Concordance between gene expression in peripheral whole blood and colonic tissue in children with inflammatory bowel disease

Autoři: Nathan P. Palmer aff001;  Jocelyn A. Silvester aff002;  Jessica J. Lee aff002;  Andrew L. Beam aff001;  Inbar Fried aff001;  Vladimir I. Valtchinov aff001;  Fedik Rahimov aff004;  Sek Won Kong aff005;  Saum Ghodoussipour aff002;  Helen C. Hood aff002;  Athos Bousvaros aff002;  Richard J. Grand aff002;  Louis M. Kunkel aff004;  Isaac S. Kohane aff001
Působiště autorů: Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, United States of America aff001;  Division of Gastroenterology and Nutrition, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America aff002;  Center for Evidence Based Imaging, Brigham and Women’s Hospital, Harvard Medical School, Massachusetts, United States of America aff003;  Division of Genetics and Genomics, Boston Children’s Hospital, Departments of Genetics and Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America aff004;  Computational Health Informatics Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America aff005
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222952



Presenting features of inflammatory bowel disease (IBD) are non-specific. We hypothesized that mRNA profiles could (1) identify genes and pathways involved in disease pathogenesis; (2) identify a molecular signature that differentiates IBD from other conditions; (3) provide insight into systemic and colon-specific dysregulation through study of the concordance of the gene expression.


Children (8–18 years) were prospectively recruited at the time of diagnostic colonoscopy for possible IBD. We used transcriptome-wide mRNA profiling to study gene expression in colon biopsies and paired whole blood samples. Using blood mRNA measurements, we fit a regression model for disease state prediction that was validated in an independent test set of adult subjects (GSE3365).


Ninety-eight children were recruited [39 Crohn’s disease, 18 ulcerative colitis, 2 IBDU, 39 non-IBD]. There were 1,118 significantly differentially (IBD vs non-IBD) expressed genes in colon tissue, and 880 in blood. The direction of relative change in expression was concordant for 106/112 genes differentially expressed in both tissue types. The regression model from the blood mRNA measurements distinguished IBD vs non-IBD disease status in the independent test set with 80% accuracy using only 6 genes. The overlap of 5 immune and metabolic pathways in the two tissue types was significant (p<0.001).


Blood and colon tissue from patients with IBD share a common transcriptional profile dominated by immune and metabolic pathways. Our results suggest that peripheral blood expression levels of as few as 6 genes (IL7R, UBB, TXNIP, S100A8, ALAS2, and SLC2A3) may distinguish patients with IBD from non-IBD.

Klíčová slova:

Biopsy – Blood – Colon – Crohn's disease – Endoscopy – Gene expression – Inflammatory bowel disease – Ulcerative colitis


1. Kappelman MD, Bousvaros A. Nutritional concerns in pediatric inflammatory bowel disease patients. Mol Nutr Food Res. 2008;52: 867–874. doi: 10.1002/mnfr.200700156 18324705

2. Escher JC. Inflammatory bowel disease in children and adolescents: Recommendations for diagnosis—The Porto criteria. J Pediatr Gastroenterol Nutr. 2005;41: 1–7. doi: 10.1097/01.mpg.0000163736.30261.82 15990620

3. Bousvaros A, Antonioli DA, Colletti RB, Dubinsky MC, Glickman JN, Gold BD, et al. Differentiating ulcerative colitis from Crohn disease in children and young adults: report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn’s and Colitis Foundation of America. J Pediatr Gastroenterol Nutr. 2007;44: 653–74. doi: 10.1097/MPG.0b013e31805563f3 17460505

4. Mack DR, Langton C, Markowitz J, LeLeiko N, Griffiths a, Bousvaros a, et al. Laboratory values for children with newly diagnosed inflammatory bowel disease. Pediatrics. 2007;119: 1113–1119. doi: 10.1542/peds.2006-1865 17545378

5. Dalal SR, Chang EB. The microbial basis of inflammatory bowel diseases. J Clin Invest. 2014;124: 4190–6. doi: 10.1172/JCI72330 25083986

6. Uniken Venema WT, Voskuil MD, Dijkstra G, Weersma RK, Festen EA. The genetic background of inflammatory bowel disease: from correlation to causality. J Pathol. 2017;241: 146–158. doi: 10.1002/path.4817 27785786

7. Noble CL, Abbas a R, Cornelius J, Lees CW, Ho G-T, Toy K, et al. Regional variation in gene expression in the healthy colon is dysregulated in ulcerative colitis. Gut. 2008;57: 1398–1405. doi: 10.1136/gut.2008.148395 18523026

8. Olsen J, Gerds TA, Seidelin JB, Csillag C, Bjerrum JT, Troelsen JT, et al. Diagnosis of ulcerative colitis before onset of inflammation by multivariate modeling of genome-wide gene expression data. Inflamm Bowel Dis. 2009;15: 1032–1038. doi: 10.1002/ibd.20879 19177426

