH (area under the curve, 0.86; positive predictive value, 80%; negative predictive value, 87%). Patients with baseline LN exhibited increased Enterobacteriaceae and inflammatory and extracellular matrix gene signatures, coupled with reduced levels of butyrate-producing commensals and a respiratory electron transport gene signature. Taxa including Lachnospiraceae and the genus Roseburia were associated with increased respiratory and decreased inflammatory gene signatures, and Aggregatibacter and Blautia bacteria were associated with reduced extracellular matrix gene expression.ConclusionsPediatric patients with CD with LN at diagnosis are less likely to achieve TH. The association between specific microbiota, wound healing gene programs, and LN may suggest future therapeutic targets.

Published
2021

10. Progression of Pediatric Crohn’s Disease Is Associated With Anti–Tumor Necrosis Factor Timing and Body Mass Index Z-Score Normalization

Author

Geem, Duke, Hercules, David, Pelia, Ranjit S., Venkateswaran, Suresh, Griffiths, Anne, Noe, Joshua D., Dotson, Jennifer L., Snapper, Scott, Rabizadeh, Shervin, Rosh, Joel R., Baldassano, Robert N., Markowitz, James F., Walters, Thomas D., Ananthakrishnan, Ashwin, Sharma, Garima, Denson, Lee A., Hyams, Jeffrey S., and Kugathasan, Subra

Published
2024
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11. Yield of Serial Testing for Tuberculosis Exposure in Patients With Inflammatory Bowel Diseases: One Test is Not Enough

Author

Kaur, Manreet, Dassopoulos, Themistocles, Snapper, Scott B., Korzenik, Joshua R., Bohm, Matthew, Raffals, Laura, Poonam, Beniwal-Patel, Hudesman, David, Russ, Kirk, Brook, Loren, Pekow, Joel, Cross, Raymond, Wong, Uni, Bishu, Shrinivas, Bewtra, Meenakshi, Lewis, James D., Duerr, Richard, Saha, Sumona, Caldera, Freddy, Scoville, Elizabeth, Deepak, Parakkal, Ciorba, Matthew, and Lapp, Sean L.

Published
2024
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12. Type III interferons induce pyroptosis in gut epithelial cells and impair mucosal repair

Author

Jena, Kautilya K., Mambu, Julien, Boehmer, Daniel, Sposito, Benedetta, Millet, Virginie, de Sousa Casal, Joshua, Muendlein, Hayley I., Spreafico, Roberto, Fenouil, Romain, Spinelli, Lionel, Wurbel, Sarah, Riquier, Chloé, Galland, Franck, Naquet, Philippe, Chasson, Lionel, Elkins, Megan, Mitsialis, Vanessa, Ketelut-Carneiro, Natália, Bugda Gwilt, Katlynn, Thiagarajah, Jay R., Ruan, Hai-Bin, Lin, Zhaoyu, Lien, Egil, Shao, Feng, Chou, Janet, Poltorak, Alexander, Ordovas-Montanes, Jose, Fitzgerald, Katherine A., Snapper, Scott B., Broggi, Achille, and Zanoni, Ivan

Published
2024
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13. Surgery for Crohn’s Disease Is Associated With a Dysbiotic Microbiome and Metabolome: Results From Two Prospective Cohorts

Author

Wolf, Douglas C., Hron, Bridget, Hanson, John S., Mohanty, Sanjib P., Fogel, Ronald P., Levy, L. Campbell, Iskandar, Heba N., Fischer, Monika, Cohen, Benjamin, Swaminath, Arun, Kane, Sunanda, McCabe, Robert P., Jr., Yen, Eugene F., Hanauer, Stephen B., Hudesman, David P., Afzali, Anita, Kelly, Colleen, Weber, John R., Mahadevan, Uma, Herfarth, Hans, Katz, Jeffery, Taleban, Sasha, Rubin, David T., Yachyshyn, Bruce, Reynolds, Gorman J., Gerich, Mark, Dryden, Gerald W., Quezada, Sandra, Higgins, Peter D.R., Shmidt, Eugenia, Lewis, James D., Schwartz, Marc B., Flynn, Ann D., Saha, Sumona, Horst, Sara N., Chiorean, Michael, Green, Patrick D., Scherl, Ellen J., Sandler, Robert, Brotherton, Carol, Albenberg, Lindsey, Valentine, John F., Suskind, David, Meyer, Andrea, Compher, Charlene W., Bewtra, Meenakshi, Kaur, Manreet, Dassopoulos, Themistocles, Snapper, Scott B., Korzenik, Joshua R., Bohm, Matthew, Raffals, Laura, Beniwal-Patel, Poonam, Hudesman, David, Russ, Kirk, Brook, Loren, Pekow, Joel, Cross, Raymond, Wong, Uni, Bishu, Shrinivas, Duerr, Richard, Caldera, Freddy, Scoville, Elizabeth, Deepak, Parakkal, Ciorba, Matthew, Daniel, Scott G., Li, Hongzhe, Hao, Fuhua, Patterson, Andrew D., Hecht, Aaron L., Brensinger, Colleen M., Wu, Gary D., and Bittinger, Kyle

Published
2024
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15. PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants

Author

Abbott, Jordan K., Aldave Becerra, Juan Carlos, Allenspach, Eric J., Assing, Kristian, Atkinson, T. Prescott, Bargir, Umair A., Baxter, Sarah K., Bergerson, Jenna R.E., Bista, Ranjan, Blanche, Stephane, Buckley, Lenore M., Butte, Manish, Carcamo, Benjamin, Chandrakala, Shanmukhaiah, Chen, Karin, Chervinskiy, Sheva, Chinn, Ivan K., Chong, Hey J., Coffey, Kara E., Copland, Andrew P., Cowen, Edward W., Cros, Guilhem, De Bruycker, Jean Jacques, Teresa de la Morena, Maria, Ehlayel, Mohammed, Forbes Satter, Lisa R., Gelfand, Erwin W., Gilliaux, Olivier, Glover, Sara C., Gorman, Mark, Griffin, Thomas A., Grimbacher, Bodo, Gru, Alejandro A., Haddad, Elie, Hadjadj, Jerome, Hajjar, Joud, Hauck, Fabian, Hautala, Timo, Holland, Steven M., Hsieh, Elena W.Y., Hsu, Florence Ida, Jacquemin, Emmanuel, Jindal, Ankur Kumar, Kahn, Stacy A., Keller, Michael D., Kobayashi, Roger H., Krupski, Christa, Larkin, Allyson, Lawrence, Monica G., Madkaikar, Manisha, Malphettes, Marion, Martelius, Timi, Mehta, Mehek, Metcalfe, Dean D., Meyts, Isabelle, Nannapaneni, Naveen, Ocejo Vinyals, J. Gonzalo, Olivier, Kenneth, Ombrello, Amanda K., Orange, Jordan S., Rabinovitch, Nathan, Rauscher, Christine K., Redfern, Ann, Reynolds, Paul R., Rieux-Laucat, Frederic, Secord, Elizabeth, Seeborg, Filiz O., Seppänen, Mikko R.J., Sereti, Irini, Shin, Daniel S., Shin, Junghee J., Snapper, Scott B., Suri, Deepti, Tangcheewinsirikul, Sirikarn, Thatayatikom, Akaluck, Torgerson, Troy, Touzot, Fabien, Uzel, Gulbu, Varjosalo, Markku, Vasconcelos, Dewton F.P., von Bernuth, Horst, Walsh, Thomas, Walter, Jolan E., Ward, Brant R., Wittkowski, Helmut, Wysocki, Christian A., Baysac, Kathleen, Sun, Guangping, Nakano, Hiroto, Schmitz, Elizabeth G., Cruz, Anthony C., Fisher, Charles, Bailey, Alexis C., Mace, Emily, Milner, Joshua D., and Ombrello, Michael J.

