The Journal of Pediatrics
Volume 150, Issue 3 , Pages 268-273 , March 2007

The Contribution of the DLG5 113A Variant in Early-Onset Inflammatory Bowel Disease

  • R.K. Russell, MRCPCH

      Affiliations

    • Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, United Kingdom
    • Public Health Sciences, Edinburgh University, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom
    • Department of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, United Kingdom
    • Department of Child Health, University of Glasgow, Glasgow, United Kingdom
    • Department of Paediatric Gastroenterology, Royal Aberdeen Children’s Hospital, Aberdeen, United Kingdom.
    • Corresponding Author InformationReprint requests: Dr R. K. Russell, MRCPCH, Gastrointestinal Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU.
  • ,
  • H.E. Drummond, BSc

      Affiliations

    • Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, United Kingdom
    • Public Health Sciences, Edinburgh University, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom
    • Department of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, United Kingdom
    • Department of Child Health, University of Glasgow, Glasgow, United Kingdom
    • Department of Paediatric Gastroenterology, Royal Aberdeen Children’s Hospital, Aberdeen, United Kingdom.
  • ,
  • E.R. Nimmo, BSc, MSc, PhD

      Affiliations

    • Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, United Kingdom
    • Public Health Sciences, Edinburgh University, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom
    • Department of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, United Kingdom
    • Department of Child Health, University of Glasgow, Glasgow, United Kingdom
    • Department of Paediatric Gastroenterology, Royal Aberdeen Children’s Hospital, Aberdeen, United Kingdom.
  • ,
  • N. Anderson, BSc, PhD

      Affiliations

    • Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, United Kingdom
    • Public Health Sciences, Edinburgh University, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom
    • Department of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, United Kingdom
    • Department of Child Health, University of Glasgow, Glasgow, United Kingdom
    • Department of Paediatric Gastroenterology, Royal Aberdeen Children’s Hospital, Aberdeen, United Kingdom.
  • ,
  • D.C. Wilson, MD, FRCPCH

      Affiliations

    • Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, United Kingdom
    • Public Health Sciences, Edinburgh University, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom
    • Department of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, United Kingdom
    • Department of Child Health, University of Glasgow, Glasgow, United Kingdom
    • Department of Paediatric Gastroenterology, Royal Aberdeen Children’s Hospital, Aberdeen, United Kingdom.
  • ,
  • P.M. Gillett, MBChB, FRCPCH

      Affiliations

    • Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, United Kingdom
    • Public Health Sciences, Edinburgh University, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom
    • Department of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, United Kingdom
    • Department of Child Health, University of Glasgow, Glasgow, United Kingdom
    • Department of Paediatric Gastroenterology, Royal Aberdeen Children’s Hospital, Aberdeen, United Kingdom.
  • ,
  • P. McGrogan, MBChB, MRCP

      Affiliations

    • Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, United Kingdom
    • Public Health Sciences, Edinburgh University, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom
    • Department of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, United Kingdom
    • Department of Child Health, University of Glasgow, Glasgow, United Kingdom
    • Department of Paediatric Gastroenterology, Royal Aberdeen Children’s Hospital, Aberdeen, United Kingdom.
  • ,
  • K. Hassan, MBBS, FRCPCH

      Affiliations

    • Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, United Kingdom
    • Public Health Sciences, Edinburgh University, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom
    • Department of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, United Kingdom
    • Department of Child Health, University of Glasgow, Glasgow, United Kingdom
    • Department of Paediatric Gastroenterology, Royal Aberdeen Children’s Hospital, Aberdeen, United Kingdom.
  • ,
  • L.T. Weaver, MD, FRCPCH

      Affiliations

    • Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, United Kingdom
    • Public Health Sciences, Edinburgh University, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom
    • Department of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, United Kingdom
    • Department of Child Health, University of Glasgow, Glasgow, United Kingdom
    • Department of Paediatric Gastroenterology, Royal Aberdeen Children’s Hospital, Aberdeen, United Kingdom.
  • ,
  • W.M. Bisset, MD, FRCPCH

      Affiliations

    • Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, United Kingdom
    • Public Health Sciences, Edinburgh University, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom
    • Department of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, United Kingdom
    • Department of Child Health, University of Glasgow, Glasgow, United Kingdom
    • Department of Paediatric Gastroenterology, Royal Aberdeen Children’s Hospital, Aberdeen, United Kingdom.
  • ,
  • G. Mahdi, FRCPCH

      Affiliations

    • Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, United Kingdom
    • Public Health Sciences, Edinburgh University, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom
    • Department of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, United Kingdom
    • Department of Child Health, University of Glasgow, Glasgow, United Kingdom
    • Department of Paediatric Gastroenterology, Royal Aberdeen Children’s Hospital, Aberdeen, United Kingdom.
  • ,
  • J. Satsangi, DPhil, FRCP

      Affiliations

    • Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, United Kingdom
    • Public Health Sciences, Edinburgh University, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom
    • Department of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom
    • Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, United Kingdom
    • Department of Child Health, University of Glasgow, Glasgow, United Kingdom
    • Department of Paediatric Gastroenterology, Royal Aberdeen Children’s Hospital, Aberdeen, United Kingdom.

