Age-of-onset-dependent influence of NOD2 gene variants on disease behaviour and treatment in Crohn’s disease

BMC Gastroenterology

Georg BT von Boyen⁴  Klaus-Michael Debatin³  Benjamin Mayer¹  Jochen Klaus²  Jan Hendrik Niess²  Georgia Lahr³  Veronika Pfalzer³  Carsten Posovszky³ 

[1] Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany;Internal Medicine, University Medical Center Ulm, Albert Einstein Allee 24, Ulm, 89081, Germany;Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstr. 24, Ulm, 89075, Germany;Medical department of the Academic Clinic Sigmaringen, Hohenzollernstr. 40, Sigmaringen, 72488, Germany

关键词: Pediatric-onset;    Osteoporosis;    CARD 15;    NOD2;    Crohn’s disease;   

Others  :  858014
DOI  :  10.1186/1471-230X-13-77

 received in 2012-08-07, accepted in 2013-04-26,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Posovszky et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Orholm M, Binder V, Sorensen TI, Rasmussen LP, Kyvik KO: Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol 2000, 35(10):1075-1081.
• [2]Biank V, Broeckel U, Kugathasan S: Pediatric inflammatory bowel disease: clinical and molecular genetics. Inflamm Bowel Dis 2007, 13(11):1430-1438.
• [3]Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, MacPherson AJ: Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet 2001, 357(9272):1925-1928.
• [4]Hampe J, Grebe J, Nikolaus S, Solberg C, Croucher PJ, Mascheretti S, Jahnsen J, Moum B, Klump B, Krawczak M: Association of NOD2 (CARD 15) genotype with clinical course of Crohn’s disease: a cohort study. Lancet 2002, 359(9318):1661-1665.
• [5]Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001, 411(6837):599-603.
• [6]Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, Fukase K, Inamura S, Kusumoto S, Hashimoto M: Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn’s disease. J Biol Chem 2003, 278(8):5509-5512.
• [7]Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, Flavell RA: Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 2005, 307(5710):731-734.
• [8]Voss E, Wehkamp J, Wehkamp K, Stange EF, Schroder JM, Harder J: NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2. J Biol Chem 2006, 281(4):2005-2011.
• [9]Cosnes J, Beaugerie L, Carbonnel F, Gendre JP: Smoking cessation and the course of Crohn’s disease: an intervention study. Gastroenterology 2001, 120(5):1093-1099.
• [10]Freeman HJ: Long-term prognosis of early-onset Crohn’s disease diagnosed in childhood or adolescence. Can J Gastroenterol 2004, 18(11):661-665.
• [11]Russell RK, Drummond HE, Nimmo EE, Anderson N, Smith L, Wilson DC, Gillett PM, McGrogan P, Hassan K, Weaver LT: Genotype-phenotype analysis in childhood-onset Crohn’s disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease. Inflamm Bowel Dis 2005, 11(11):955-964.
• [12]Lacher M, Helmbrecht J, Schroepf S, Koletzko S, Ballauff A, Classen M, Uhlig H, Hubertus J, Hartl D, Lohse P: NOD2 mutations predict the risk for surgery in pediatric-onset Crohn’s disease. J Pediatr Surg 2010, 45(8):1591-1597.
• [13]Walther F, Fusch C, Radke M, Beckert S, Findeisen A: Osteoporosis in pediatric patients suffering from chronic inflammatory bowel disease with and without steroid treatment. J Pediatr Gastroenterol Nutr 2006, 43(1):42-51.
• [14]Tilg H, Moschen AR, Kaser A, Pines A, Dotan I: Gut, inflammation and osteoporosis: basic and clinical concepts. Gut 2008, 57(5):684-694.
• [15]Cravo M, Guerreiro CS, dos Santos PM, Brito M, Ferreira P, Fidalgo C, Tavares L, Pereira AD: Risk factors for metabolic bone disease in Crohn’s disease patients. Inflamm Bowel Dis 2010, 16(12):2117-2124.