Published
2024
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16. Small intestinal immunopathology and GI-associated antibody formation in hereditary alpha-tryptasemia.

Author

Konnikova, Liza, Robinson, Tanya, Owings, Anna, Shirley, James, Davis, Elisabeth, Tang, Ying, Wall, Sarah, Li, Jian, Hasan, Mohammad, Gharaibeh, Raad, Mendoza Alvarez, Lybil, Ryan, Lisa, Doty, Andria, Chovanec, Jack, OConnell, Michael, Grunes, Dianne, Daley, William, Mayer, Emeran, Chang, Lin, Liu, Julia, Snapper, Scott, Milner, Joshua, Glover, Sarah, and Lyons, Jonathan

Subjects
CyTOF, Mast cells, double-negative T cells, hereditary alpha-tryptasemia, mast cell activation, memory B cells, pyroptosis, small intestine, Adult, Epithelial Cells, Female, Gastrointestinal Diseases, Genetic Diseases, Inborn, Genotype, Humans, Immunoglobulin G, Intestine, Small, Male, Mast Cells, Mastocytosis, Middle Aged, Pyroptosis, Tryptases, Young Adult
Abstract

BACKGROUND: Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase due to increased copies of the TPSAB1 gene. Individuals with HαT frequently present with multisystem complaints, including anaphylaxis and seemingly functional gastrointestinal (GI) symptoms. OBJECTIVE: We sought to determine the prevalence of HαT in an irritable bowel syndrome cohort and associated immunologic characteristics that may distinguish patients with HαT from patients without HαT. METHODS: Tryptase genotyping by droplet digital PCR, flow cytometry, cytometry by time-of-flight, immunohistochemistry, and other molecular biology techniques was used. RESULTS: HαT prevalence in a large irritable bowel syndrome cohort was 5% (N = 8/158). Immunophenotyping of HαT PBMCs (N ≥ 27) revealed increased total and class-switched memory B cells. In the small bowel, expansion of tissue mast cells with expression of CD203c, HLA-DR, and FcεRI, higher intestinal epithelial cell pyroptosis, and increased class-switched memory B cells were observed. IgG profiles in sera from individuals with HαT (N = 21) significantly differed from those in individuals with quiescent Crohn disease (N = 20) and non-HαT controls (N = 19), with increased antibodies directed against GI-associated proteins identified in individuals with HαT. CONCLUSIONS: Increased mast cell number and intestinal epithelial cell pyroptosis in the small intestine, and class-switched memory B cells in both the gut and peripheral blood associated with IgG reactive to GI-related proteins, distinguish HαT from functional GI disease. These innate and adaptive immunologic findings identified in association with HαT are suggestive of subclinical intestinal inflammation in symptomatic individuals.

Published
2021

17. Outcomes of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome

Author

Labrosse, Roxane, Chu, Julia I., Armant, Myriam A., Everett, John K., Pellin, Danilo, Kareddy, Niharika, Frelinger, Andrew L., Henderson, Lauren A., O’Connell, Amy E., Biswas, Amlan, Coenen-van der Spek, Jet, Miggelbrink, Alexandra, Fiorini, Claudia, Adhikari, Hriju, Berry, Charles C., Cantu, Vito Adrian, Fong, Johnson, Jaroslavsky, Jason, Karadeniz, Derin F., Li, Quan-Zhen, Reddy, Shantan, Roche, Aoife M., Zhu, Chengsong, Whangbo, Jennifer S., Dansereau, Colleen, Mackinnon, Brenda, Morris, Emily, Koo, Stephanie M., London, Wendy B., Baris, Safa, Ozen, Ahmet, Karakoc-Aydiner, Elif, Despotovic, Jenny M., Forbes Satter, Lisa R., Saitoh, Akihiko, Aizawa, Yuta, King, Alejandra, Nguyen, Mai Anh Thi, Vu, Vy Do Uyen, Snapper, Scott B., Galy, Anne, Notarangelo, Luigi D., Bushman, Frederic D., Williams, David A., and Pai, Sung-Yun

Published
2023
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18. Mucosal Inflammatory and Wound Healing Gene Programs Reveal Targets for Stricturing Behavior in Pediatric Crohn's Disease.

Author

Haberman, Yael, Minar, Phillip, Karns, Rebekah, Dexheimer, Phillip J, Ghandikota, Sudhir, Tegge, Samuel, Shapiro, Daniel, Shuler, Brianne, Venkateswaran, Suresh, Braun, Tzipi, Ta, Allison, Walters, Thomas D, Baldassano, Robert N, Noe, Joshua D, Rosh, Joel, Markowitz, James, Dotson, Jennifer L, Mack, David R, Kellermayer, Richard, Griffiths, Anne M, Heyman, Melvin B, Baker, Susan S, Moulton, Dedrick, Patel, Ashish S, Gulati, Ajay S, Steiner, Steven J, LeLeiko, Neal, Otley, Anthony, Oliva-Hemker, Maria, Ziring, David, Gokhale, Ranjana, Kim, Sandra, Guthery, Stephen L, Cohen, Stanley A, Snapper, Scott, Aronow, Bruce J, Stephens, Michael, Gibson, Greg, Dillman, Jonathan R, Dubinsky, Marla, Hyams, Jeffrey S, Kugathasan, Subra, Jegga, Anil G, and Denson, Lee A

Subjects
Crohn's Disease, Pediatric, Clinical Research, Genetics, Digestive Diseases, Inflammatory Bowel Disease, Paediatric Crohn disease, ileum, small molecule, surgery, transcriptome, pediatric Crohn Disease, Clinical Sciences, Gastroenterology & Hepatology
Abstract

Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures. Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)). An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.

