title: Age-of-onset-dependent influence of NOD2 gene variants on disease behaviour and treatment in Crohn's disease.
abstract: BACKGROUND
  Influence of genetic variants in the NOD2 gene may play a more important role in disease activity, behaviour and treatment of pediatric- than adult-onset Crohn's disease (CD).
  
  
  METHODS
  85 pediatric- and 117 adult-onset CD patients were tested for the three main NOD2 CD-associated variants (p.R702W, p.G908R and p.10007fs) and clinical data of at least two years of follow-up were compared regarding disease behaviour and activity, response to therapy and bone mineral density (BMD).
  
  
  RESULTS
  Chronic active and moderate to severe course of CD is associated in patients with pediatric-onset (p=0.0001) and NOD2 variant alleles (p=0.0001). In pediatric-onset CD the average PCDAI-Score was significantly higher in patients carrying NOD2 variants (p=0.0008). In addition, underweight during course of the disease (p=0.012) was associated with NOD2 variants. Interestingly, osteoporosis was found more frequently in patients carrying NOD2 variant alleles (p=0.033), especially in pediatric-onset CD patients with homozygous NOD2 variants (p=0.037). Accordingly, low BMD in pediatric-onset CD is associated with a higher PCDAI (p=0.0092), chronic active disease (p=0.0148), underweight at diagnosis (p=0.0271) and during follow-up (p=0.0109). Furthermore, pediatric-onset CD patients with NOD2 variants are more frequently steroid-dependent or refractory (p=0.048) and need long-term immunosuppressive therapy (p=0.0213).
  
  
  CONCLUSIONS
  These data suggests that the presence of any of the main NOD2 variants in CD is associated with osteoporosis and an age of onset dependent influence towards underweight, higher disease activity and a more intensive immunosuppressive therapy. This observation supports the idea for an early intensive treatment strategy in children and adolescent CD patients with NOD2 gene variants.
authors: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstr, 24, Ulm, 89075, Germany. carsten.posovszky@uniklinik-ulm.de
authors: Carsten
authors: C
authors: Posovszky
authors: Veronika
authors: V
authors: Pfalzer
authors: Georgia
authors: G
authors: Lahr
authors: Jan Hendrik
authors: JH
authors: Niess
authors: Jochen
authors: J
authors: Klaus
authors: Benjamin
authors: B
authors: Mayer
authors: Klaus-Michael
authors: KM
authors: Debatin
authors: Georg B T
authors: GB
authors: von Boyen
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D015519:Bone Density; D002648:Child; D003424:Crohn Disease / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006720:Homozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010024:Osteoporosis / Q000150:complications / Q000235:genetics; D012720:Severity of Illness Index; D013851:Thinness / Q000150:complications / Q000235:genetics; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein
references: Gut. 1991 Aug;32(8):913-7
references: 1885073
references: Lancet. 2002 May 11;359(9318):1661-5
references: 12020527
references: Inflamm Bowel Dis. 2005 Nov;11(11):955-64
references: 16239840
references: Inflamm Bowel Dis. 2010 Dec;16(12):2117-24
references: 20848459
references: J Biol Chem. 2006 Jan 27;281(4):2005-11
references: 16319062
references: Nature. 2001 May 31;411(6837):599-603
references: 11385576
references: Can J Gastroenterol. 2004 Nov;18(11):661-5
references: 15565205
references: J Clin Gastroenterol. 2006 Jan;40(1):55-63
references: 16340635
references: J Pediatr Gastroenterol Nutr. 2005 Mar;40(3):295-300
references: 15750387
references: Am J Gastroenterol. 2011 Apr;106(4):699-712
references: 21343918
references: Pediatrics. 2004 Nov;114(5):1281-6
references: 15520108
references: Gastroenterology. 1995 Feb;108(2):417-22
references: 7835582
references: Clin Gastroenterol Hepatol. 2004 Nov;2(11):1003-9
references: 15551253
references: J Pediatr Gastroenterol Nutr. 1993 Nov;17(4):401-6
references: 8145096
references: Z Gastroenterol. 2003 Dec;41(12):1145-50
references: 14661123
references: Z Gastroenterol. 2008 Sep;46(9):1094-146
references: 18810679
references: J Pediatr Gastroenterol Nutr. 2006 Jul;43(1):42-51
references: 16819376
references: Gastroenterology. 2001 Apr;120(5):1093-9
references: 11266373
references: Gut. 2001 Nov;49(5):644-9
references: 11600466
references: Gut. 1984 Apr;25(4):329-36
references: 6706211
references: J Pediatr Gastroenterol Nutr. 2005 Oct;41(4):416-21
references: 16205508
references: J Pediatr Gastroenterol Nutr. 2005 Jul;41(1):27-32
references: 15990626
references: Pediatrics. 2007 Mar;119 Suppl 2:S166-74
references: 17332238
references: Curr Osteoporos Rep. 2011 Dec;9(4):251-7
references: 21935582
references: Can J Gastroenterol. 2005 Sep;19 Suppl A:5A-36A
references: 16151544
references: Gastroenterology. 2002 Jul;123(1):106-11
references: 12105838
references: Inflamm Bowel Dis. 2007 Apr;13(4):416-23
references: 17206686
references: Calcif Tissue Int. 1996 Nov;59(5):344-51
references: 8849400
references: Gut. 2008 May;57(5):684-94
references: 18408105
references: Eur J Gastroenterol Hepatol. 2009 Feb;21(2):159-66
references: 19098682
references: Scand J Gastroenterol. 2000 Oct;35(10):1075-81
references: 11099061
references: Am J Hum Genet. 2002 Apr;70(4):845-57
references: 11875755
references: Inflamm Bowel Dis. 1998 Nov;4(4):261-7
references: 9836077
references: Scand J Gastroenterol. 2002 Jul;37(7):818-24
references: 12190096
references: J Pediatr Surg. 2010 Aug;45(8):1591-7
references: 20713205
references: Inflamm Bowel Dis. 2007 Nov;13(11):1430-8
references: 17600381
references: Am J Gastroenterol. 2005 Jan;100(1):84-92
references: 15654786
references: Dig Dis Sci. 2012 Apr;57(4):879-86
references: 22147245
references: Dig Dis Sci. 2010 Jun;55(6):1674-80
references: 19693669
references: Inflamm Bowel Dis. 2007 Sep;13(9):1083-92
references: 17476680
references: J Pediatr Gastroenterol Nutr. 2003 Oct;37(4):492-7
references: 14508222
references: Lancet. 2001 Jun 16;357(9272):1925-8
references: 11425413
references: Am J Gastroenterol. 2003 Nov;98(11):2479-84
references: 14638352
references: Science. 2005 Feb 4;307(5710):731-4
references: 15692051
references: Nat Rev Immunol. 2003 May;3(5):371-82
references: 12766759
references: J Biol Chem. 2003 Feb 21;278(8):5509-12
references: 12514169