Received 14 July 2006 ,Revised 4 October 2006 ,Accepted 7 December 2006.

References 

  1. Russell RK, Satsangi J. IBD: a family affair. Best Practice Res Clin Gastroenterol. 2004;18:525–539
  2. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411:599–603
  3. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411:603–606
  4. Stoll M, Corneliussen B, Costello CM, Waetzig GH, Mellgard B, Koch WA, et al. Genetic variation in DLG5 is associated with inflammatory bowel disease. Nature Genet. 2004;36:476–480
  5. Peltekova VD, Wintle RF, Rubin LA, Amos CI, Huang Q, Gu X, et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nature Genet. 2004;36:471–475
  6. Brant SR, Panhuysen CI, Nicolae D, Reddy DM, Bonen DK, Karaliukas R, et al. MDR1 Ala893 polymorphism is associated with inflammatory bowel disease. Am J Hum Genet. 2003;73:1282–1292
  7. McGovern DPB, Hysi P, Ahmad T, van Heel DA, Moffatt MF, Carey A, et al. Association between a complex insertion/deletion polymorphism in NOD1(CARD4) and susceptibility to inflammatory bowel disease. Hum Mol Genet. 2005;14:1245–1250
  8. Ahmad T, Satsangi J, McGovern D, Bunce M, Jewell DP. Review article: the genetics of inflammatory bowel disease. Aliment Pharmacol Ther. 2001;15:731–748
  9. Armitage E, Drummond H, Ghosh S, Ferguson A. Incidence of juvenile-onset Crohn’s disease in Scotland. Lancet. 1999;353:1496–1497
  10. Armitage E, Drummond HE, Wilson DC, Ghosh S. Increasing incidence of both juvenile-onset Crohn’s disease and ulcerative colitis in Scotland. Eur J Gastroenterol Hepatol. 2001;13:1439–1447
  11. Armitage EL, Aldhous MC, Anderson N, Drummond HE, Riemersma RA, Ghosh S, et al. Incidence of juvenile-onset Crohn’s disease in Scotland: association with northern latitude and affluence. Gastroenterology. 2004;127:1051–1057
  12. Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet. 1995;11:241–247
  13. Russell RK, Drummond HE, Nimmo ER, Anderson N, Smith L, Wilson DC, et al. Genotype-phenotype analysis in childhood-onset Crohn’s disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease. Inflamm Bowel Dis. 2005;11:955–964
  14. Russell RK, Drummond HE, Nimmo ER, Anderson NH, Noble CL, Wilson DC, et al. Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth indices in early onset inflammatory bowel disease. Gut. 2006;55:1114–1123
  15. Hampe J, Schreiber S, Shaw SH, Lau KF, Bridger S, Macpherson AJ, et al. A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort. Am J Hum Genet. 1999;64:808–816
  16. Friedrichs F, Stoll M. Role of discs large homolog 5. World J Gastroenterol. 2006;12:3651–3656
  17. Vermeire S, Pierik M, Hlavaty T, Claessens G, van Schuerbeeck N, Joossens S, et al. Association of organic cation transporter risk haplotype with perianal penetrating Crohn’s disease but not with susceptibility to IBD. Gastroenterology. 2005;129:1845–1853
  18. Buning C, Geerdts L, Fiedler T, Gentz E, Pitre G, Reuter W, et al. DLG5 variants in inflammatory bowel disease. Am J Gastroenterol. 2006;101:786–792
  19. Daly MJ, Pearce AV, Farwell L, Fisher SA, Latiano A, Prescott NJ, et al. Association of DLG5 R30Q variant with inflammatory bowel disease. Eur J Hum Genet. 2005;13:835–839
  20. Gazouli M, Mantzaris G, Archimandritis AJ, Nasioulas G, Anagnou NP. Single nucleotide polymorphisms of OCTN1, OCTN2, and DLG5 genes in Greek patients with Crohn’s disease. World J Gastroenterol. 2005;11:7525–7530
  21. Tremelling M, Waller S, Bredin F, Greenfield S, Parkes M. Genetic variants in TNF-alpha but not DLG5 are associated with inflammatory bowel disease in a large United Kingdom cohort. Inflamm Bowel Dis. 2006;12:178–184
  22. Noble CL, Nimmo ER, Drummond H, Smith L, Arnott ID, Satsangi J. DLG5 variants do not influence susceptibility to inflammatory bowel disease in the Scottish population. Gut. 2005;54:1416–1420
  23. Torok HP, Glas J, Tonenchi L, Lohse P, Muller-Myhsok B, Limbersky O, et al. Polymorphisms in the DLG5 and OCTN cation transporter genes in Crohn’s disease. Gut. 2005;54:1421–1427