Published
2021

20. Gut Microbiome Composition Is Associated With Future Onset of Crohn’s Disease in Healthy First-Degree Relatives

Author

Abreu, Maria, Beck, Paul, Bernstein, Charles, Croitoru, Kenneth, Dieleman, Levinus A., Feagan, Brian, Griffiths, Anne, Guttman, David, Jacobson, Kevan, Kaplan, Gilaad, Krause, Denis O., Madsen, Karen, Marshall, John, Moayyedi, Paul, Ropeleski, Mark, Seidman, Ernest, Silverberg, Mark, Snapper, Scott, Stadnyk, Andy, Steinhart, Hillary, Surette, Michael, Turner, Dan, Walters, Thomas, Vallance, Bruce, Aumais, Guy, Bitton, Alain, Cino, Maria, Critch, Jeff, Denson, Lee, Deslandres, Colette, El-Matary, Wael, Herfarth, Hans, Higgins, Peter, Huynh, Hien, Hyams, Jeffrey S., Mack, David, McGrath, Jerry, Otley, Anthony, Panancionne, Remo, Raygoza Garay, Juan Antonio, Turpin, Williams, Lee, Sun-Ho, Smith, Michelle I., Goethel, Ashleigh, Griffiths, Anne M., Espin-Garcia, Osvaldo, Aumais, Guy L., Bernstein, Charles N., Biron, Irit A., Dotan, Iris, Guttman, David S., Marshall, John K., Panaccione, Remo, Silverberg, Mark S., Steinhart, A. Hillary, Yerushalmi, Baruch, Paterson, Andrew D., and Xu, Wei

Published
2023
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21. Low-Dose Interleukin 2 for the Treatment of Moderate to Severe Ulcerative Colitis

Author

Hamilton, Matthew, Barends, Jared, Carrellas, Madeline, Freer, Katherine, Gringauz, Jordan, Green, Julia, Herwood, Noah, Hurtado, Jonathan, Kelly, Ryan, Mitri, Jennifer, Rourke, Caroline, Saccocia, Gwen, Whitcomb, Sydney, Liu, Enju, Klatzmann, David, de Silva, Punyanganie, Farraye, Frank A., Feuerstein, Joseph D., Moss, Alan, Shah, Samir A., Korzenik, Joshua R., Bousvaros, Athos, Koreth, John, Soiffer, Robert, Ritz, Jerome, Logvinenko, Tanya, Ananthakrishnan, Ashwin, Herfath, Hans, Allegretti, Jessica R., Mitsialis, Vanessa, Canavan, James B., and Snapper, Scott B.

Published
2023
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23. Anti-Integrin αvβ6 Autoantibodies Are a Novel Biomarker That Antedate Ulcerative Colitis

Author

Abreu, Maria, Beck, Paul, Bernstein, Charles, Croitoru, Kenneth, Dieleman, Leo, Feagan, Brian, Griffiths, Anne, Guttman, David, Jacobson, Kevan, Kaplan, Gilaad, Krause, Denis O., Madsen, Karen, Marshall, John, Moayyedi, Paul, Ropeleski, Mark, Seidman, Ernest, Silverberg, Mark, Snapper, Scott, Stadnyk, Andy, Steinhart, Hillary, Surette, Michael, Turner, Dan, Walters, Thomas, Vallance, Bruce, Aumais, Guy, Bitton, Alain, Cino, Maria, Critch, Jeff, Denson, Lee, Deslandres, Colette, El-Matary, Wael, Herfarth, Hans, Higgins, Peter, Huynh, Hien, Hyams, Jeff, Mack, David, McGrath, Jerry, Otley, Anthony, Panancionne, Remo, Shapiro, Jason, Shah, Samir, Leleiko, Neal S., Livanos, Alexandra E., Dunn, Alexandra, Fischer, Jeremy, Ungaro, Ryan C., Turpin, Williams, Lee, Sun-Ho, Rui, Shumin, Del Valle, Diane Marie, Jougon, Julia J., Martinez-Delgado, Gustavo, Riddle, Mark S., Murray, Joseph A., Laird, Renee M., Torres, Joana, Agrawal, Manasi, Magee, Jared S., Dervieux, Thierry, Gnjatic, Sacha, Sheppard, Dean, Sands, Bruce E., Porter, Chad K., Petralia, Francesca, Colombel, Jean-Frederic, and Mehandru, Saurabh

Published
2023
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24. Identification of environmental factors that promote intestinal inflammation

Author

Sanmarco, Liliana M., Chao, Chun-Cheih, Wang, Yu-Chao, Kenison, Jessica E., Li, Zhaorong, Rone, Joseph M., Rejano-Gordillo, Claudia M., Polonio, Carolina M., Gutierrez-Vazquez, Cristina, Piester, Gavin, Plasencia, Agustin, Li, Lucinda, Giovannoni, Federico, Lee, Hong-Gyun, Faust Akl, Camilo, Wheeler, Michael A., Mascanfroni, Ivan, Jaronen, Merja, Alsuwailm, Moneera, Hewson, Patrick, Yeste, Ada, Andersen, Brian M., Franks, Diana G., Huang, Chien-Jung, Ekwudo, Millicent, Tjon, Emily C., Rothhammer, Veit, Takenaka, Maisa, de Lima, Kalil Alves, Linnerbauer, Mathias, Guo, Lydia, Covacu, Ruxandra, Queva, Hugo, Fonseca-Castro, Pedro Henrique, Bladi, Maha Al, Cox, Laura M., Hodgetts, Kevin J., Hahn, Mark E., Mildner, Alexander, Korzenik, Joshua, Hauser, Russ, Snapper, Scott B., and Quintana, Francisco J.

Published
2022
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26. CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease.

Author

Magg, Thomas, Shcherbina, Anna, Arslan, Duran, Desai, Mukesh M, Wall, Sarah, Mitsialis, Vanessa, Conca, Raffaele, Unal, Ekrem, Karacabey, Neslihan, Mukhina, Anna, Rodina, Yulia, Taur, Prasad D, Illig, David, Marquardt, Benjamin, Hollizeck, Sebastian, Jeske, Tim, Gothe, Florian, Schober, Tilmann, Rohlfs, Meino, Koletzko, Sibylle, Lurz, Eberhard, Muise, Aleixo M, Snapper, Scott B, Hauck, Fabian, Klein, Christoph, and Kotlarz, Daniel

Subjects
Autoimmune Disease, Clinical Research, Genetics, Human Genome, Inflammatory Bowel Disease, Pediatric, Crohn's Disease, Digestive Diseases, 2.1 Biological and endogenous factors, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, Inflammatory and immune system, Oral and gastrointestinal, Age of Onset, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Humans, Inflammatory Bowel Diseases, Lymphocytes, Male, Microfilament Proteins, Mutation, Phenotype, Exome Sequencing, immunodeficiency, very early onset inflammatory bowel diseases, CARMIL2, Clinical Sciences, Gastroenterology & Hepatology
Abstract

BackgroundChildren with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes.MethodsTo identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID.ResultsWhole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency.ConclusionOur study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.