9. Wu F, Dassopoulos T, Cope L, Maitra A, Brant SR, Harris ML, et al. Genome-wide gene expression differences in Crohn’s disease and ulcerative colitis from endoscopic pinch biopsies: Insights into distinctive pathogenesis. Inflamm Bowel Dis. 2007;13: 807–821. doi: 10.1002/ibd.20110 17262812

10. Haberman Y, Tickle TL, Dexheimer PJ, Kim MO, Tang D, Karns R, et al. Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature. J Clin Invest. 2014;124: 3617–3633. doi: 10.1172/JCI75436 25003194

11. Kuo B, Bhasin M, Jacquart J, Scult MA, Slipp L, Riklin EIK, et al. Genomic and clinical effects associated with a relaxation response mind-body intervention in patients with irritable bowel syndrome and inflammatory bowel disease. PLoS One. 2015;10: 1–26. doi: 10.1371/journal.pone.0123861 25927528

12. Burczynski ME, Peterson RL, Twine NC, Zuberek KA, Brodeur BJ, Casciotti L, et al. Molecular classification of Crohn’s disease and ulcerative colitis patients using transcriptional profiles in peripheral blood mononuclear cells. J Mol diagnostics. 2006;8: 51–61. doi: 10.2353/jmoldx.2006.050079 16436634

13. Kabakchiev B, Turner D, Hyams J, Mack D, Leleiko N, Crandall W, et al. Gene expression changes associated with resistance to intravenous corticosteroid therapy in children with severe ulcerative colitis. PLoS One. 2010;5: 1–8. doi: 10.1371/journal.pone.0013085 20941359

14. Burakoff R, Chao S, Perencevich M, Ying J, Friedman S, Makrauer F, et al. Blood-based biomarkers can differentiate ulcerative colitis from Crohn’s disease and noninflammatory diarrhea. Inflamm Bowel Dis. 2011;17: 1719–1725. doi: 10.1002/ibd.21574 21744426

15. Van Lierop PPE, Swagemakers SM, De Bie CI, Middendorp S, Van Baarlen P, Samsom JN, et al. Gene expression analysis of peripheral cells for subclassification of pediatric inflammatory bowel disease in remission. PLoS One. 2013;8: 1–8. doi: 10.1371/journal.pone.0079549 24260248

16. Planell N, Masamunt MC, Leal RF, Rodríguez L, Esteller M, Lozano JJ, et al. Usefulness of Transcriptional Blood Biomarkers as a Non-invasive Surrogate Marker of Mucosal Healing and Endoscopic Response in Ulcerative Colitis. J Crohns Colitis. 2017;11: 1335–1346. doi: 10.1093/ecco-jcc/jjx091 28981629

17. Hyams JS, Ferry GD, Mandel FS, Gryboski JD, Kibort PM, Kirschner BS, et al. Development and validation of a pediatric Crohn’s disease activity index. [Internet]. Journal of pediatric gastroenterology and nutrition. 1991. pp. 439–47. Available: 1678008

18. Turner D, Otley AR, Mack D, Hyams J, de Bruijne J, Uusoue K, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology. 2007;133: 423–32. doi: 10.1053/j.gastro.2007.05.029 17681163

19. Fumery M, Duricova D, Gower-Rousseau C, Annese V, Peyrin-Biroulet L, Lakatos PL. Review article: The natural history of paediatric-onset ulcerative colitis in population-based studies. Aliment Pharmacol Ther. 2016;43: 346–355. doi: 10.1111/apt.13478 26582737

20. Gentleman R, Carey V, Bates D, Bolstad B, Dettling M, Dudoit S, et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 2004;5: R80. doi: 10.1186/gb-2004-5-10-r80 15461798

21. R Core Team. R: A Language and Environment for Statistical Computing [Internet]. Vienna, Austria: R Foundation for Statistical Computing; 2016. Available:

22. Kamburov A, Pentchev K, Galicka H, Wierling C, Lehrach H, Herwig R. ConsensusPathDB: Toward a more complete picture of cell biology. Nucleic Acids Res. 2011;39: 712–717. doi: 10.1093/nar/gkq779

23. The Gene Ontology Consortium, Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25: 25–9. doi: 10.1038/75556 10802651

24. Kanehisa M, Sato Y, Kawashima M, Furumichi M, Tanabe M. KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res. 2016;44: D457–D462. doi: 10.1093/nar/gkv1070 26476454

25. Fabregat A, Sidiropoulos K, Garapati P, Gillespie M, Hausmann K, Haw R, et al. The reactome pathway knowledgebase. Nucleic Acids Res. 2016;44: D481–D487. doi: 10.1093/nar/gkv1351 26656494

26. De Bie CI, Paerregaard A, Kolacek S, Ruemmele FM, Koletzko S, Fell JME, et al. Disease phenotype at diagnosis in pediatric Crohn’s disease: 5-year analyses of the EUROKIDS registry. Inflamm Bowel Dis. 2013;19: 378–385. doi: 10.1002/ibd.23008 22573581