  24. Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol. 1989;170:2–6
  25. Gasche C, Scholmerich J, Brynskov J, D’Haens G, Hanauer SB, Irvine EJ, et al. A simple classification of Crohn’s disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis. 2000;6:8–15
  26. Carstairs V, Morris R. Deprivation and health in Scotland. Health Bull (Edinburgh). 1990;48:162–175
  27. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215
  28. Clayton D. A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet. 1999;65:1170–1177
  29. O’Connell JR, Weeks DE. PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet. 1998;63:259–266
  30. Blanchard JF, Bernstein CN, Wajda A, Rawsthorne P. Small-area variations and sociodemographic correlates for the incidence of Crohn’s disease and ulcerative colitis. Am J Epidemiol. 2001;154:328–335
  31. Duggan AE, Usmani I, Neal KR, Logan RF. Appendicectomy, childhood hygiene, Helicobacter pylori status, and risk of inflammatory bowel disease: a case control study. Gut. 1998;43:494–498
  32. Gent AE, Hellier MD, Grace RH, Swarbrick ET, Coggon D. Inflammatory bowel disease and domestic hygiene in infancy. Lancet. 1994;343:766–767
  33. Hugot JP, Alberti C, Berrebi D, Bingen E, Ca C. Crohn’s disease: the cold chain hypothesis. Lancet. 2003;362:2012–2015
  34. Malcolm CA, MacKay WG, Shepherd A, Weaver LT. Helicobacter pylori in children is strongly associated with poverty. Scottish Med J. 2004;49:136–138
  35. Radford JR, Ballantyne HM, Nugent Z, Beighton D, Robertson M, Longbottom C, et al. Caries-associated micro-organisms in infants from different socio-economic backgrounds in Scotland. J Dentistry. 2000;28:307–312
  36. Gavin S, Strange E, Delaney K, Houston J. Child Health Information Team (CHIT), Information and services division Scotland. http://www.isdscotland.org/isd/files/ch_surv_HB_Nov1999.pdf.
  37. Smith C, Burlison A. Closing the gap: Tackling inequalities in health in Argyll and Clyde (available from Argyll and Clyde Health Board, Department of Public Health, Ross House, Hawkhead Rd, Paisley, PA2 7BN) Also available at: www.achb.scot.nhs.uk/reports/closing%20the%20gap.pdf.
  38. Levine A, Shamir R, Wine E, Weiss B, Karban A, Shaoul RR, et al. TNF promoter polymorphisms and modulation of growth retardation and disease severity in pediatric Crohn’s disease. Am J Gastroenterol. 2005;100:1598–1604
  39. Friedrichs F, Brescianini S, Annese V, Latiano A, Berger K, Kugathasan S, et al. Evidence of transmission ratio distortion of DLG5 R30Q variant in general and implication of an association with Crohn disease in men. Hum Genet. 2006;119:305–311
  40. Griffiths AM. Specificities of inflammatory bowel disease in childhood. Best Practice Res Clin Gastroenterol. 2004;18:509–523
  41. Loftus EV. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterol. 2004;126:1504–1517
  42. Tenesa A, Noble CL, Satsangi J, Dunlop M. Association of DLG5 and inflammatory bowel disease across populations. Eur J Hum Genet. 2006;14:259–260
  43. Arnott ID, Ho GT, Nimmo ER, Satsangi J. Toll-like receptor 4 gene in IBD: further evidence for genetic heterogeneity in Europe. Gut. 2005;54:308
  44. Arnott ID, Nimmo ER, Drummond HE, Fennell J, Smith BR, MacKinlay E, et al. NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn’s disease patients: evidence for genetic heterogeneity within Europe?. Genes Immunity. 2004;5:417–425
  45. Hattersley AT, McCarthy MI. What makes a good genetic association study?. Lancet. 2005;366:1315–1323

 The University of Edinburgh Medical Faculty Fellowship funds R.K.R. This study is supported by a Wellcome Trust Programme Grant (072789/Z/03/Z) with additional support from Schering Plough and the GI/Nutrition research fund, Child Life and Health, University of Edinburgh.

PII: S0022-3476(06)01187-5

doi: 10.1016/j.jpeds.2006.12.010

The Journal of Pediatrics
Volume 150, Issue 3 , Pages 268-273 , March 2007