Published
2019

27. The Pediatric Cell Atlas: Defining the Growth Phase of Human Development at Single-Cell Resolution.

Author

Taylor, Deanne, Aronow, Bruce, Tan, Kai, Bernt, Kathrin, Salomonis, Nathan, Greene, Casey, Frolova, Alina, Henrickson, Sarah, Wells, Andrew, Pei, Liming, Jaiswal, Jyoti, Whitsett, Jeffrey, Hamilton, Kathryn, MacParland, Sonya, Kelsen, Judith, Heuckeroth, Robert, Potter, S, Vella, Laura, Terry, Natalie, Ghanem, Louis, Kennedy, Benjamin, Helbig, Ingo, Sullivan, Kathleen, Castelo-Soccio, Leslie, Kreigstein, Arnold, Herse, Florian, Nawijn, Martijn, Koppelman, Gerard, Haendel, Melissa, Harris, Nomi, Rokita, Jo, Zhang, Yuanchao, Regev, Aviv, Rozenblatt-Rosen, Orit, Rood, Jennifer, Tickle, Timothy, Vento-Tormo, Roser, Alimohamed, Saif, Lek, Monkol, Mar, Jessica, Loomes, Kathleen, Barrett, David, Uapinyoying, Prech, Beggs, Alan, Agrawal, Pankaj, Chen, Yi-Wen, Muir, Amanda, Garmire, Lana, Snapper, Scott, Nazarian, Javad, Seeholzer, Steven, Fazelinia, Hossein, Singh, Larry, Faryabi, Robert, Raman, Pichai, Dawany, Noor, Xie, Hongbo, Devkota, Batsal, Diskin, Sharon, Anderson, Stewart, Rappaport, Eric, Peranteau, William, Wikenheiser-Brokamp, Kathryn, Teichmann, Sarah, Wallace, Douglas, Peng, Tao, Ding, Yang-Yang, Kim, Man, Xing, Yi, Kong, Sek, Bönnemann, Carsten, Mandl, Kenneth, and White, Peter

Subjects
Embryonic Development, Gene Expression Profiling, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Humans, Pediatrics, Single-Cell Analysis, Tissue Distribution
Abstract

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan.

Published
2019

28. Age-of-diagnosis dependent ileal immune intensification and reduced alpha-defensin in older versus younger pediatric Crohn Disease patients despite already established dysbiosis

Author

Haberman, Yael, Schirmer, Melanie, Dexheimer, Phillip J, Karns, Rebekah, Braun, Tzipi, Kim, Mi-Ok, Walters, Thomas D, Baldassano, Robert N, Noe, Joshua D, Rosh, Joel, Markowitz, James, Crandall, Wallace V, Mack, David R, Griffiths, Anne M, Heyman, Melvin B, Baker, Susan S, Kellermayer, Richard, Moulton, Dedrick, Patel, Ashish S, Gulati, Ajay S, Steiner, Steven J, LeLeiko, Neal, Otley, Anthony, Oliva-Hemker, Maria, Ziring, David, Kirschner, Barbara S, Keljo, David J, Guthery, Stephen L, Cohen, Stanley A, Snapper, Scott, Evans, Jonathan, Dubinsky, Marla, Aronow, Bruce, Hyams, Jeffrey S, Kugathasan, Subra, Huttenhower, Curtis, Xavier, Ramnik J, and Denson, Lee A

Subjects
Biomedical and Clinical Sciences, Immunology, Prevention, Genetics, Inflammatory Bowel Disease, Clinical Research, Digestive Diseases, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Age Factors, Aging, Child, Child, Preschool, Cohort Studies, Crohn Disease, Dysbiosis, Female, Gene Expression Regulation, Humans, Ileum, Male, Peyer's Patches, Puberty, Risk, Th1 Cells, alpha-Defensins, Biological Sciences, Medical and Health Sciences
Abstract

Age-of-diagnosis associated variation in disease location and antimicrobial sero-reactivity has suggested fundamental differences in pediatric Crohn Disease (CD) pathogenesis. This variation may be related to pubertal peak incidence of ileal involvement and Peyer's patches maturation, represented by IFNγ-expressing Th1 cells. However, direct mucosal evidence is lacking. We characterize the global pattern of ileal gene expression and microbial communities in 525 treatment-naive pediatric CD patients and controls (Ctl), stratifying samples by their age-of-diagnosis. We show a robust ileal gene signature notable for higher expression of specific immune genes including GM-CSF and INFγ, and reduced expression of antimicrobial Paneth cell α-defensins, in older compared to younger patients. Reduced α-defensin expression in older patients was associated with higher IFNγ expression. By comparison, the CD-associated ileal dysbiosis, characterized by expansion of Enterobacteriaceae and contraction of Lachnospiraceae and Ruminococcaceae, was already established within the younger group and did not vary systematically with increasing age-of-diagnosis. Multivariate analysis considering individual taxa, however did demonstrate negative associations between Lachnospiraceae and IFNγ, and positive associations between Bacteroides and α-defensin expression. These data provide evidence for maturation of mucosal Th1 immune responses and loss of epithelial antimicrobial α-defensins which are associated with specific taxa with increasing age-of-diagnosis in pediatric CD.

Published
2019

29. Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte-Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn's Disease.

Author

Denson, Lee A, Jurickova, Ingrid, Karns, Rebekah, Shaw, Kelly A, Cutler, David J, Okou, David, Valencia, C Alexander, Dodd, Anne, Mondal, Kajari, Aronow, Bruce J, Haberman, Yael, Linn, Aaron, Price, Adam, Bezold, Ramona, Lake, Kathleen, Jackson, Kimberly, Walters, Thomas D, Griffiths, Anne, Baldassano, Robert N, Noe, Joshua D, Hyams, Jeffrey S, Crandall, Wallace V, Kirschner, Barbara S, Heyman, Melvin B, Snapper, Scott, Guthery, Stephen L, Dubinsky, Marla C, Leleiko, Neal S, Otley, Anthony R, Xavier, Ramnik J, Stevens, Christine, Daly, Mark J, Zwick, Michael E, and Kugathasan, Subra

Subjects
Genetics, Autoimmune Disease, Crohn's Disease, Clinical Research, Inflammatory Bowel Disease, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Adult, Case-Control Studies, Child, Child, Preschool, Crohn Disease, Cytokine Receptor Common beta Subunit, Female, Follow-Up Studies, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Infant, Male, Mutation, Missense, Neutrophils, Prognosis, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Transcriptome, Young Adult, GM-CSF, neutrophil, pediatric inflammatory bowel disease, RNA sequencing, STAT5, whole-exome sequencing, Clinical Sciences, Gastroenterology & Hepatology
Abstract