27. Novak EA, Mollen KP. Mitochondrial dysfunction in inflammatory bowel disease. Front cell Dev Biol. 2015;3: 62. doi: 10.3389/fcell.2015.00062 26484345

28. Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43: 246–252. doi: 10.1038/ng.764 21297633

29. Cantarino N, Musulen E, Valero V, Peinado MA, Perucho M, Moreno V, et al. Downregulation of the Deiminase PADI2 Is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis. Mol Cancer Res. 2016;14: 841–848. doi: 10.1158/1541-7786.MCR-16-0034 27280713

30. Simmons JD, Mullighan C, Welsh KI, Jewell DP. Vitamin D receptor gene polymorphism: association with Crohn’s disease susceptibility. Gut. 2000;47: 211–214. doi: 10.1136/gut.47.2.211 10896912

31. Del Pinto R, Pietropaoli D, Chandar AK, Ferri C, Cominelli F. Association Between Inflammatory Bowel Disease and Vitamin D Deficiency: A Systematic Review and Meta-analysis. Inflamm Bowel Dis. 2015;21: 2708–2717. doi: 10.1097/MIB.0000000000000546 26348447

32. Kohane IS, Valtchinov VI. Quantifying the white blood cell transcriptome as an accessible window to the multiorgan transcriptome. Bioinformatics. 2012;28: 538–545. doi: 10.1093/bioinformatics/btr713 22219206

33. Fumagalli M, Pozzoli U, Cagliani R, Comi GP, Riva S, Clerici M, et al. Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions. J Exp Med. 2009;206: 1395–408. doi: 10.1084/jem.20082779 19468064

34. Palmela C, Chevarin C, Xu Z, Torres J, Sevrin G, Hirten R, et al. Adherent-invasive Escherichia coli in inflammatory bowel disease. Gut. 2017; gutjnl-2017-314903. doi: 10.1136/gutjnl-2017-314903 29141957

35. Takahashi Y, Ishii Y, Murata A, Nagata T, Asai S. Localization of thioredoxin-interacting protein (TXNIP) mRNA in epithelium of human gastrointestinal tract. J Histochem Cytochem. 2003;51: 973–6. doi: 10.1177/002215540305100713 12810848

36. Kalla R, Kennedy NA, Ventham NT, Boyapati RK, Adams AT, Nimmo ER, et al. Serum Calprotectin: A Novel Diagnostic and Prognostic Marker in Inflammatory Bowel Diseases. Am J Gastroenterol. 2016;111: 1796–1805. doi: 10.1038/ajg.2016.342 27596694

37. Perl A. Review: Metabolic Control of Immune System Activation in Rheumatic Diseases. Arthritis Rheumatol. 2017;69: 2259–2270. doi: 10.1002/art.40223 28841779

38. Maratou E, Dimitriadis G, Kollias A, Boutati E, Lambadiari V, Mitrou P, et al. Glucose transporter expression on the plasma membrane of resting and activated white blood cells. Eur J Clin Invest. 2007;37: 282–90. doi: 10.1111/j.1365-2362.2007.01786.x 17373964

39. Veal CD, Reekie KE, Lorentzen JC, Gregersen PK, Padyukov L, Brookes AJ. A 129-kb deletion on chromosome 12 confers substantial protection against rheumatoid arthritis, implicating the gene SLC2A3. Hum Mutat. 2014;35: 248–256. doi: 10.1002/humu.22471 24178905

40. Buck MD, Sowell RT, Kaech SM, Pearce EL. Review Metabolic Instruction of Immunity. Cell. 2017;169: 570–586. doi: 10.1016/j.cell.2017.04.004 28475890

41. Csillag C, Haagen Nielsen O, Vainer B, Olsen J, Dieckgraefe BK, Hendel J, et al. Expression of the genes dual oxidase 2, lipocalin 2 and regenerating islet-derived 1 alpha in Crohn’s disease. Scand J Gastroenterol. 2007;42: 454–463. doi: 10.1080/00365520600976266 17454855

42. Thorsvik S, Damäs J, Granlund A, Flo T, Østvik A, Sandvik A. Fecal neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker for inflammatory bowel disease and NGAL is expressed in paneth cells. Inflamm Bowel Dis. 2016;22: S44. doi: 10.1111/jgh.13598

43. Shi Y, Liu T, He L, Dougherty U, Chen L, Adhikari S, et al. Activation of the Renin-Angiotensin System Promotes Colitis Development. Sci Rep. 2016;6: 27552. doi: 10.1038/srep27552 27271344

44. Mizushima T, Sasaki M, Ando T, Wada T, Tanaka M, Okamoto Y, et al. Blockage of angiotensin II type 1 receptor regulates TNF- -induced MAdCAM-1 expression via inhibition of NF- B translocation to the nucleus and ameliorates colitis. AJP Gastrointest Liver Physiol. 2010;298: G255–G266. doi: 10.1152/ajpgi.00264.2009 19940029

Článek vyšel v časopise


2019 Číslo 10