BACKGROUND:Granulocyte-macrophage colony-stimulating factor auto-antibodies (GMAbs) suppress neutrophil-extrinsic GM-CSF signaling and increase risk for stricturing behavior in Crohn's disease (CD). We aimed to define clinical, genomic, and functional associations with neutrophil-intrinsic GM-CSF signaling. METHODS:Missense mutations in CSF2RA, CSF2RB, JAK2, STAT5A, and STAT5B were identified using whole-exome sequencing in 543 pediatric inflammatory bowel disease (IBD) patients. Neutrophil-intrinsic GM-CSF signaling was defined using the GM-CSF-induced STAT5 stimulation index (GMSI) in 180 pediatric IBD patients and 26 non-IBD controls. Reduced GM-CSF signaling (GMSI-Lo) was defined as the 20th percentile within the control group. Variation in neutrophil phospho-protein abundance, bacterial killing, and the global pattern of gene expression with the GMSI was determined. RESULTS:We validated 18 potentially damaging missense mutations in CSF2RA and CSF2RB. CSF2RA A17G carriage increased from 10% in those with intact neutrophil GMSI to 32% in those with low GMSI (P = 0.02). The frequency of reduced Staphylococcus aureus killing increased from 17% in those with intact neutrophil GMSI to 35% in GMSI-Lo neutrophils (P = 0.043). Crohn's disease neutrophils with low GMSI exhibited specific alterations in phospho-protein networks and genes regulating cytokine production, wound healing, and cell survival and proliferation. Stricturing behavior increased from 7% in patients with both low GMAb and intact GMSI to 64% in patients with both elevated GMAb and low GMSI (P < 0.0001). CONCLUSIONS:Low/normal neutrophil-intrinsic GM-CSF signaling is associated with CSF2RA missense mutations, alterations in gene expression networks, and higher rates of disease complications in pediatric CD.

Published
2019

30. Genetic variants and pathways implicated in a pediatric inflammatory bowel disease cohort

Author

Shaw, Kelly A, Cutler, David J, Okou, David, Dodd, Anne, Aronow, Bruce J, Haberman, Yael, Stevens, Christine, Walters, Thomas D, Griffiths, Anne, Baldassano, Robert N, Noe, Joshua D, Hyams, Jeffrey S, Crandall, Wallace V, Kirschner, Barbara S, Heyman, Melvin B, Snapper, Scott, Guthery, Stephen, Dubinsky, Marla C, Shapiro, Jason M, Otley, Anthony R, Daly, Mark, Denson, Lee A, Kugathasan, Subra, and Zwick, Michael E

Subjects
Biological Sciences, Genetics, Clinical Research, Biotechnology, Autoimmune Disease, Pediatric, Inflammatory Bowel Disease, Crohn's Disease, Digestive Diseases, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Oral and gastrointestinal, Inflammatory and immune system, Adolescent, Child, Child, Preschool, Female, Genome-Wide Association Study, Humans, Infant, Inflammatory Bowel Diseases, Male, Polymorphism, Genetic, Exome Sequencing, Immunology
Abstract

In the United States, approximately 5% of individuals with inflammatory bowel disease (IBD) are younger than 20 years old. Studies of pediatric cohorts can provide unique insights into genetic architecture of IBD, which includes Crohn's disease (CD) and ulcerative colitis (UC). Large genome-wide association studies have found more than 200 IBD-associated loci but explain a minority of disease variance for CD and UC. We sought to characterize the contribution of rare variants to disease development, comparing exome sequencing of 368 pediatric IBD patients to publicly available exome sequencing (dbGaP) and aggregate frequency data (ExAC). Using dbGaP data, we performed logistic regression for common variants and optimal unified association tests (SKAT-O) for rare, likely-deleterious variants. We further compared rare variants to ExAC counts with Fisher's exact tests. We did pathway enrichment analysis on the most significant genes from each comparison. Many variants overlapped with known IBD-associated genes (e.g. NOD2). Rare variants were enriched in CD-associated loci (p = 0.009) and showed suggestive enrichment in neutrophil function genes (p = 0.05). Pathway enrichment implicated immune-related pathways, especially cell killing and apoptosis. Variants in extracellular matrix genes also emerged as an important theme in our analysis.

Published
2019

33. Mediterranean-Like Dietary Pattern Associations With Gut Microbiome Composition and Subclinical Gastrointestinal Inflammation

Author

Abreu, Maria, Beck, Paul, Bernstein, Charles, Croitoru, Kenneth, Dieleman, Leo, Feagan, Brian, Griffiths, Anne, Guttman, David, Jacobson, Kevan, Kaplan, Gilaad, Krause, Denis O., Madsen, Karen, Marshall, John, Moayyedi, Paul, Ropeleski, Mark, Seidman, Ernest, Silverberg, Mark, Snapper, Scott, Stadnyk, Andy, Steinhart, Hillary, Surette, Michael, Turner, Dan, Walters, Thomas, Vallance, Bruce, Aumais, Guy, Bitton, Alain, Cino, Maria, Critch, Jeff, Denson, Lee, Deslandres, Colette, El-Matary, Wael, Herfarth, Hans, Higgins, Peter, Huynh, Hien, Hyams, Jeff, Mack, David, McGrath, Jerry, Otley, Anthony, Panancionne, Remo, Baldassano, Robert, Griffiths, Anne M., Hedin, Charlotte, Hussey, Seamus, Hyams, Hien, Keljo, David, Kevans, David, Lees, Charlie, Murthy, Sanjay, Panaccione, Remo, Parekh, Nimisha, Plamondon, Sophie, Radford-Smith, Graham, Rosh, Joel, Rubin, David, Schultz, Michael, Siegel, Corey, Turpin, Williams, Dong, Mei, Sasson, Gila, Raygoza Garay, Juan Antonio, Espin-Garcia, Osvaldo, Lee, Sun-Ho, Neustaeter, Anna, Smith, Michelle I., Leibovitzh, Haim, Guttman, David S., Goethel, Ashleigh, Huynh, Hien Q., Dieleman, Levinus A., Steinhart, A. Hillary, Silverberg, Mark S., Murthy, Sanjay K., Marshall, John K., Bernstein, Charles N., Abreu, Maria T., Paterson, Andrew D., and Xu, Wei

Published
2022
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35. Mucus sialylation determines intestinal host-commensal homeostasis

Author

Yao, Yikun, Kim, Girak, Shafer, Samantha, Chen, Zuojia, Kubo, Satoshi, Ji, Yanlong, Luo, Jialie, Yang, Weiming, Perner, Sebastian P., Kanellopoulou, Chrysi, Park, Ann Y., Jiang, Ping, Li, Jian, Baris, Safa, Aydiner, Elif Karakoc, Ertem, Deniz, Mulder, Daniel J., Warner, Neil, Griffiths, Anne M., Topf-Olivestone, Chani, Kori, Michal, Werner, Lael, Ouahed, Jodie, Field, Michael, Liu, Chengyu, Schwarz, Benjamin, Bosio, Catharine M., Ganesan, Sundar, Song, Jian, Urlaub, Henning, Oellerich, Thomas, Malaker, Stacy A., Zheng, Lixin, Bertozzi, Carolyn R., Zhang, Yu, Matthews, Helen, Montgomery, Will, Shih, Han-Yu, Jiang, Jiansheng, Jones, Marcus, Baras, Aris, Shuldiner, Alan, Gonzaga-Jauregui, Claudia, Snapper, Scott B., Muise, Aleixo M., Shouval, Dror S., Ozen, Ahmet, Pan, Kuan-Ting, Wu, Chuan, and Lenardo, Michael J.

Published
2022
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36. An Integrated Taxonomy for Monogenic Inflammatory Bowel Disease

Author

Bolton, Chrissy, Smillie, Christopher S., Pandey, Sumeet, Elmentaite, Rasa, Wei, Gabrielle, Argmann, Carmen, Aschenbrenner, Dominik, James, Kylie R., McGovern, Dermot P.B., Macchi, Marina, Cho, Judy, Shouval, Dror S., Kammermeier, Jochen, Koletzko, Sibylle, Bagalopal, Krithika, Capitani, Melania, Cavounidis, Athena, Pires, Elisabete, Weidinger, Carl, McCullagh, James, Arkwright, Peter D., Haller, Wolfram, Siegmund, Britta, Peters, Lauren, Jostins, Luke, Travis, Simon P.L., Anderson, Carl A., Snapper, Scott, Klein, Christoph, Schadt, Eric, Zilbauer, Matthias, Xavier, Ramnik, Teichmann, Sarah, Muise, Aleixo M., Regev, Aviv, and Uhlig, Holm H.

Published
2022
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37. Therapeutic options for CTLA-4 insufficiency

Author

Egg, David, Rump, Ina Caroline, Mitsuiki, Noriko, Rojas-Restrepo, Jessica, Maccari, Maria-Elena, Schwab, Charlotte, Gabrysch, Annemarie, Warnatz, Klaus, Goldacker, Sigune, Patiño, Virginia, Wolff, Daniel, Okada, Satoshi, Hayakawa, Seiichi, Shikama, Yoshiaki, Kanda, Kenji, Imai, Kohsuke, Sotomatsu, Manabu, Kuwashima, Makoto, Kamiya, Takahiro, Morio, Tomohiro, Matsumoto, Kazuaki, Mori, Takeshi, Yoshimoto, Yuri, Dybedal, Ingunn, Kanariou, Maria, Kucuk, Zeynep Yesim, Chapdelaine, Hugo, Petruzelkova, Lenka, Lorenz, Hanns-Martin, Sullivan, Kathleen E., Heimall, Jennifer, Moutschen, Michel, Litzman, Jiri, Recher, Mike, Albert, Michael H., Hauck, Fabian, Seneviratne, Suranjith, Pachlopnik Schmid, Jana, Kolios, Antonios, Unglik, Gary, Klemann, Christian, Snapper, Scott, Giulino-Roth, Lisa, Svaton, Michael, Platt, Craig D., Hambleton, Sophie, Neth, Olaf, Gosse, Geraldine, Reinsch, Steffen, Holzinger, Dirk, Kim, Yae-Jean, Bakhtiar, Shahrzad, Atschekzei, Faranaz, Schmidt, Reinhold, Sogkas, Georgios, Chandrakasan, Shanmuganathan, Rae, William, Derfalvi, Beata, Marquart, Hanne Vibeke, Ozen, Ahmet, Kiykim, Ayca, Karakoc-Aydiner, Elif, Králíčková, Pavlína, de Bree, Godelieve, Kiritsi, Dimitra, Seidel, Markus G., Kobbe, Robin, Dantzer, Jennifer, Alsina, Laia, Armangue, Thais, Lougaris, Vassilios, Agyeman, Philipp, Nyström, Sofia, Buchbinder, David, Arkwright, Peter D., and Grimbacher, Bodo

Published
2022
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38. Clinical and Genomic Correlates of Neutrophil Reactive Oxygen Species Production in Pediatric Patients With Crohn’s Disease

Author

Denson, Lee A, Jurickova, Ingrid, Karns, Rebekah, Shaw, Kelly A, Cutler, David J, Okou, David T, Dodd, Anne, Quinn, Kathryn, Mondal, Kajari, Aronow, Bruce J, Haberman, Yael, Linn, Aaron, Price, Adam, Bezold, Ramona, Lake, Kathleen, Jackson, Kimberly, Walters, Thomas D, Griffiths, Anne, Baldassano, Robert N, Noe, Joshua D, Hyams, Jeffrey S, Crandall, Wallace V, Kirschner, Barbara S, Heyman, Melvin B, Snapper, Scott, Guthery, Stephen L, Dubinsky, Marla C, Leleiko, Neal S, Otley, Anthony R, Xavier, Ramnik J, Stevens, Christine, Daly, Mark J, Zwick, Michael E, and Kugathasan, Subra

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Autoimmune Disease, Pediatric, Crohn's Disease, Digestive Diseases, Inflammatory Bowel Disease, Clinical Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Alleles, Child, Child, Preschool, Cohort Studies, Crohn Disease, Down-Regulation, Female, Gene Expression Profiling, Glucose, Humans, Infant, Male, Mutation, Missense, NADPH Oxidases, Neutrophils, Phenotype, Reactive Oxygen Species, Sequence Analysis, RNA, Up-Regulation, Exome Sequencing, WES, IBD, Neutrophil Oxidative Burst, Genetic Variant, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsIndividuals with monogenic disorders of phagocyte function develop chronic colitis that resembles Crohn's disease (CD). We tested for associations between mutations in genes encoding reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, neutrophil function, and phenotypes of CD in pediatric patients.MethodsWe performed whole-exome sequence analysis to identify mutations in genes encoding NADPH oxidases (such as CYBA, CYBB, NCF1, NCF2, NCF4, RAC1, and RAC2) using DNA from 543 pediatric patients with inflammatory bowel diseases. Blood samples were collected from an additional 129 pediatric patients with CD and 26 children without IBD (controls); we performed assays for neutrophil activation, reactive oxygen species (ROS) production, and bacteria uptake and killing. Whole-exome sequence analysis was performed using DNA from 46 of the children with CD to examine associations with NADPH gene mutations; RNA sequence analyses were performed using blood cells from 46 children with CD to test for variations in neutrophil gene expression associated with ROS production.ResultsWe identified 26 missense mutations in CYBA, CYBB, NCF1, NCF2, and NCF4. Patients with CD who carried mutations in these genes were 3-fold more likely to have perianal disease (P = .0008) and stricturing complications (P = .002) than children with CD without these mutations. Among patients with CD with none of these mutations, 9% had undergone abdominal surgery; among patients with mutations in these NADPH oxidase genes, 31% had undergone abdominal surgery (P = .0004). A higher proportion of neutrophils from children with CD had low ROS production (47%) than from controls (15%) among the 129 patients tested for ROS (P = .002). Minor alleles of the NADPH genes were detected in 7% of children with CD whose neutrophils produced normal levels of ROS vs 38% of children whose neutrophils produced low levels of ROS (P = .009). Neutrophils that produced low levels of ROS had specific alterations in genes that regulate glucose metabolism and antimicrobial responses.ConclusionsWe identified missense mutations in genes that encode NADPH oxidases in children with CD; these were associated with a more aggressive disease course and reduced ROS production by neutrophils from the patients.

Published
2018

39. Long ncRNA Landscape in the Ileum of Treatment-Naive Early-Onset Crohn Disease.

Author

Haberman, Yael, BenShoshan, Marina, Di Segni, Ayelet, Dexheimer, Phillip J, Braun, Tzipi, Weiss, Batia, Walters, Thomas D, Baldassano, Robert N, Noe, Joshua D, Markowitz, James, Rosh, Joel, Heyman, Melvin B, Griffiths, Anne M, Crandall, Wallace V, Mack, David R, Baker, Susan S, Kellermayer, Richard, Patel, Ashish, Otley, Anthony, Steiner, Steven J, Gulati, Ajay S, Guthery, Stephen L, LeLeiko, Neal, Moulton, Dedrick, Kirschner, Barbara S, Snapper, Scott, Avivi, Camila, Barshack, Iris, Oliva-Hemker, Maria, Cohen, Stanley A, Keljo, David J, Ziring, David, Anikster, Yair, Aronow, Bruce, Hyams, Jeffrey S, Kugathasan, Subra, and Denson, Lee A

Subjects
Biotechnology, Autoimmune Disease, Prevention, Crohn's Disease, Inflammatory Bowel Disease, Digestive Diseases, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Caco-2 Cells, Child, Crohn Disease, Down-Regulation, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Hepatocyte Nuclear Factor 4, Humans, Ileum, Male, Oligonucleotide Array Sequence Analysis, RNA, Long Noncoding, RNA, Messenger, Up-Regulation, Crohn disease, long ncRNA, RNAseq, RNA expression, Clinical Sciences, Gastroenterology & Hepatology
Abstract

BackgroundLong noncoding RNAs (lncRNA) are key regulators of gene transcription and many show tissue-specific expression. We previously defined a novel inflammatory and metabolic ileal gene signature in treatment-naive pediatric Crohn disease (CD). We now extend our analyses to include potential regulatory lncRNA.MethodsUsing RNAseq, we systematically profiled lncRNAs and protein-coding gene expression in 177 ileal biopsies. Co-expression analysis was used to identify functions and tissue-specific expression. RNA in situ hybridization was used to validate expression. Real-time polymerase chain reaction was used to test lncRNA regulation by IL-1β in Caco-2 enterocytes.ResultsWe characterize widespread dysregulation of 459 lncRNAs in the ileum of CD patients. Using only the lncRNA in discovery and independent validation cohorts showed patient classification as accurate as the protein-coding genes, linking lncRNA to CD pathogenesis. Co-expression and functional annotation enrichment analyses across several tissues and cell types 1showed that the upregulated LINC01272 is associated with a myeloid pro-inflammatory signature, whereas the downregulated HNF4A-AS1 exhibits association with an epithelial metabolic signature. We confirmed tissue-specific expression in biopsies using in situ hybridization, and validated regulation of prioritized lncRNA upon IL-1β exposure in differentiated Caco-2 cells. Finally, we identified significant correlations between LINC01272 and HNF4A-AS1 expression and more severe mucosal injury.ConclusionsWe systematically define differentially expressed lncRNA in the ileum of newly diagnosed pediatric CD. We show lncRNA utility to correctly classify disease or healthy states and demonstrate their regulation in response to an inflammatory signal. These lncRNAs, after mechanistic exploration, may serve as potential new tissue-specific targets for RNA-based interventions.

Published
2018

40. An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery

Author

Haghighi, Alireza, Krier, Joel B, Toth-Petroczy, Agnes, Cassa, Christopher A, Frank, Natasha Y, Carmichael, Nikkola, Fieg, Elizabeth, Bjonnes, Andrew, Mohanty, Anwoy, Briere, Lauren C, Lincoln, Sharyn, Lucia, Stephanie, Gupta, Vandana A, Söylemez, Onuralp, Sutti, Sheila, Kooshesh, Kameron, Qiu, Haiyan, Fay, Christopher J, Perroni, Victoria, Valerius, Jamie, Hanna, Meredith, Frank, Alexander, Ouahed, Jodie, Snapper, Scott B, Pantazi, Angeliki, Chopra, Sameer S, Leshchiner, Ignaty, Stitziel, Nathan O, Feldweg, Anna, Mannstadt, Michael, Loscalzo, Joseph, Sweetser, David A, Liao, Eric, Stoler, Joan M, Nowak, Catherine B, Sanchez-Lara, Pedro A, Klein, Ophir D, Perry, Hazel, Patsopoulos, Nikolaos A, Raychaudhuri, Soumya, Goessling, Wolfram, Green, Robert C, Seidman, Christine E, MacRae, Calum A, Sunyaev, Shamil R, Maas, Richard L, Vuzman, Dana, and Undiagnosed Diseases Network, Brigham and Women’s Hospital FaceBase Project, Brigham Genomic Medicine (BGM)

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, Biotechnology, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Undiagnosed Diseases Network, Brigham and Women’s Hospital FaceBase Project, Brigham Genomic Medicine, Medical biotechnology
Abstract

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs.

Published
2018

41. Author Correction: Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Author

Serra, Eva Gonçalves, Schwerd, Tobias, Moutsianas, Loukas, Cavounidis, Athena, Fachal, Laura, Pandey, Sumeet, Kammermeier, Jochen, Croft, Nicholas M., Posovszky, Carsten, Rodrigues, Astor, Russell, Richard K., Barakat, Farah, Auth, Marcus K. H., Heuschkel, Robert, Zilbauer, Matthias, Fyderek, Krzysztof, Braegger, Christian, Travis, Simon P., Satsangi, Jack, Parkes, Miles, Thapar, Nikhil, Ferry, Helen, Matte, Julie C., Gilmour, Kimberly C., Wedrychowicz, Andrzej, Sullivan, Peter, Moore, Carmel, Sambrook, Jennifer, Ouwehand, Willem, Roberts, David, Danesh, John, Baeumler, Toni A., Fulga, Tudor A., Carrami, Eli M, Ahmed, Ahmed, Wilson, Rachel, Barrett, Jeffrey C., Elkadri, Abdul, Griffiths, Anne M., Snapper, Scott B., Shah, Neil, Muise, Aleixo M., Wilson, David C., Uhlig, Holm H., and Anderson, Carl A.

Published
2022
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45. Surgery for Crohn’s Disease Is Associated with a Dysbiotic Microbiome and Metabolome: Results from Two Prospective Cohorts

Author

Lewis, James D., primary, Daniel, Scott G., additional, Li, Hongzhe, additional, Hao, Fuhua, additional, Patterson, Andrew D., additional, Hecht, Aaron, additional, Brensinger, Colleen M., additional, Wu, Gary D., additional, Bittinger, Kyle, additional, Wolf, Douglas C., additional, Hron, Bridget, additional, Hanson, John S., additional, Mohanty, Sanjib P., additional, Fogel, Ronald P., additional, Levy, L. Campbell, additional, Iskandar, Heba N., additional, Fischer, Monika, additional, Cohen, Benjamin, additional, Swaminath, Arun, additional, Kane, Sunanda, additional, McCabe, Robert P., additional, Yen, Eugene F., additional, Hanauer, Stephen B., additional, Hudesman, David P., additional, Afzali, Anita, additional, Kelly, Colleen, additional, Weber, John R., additional, Mahadevan, Uma, additional, Herfarth, Hans, additional, Katz, Jeffery, additional, Taleban, Sasha, additional, Rubin, David T., additional, Yachyshyn, Bruce, additional, Reynolds, Gorman J., additional, Gerich, Mark, additional, Dryden, Gerald W., additional, Quezada, Sandra, additional, Higgins, Peter D.R., additional, Shmidt, Eugenia, additional, Lewis, James D., additional, Schwartz, Marc B., additional, Flynn, Ann D., additional, Saha, Sumona, additional, Horst, Sara N., additional, Chiorean, Michael, additional, Green, Patrick D., additional, Scherl, Ellen J., additional, Sandler, Robert, additional, Brotherton, Carol, additional, Albenberg, Lindsey, additional, Valentine, John F., additional, Suskind, David, additional, Meyer, Andrea, additional, Compher, Charlene W., additional, Bewtra, Meenakshi, additional, Kaur, Manreet, additional, Dassopoulos, Themistocles, additional, Snapper, Scott B., additional, Korzenik, Joshua R., additional, Bohm, Matthew, additional, Raffals, Laura, additional, Beniwal-Patel, Poonam, additional, Hudesman, David, additional, Russ, Kirk, additional, Brook, Loren, additional, Pekow, Joel, additional, Cross, Raymond, additional, Wong, Uni, additional, Bishu, Shrinivas, additional, Duerr, Richard, additional, Caldera, Freddy, additional, Scoville, Elizabeth, additional, Deepak, Parakkal, additional, and Ciorba, Matthew, additional

Published
2024
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47. Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort

Author

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

Published
2021
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48. Novel Fecal Biomarkers That Precede Clinical Diagnosis of Ulcerative Colitis

Author

Beck, Paul, Bernstein, Charles, Croitoru, Kenneth, Dieleman, Leo, Feagan, Brian, Griffiths, Anne, Guttman, David, Jacobson, Kevan, Kaplan, Gilaad, Krause, Denis O., Madsen, Karen, Marshall, John, Moayyedi, Paul, Ropeleski, Mark, Seidman, Ernest, Silverberg, Mark, Snapper, Scott, Stadnyk, Andy, Steinhart, Hillary, Surette, Michael, Turner, Dan, Walters, Thomas, Vallance, Bruce, Aumais, Guy, Bitton, Alain, Cino, Maria, Critch, Jeff, Denson, Lee, Deslandres, Colette, El-Matary, Wael, Herfarth, Hans, Higgins, Peter, Huynh, Hien, Hyams, Jeff, Mack, David, McGrath, Jerry, Otley, Anthony, Panancionne, Remo, Galipeau, Heather J., Caminero, Alberto, Turpin, Williams, Bermudez-Brito, Miriam, Santiago, Alba, Libertucci, Josie, Constante, Marco, Raygoza Garay, Juan Antonio, Rueda, Gaston, Armstrong, Sarah, Clarizio, Alex, Smith, Michelle I., Surette, Michael G., Bercik, Premysl, and Verdu, Elena F.

Published
2021
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49. Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study

Author

Kugathasan, Subra, Denson, Lee A, Walters, Thomas D, Kim, Mi-Ok, Marigorta, Urko M, Schirmer, Melanie, Mondal, Kajari, Liu, Chunyan, Griffiths, Anne, Noe, Joshua D, Crandall, Wallace V, Snapper, Scott, Rabizadeh, Shervin, Rosh, Joel R, Shapiro, Jason M, Guthery, Stephen, Mack, David R, Kellermayer, Richard, Kappelman, Michael D, Steiner, Steven, Moulton, Dedrick E, Keljo, David, Cohen, Stanley, Oliva-Hemker, Maria, Heyman, Melvin B, Otley, Anthony R, Baker, Susan S, Evans, Jonathan S, Kirschner, Barbara S, Patel, Ashish S, Ziring, David, Trapnell, Bruce C, Sylvester, Francisco A, Stephens, Michael C, Baldassano, Robert N, Markowitz, James F, Cho, Judy, Xavier, Ramnik J, Huttenhower, Curtis, Aronow, Bruce J, Gibson, Greg, Hyams, Jeffrey S, and Dubinsky, Marla C

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Inflammatory Bowel Disease, Prevention, Autoimmune Disease, Clinical Research, Digestive Diseases, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Adalimumab, Adolescent, Anti-Inflammatory Agents, Non-Steroidal, Child, Cohort Studies, Crohn Disease, Disease Progression, Female, Gastrointestinal Microbiome, Humans, Infliximab, Intestinal Obstruction, Male, Prognosis, Propensity Score, Prospective Studies, Risk Assessment, Severity of Illness Index, Tumor Necrosis Factor-alpha, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundStricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown.MethodsWe did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk.FindingsBetween Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51-82) and specificity of 63% (55-71), with a negative predictive value of 95% (94-97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10-0·89; p=0·0296) but not stricturing complication (1·13, 0·51-2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12-2·57; p=0·0120). When this gene signature was included, the model's specificity improved to 71%.InterpretationOur findings support the usefulness of risk stratification of paediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFα therapy.FundingCrohn's and Colitis Foundation of America, Cincinnati Children's Hospital Research Foundation Digestive Health Center.

Published
2017

50. Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice

Author

Wang, Lin, Aschenbrenner, Dominik, Zeng, Zhiyang, Cao, Xiya, Mayr, Daniel, Mehta, Meera, Capitani, Melania, Warner, Neil, Pan, Jie, Wang, Liren, Li, Qi, Zuo, Tao, Cohen-Kedar, Sarit, Lu, Jiawei, Ardy, Rico Chandra, Mulder, Daniel J., Dissanayake, Dilan, Peng, Kaiyue, Huang, Zhiheng, Li, Xiaoqin, Wang, Yuesheng, Wang, Xiaobing, Li, Shuchao, Bullers, Samuel, Gammage, Anís N., Warnatz, Klaus, Schiefer, Ana-Iris, Krivan, Gergely, Goda, Vera, Kahr, Walter H. A., Lemaire, Mathieu, Lu, Chien-Yi, Siddiqui, Iram, Surette, Michael G., Kotlarz, Daniel, Engelhardt, Karin R., Griffin, Helen R., Rottapel, Robert, Decaluwe, Hélène, Laxer, Ronald M., Proietti, Michele, Hambleton, Sophie, Elcombe, Suzanne, Guo, Cong-Hui, Grimbacher, Bodo, Dotan, Iris, Ng, Siew C., Freeman, Spencer A., Snapper, Scott B., Klein, Christoph, Boztug, Kaan, Huang, Ying, Li, Dali, Uhlig, Holm H., and Muise, Aleixo M.

Published
2021
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