• [16]Turk N, Cukovic-Cavka S, Korsic M, Turk Z, Vucelic B: Proinflammatory cytokines and receptor activator of nuclear factor kappaB-ligand/osteoprotegerin associated with bone deterioration in patients with Crohn’s disease. Eur J Gastroenterol Hepatol 2009, 21(2):159-166.
• [17]Agrawal M, Arora S, Li J, Rahmani R, Sun L, Steinlauf AF, Mechanick JI, Zaidi M: Bone, inflammation, and inflammatory bowel disease. Curr Osteoporos Rep 2011, 9(4):251-257.
• [18]Hyams J, Markowitz J, Otley A, Rosh J, Mack D, Bousvaros A, Kugathasan S, Pfefferkorn M, Tolia V, Evans J: Evaluation of the pediatric crohn disease activity index: a prospective multicenter experience. J Pediatr Gastroenterol Nutr 2005, 41(4):416-421.
• [19]Faulkner RA, Bailey DA, Drinkwater DT, McKay HA, Arnold C, Wilkinson AA: Bone densitometry in Canadian children 8–17 years of Age. Calcif Tissue Int 1996, 59(5):344-351.
• [20]Abitbol V, Roux C, Chaussade S, Guillemant S, Kolta S, Dougados M, Couturier D, Amor B: Metabolic bone assessment in patients with inflammatory bowel disease. Gastroenterology 1995, 108(2):417-422.
• [21]Hoffmann JC, Preiss JC, Autschbach F, Buhr HJ, Hauser W, Herrlinger K, Hohne W, Koletzko S, Krieglstein CF, Kruis W: [Clinical practice guideline on diagnosis and treatment of Crohn’s disease]. Z Gastroenterol 2008, 46(9):1094-1146.
• [22]Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, Caprilli R, Colombel JF, Gasche C, Geboes K: Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005, 19(Suppl A):5-36.
• [23]de Ridder L, Weersma RK, Dijkstra G, van der Steege G, Benninga MA, Nolte IM, Taminiau JA, Hommes DW, Stokkers PC: Genetic susceptibility has a more important role in pediatric-onset Crohn’s disease than in adult-onset Crohn’s disease. Inflamm Bowel Dis 2007, 13(9):1083-1092.
• [24]Sun L, Roesler J, Rosen-Wolff A, Winkler U, Koch R, Thurigen A, Henker J: CARD15 genotype and phenotype analysis in 55 pediatric patients with Crohn disease from Saxony, Germany. J Pediatr Gastroenterol Nutr 2003, 37(4):492-497.
• [25]Lesage S, Zouali H, Cezard JP, Colombel JF, Belaiche J, Almer S, Tysk C, O’Morain C, Gassull M, Binder V: CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet 2002, 70(4):845-857.
• [26]Adler J, Rangwalla SC, Dwamena BA, Higgins PD: The prognostic power of the NOD2 genotype for complicated Crohn’s disease: a meta-analysis. Am J Gastroenterol 2011, 106(4):699-712.
• [27]Puntis J, McNeish AS, Allan RN: Long term prognosis of Crohn’s disease with onset in childhood and adolescence. Gut 1984, 25(4):329-336.
• [28]Tomer G, Ceballos C, Concepcion E, Benkov KJ: NOD2/CARD15 variants are associated with lower weight at diagnosis in children with Crohn’s disease. Am J Gastroenterol 2003, 98(11):2479-2484.
• [29]Wine E, Reif SS, Leshinsky-Silver E, Weiss B, Shaoul RR, Shamir R, Wasserman D, Lerner A, Boaz M, Levine A: Pediatric Crohn’s disease and growth retardation: the role of genotype, phenotype, and disease severity. Pediatrics 2004, 114(5):1281-1286.
• [30]Roesler J, Thurigen A, Sun L, Koch R, Winkler U, Laass MW, Gahr M, Rosen-Wolff A, Henker J: Influence of CARD15 mutations on disease activity and response to therapy in 65 pediatric Crohn patients from Saxony, Germany. J Pediatr Gastroenterol Nutr 2005, 41(1):27-32.
• [31]Murch SH, Lamkin VA, Savage MO, Walker-Smith JA, MacDonald TT: Serum concentrations of tumour necrosis factor alpha in childhood chronic inflammatory bowel disease. Gut 1991, 32(8):913-917.
• [32]Annese V, Lombardi G, Perri F, D’Inca R, Ardizzone S, Riegler G, Giaccari S, Vecchi M, Castiglione F, Gionchetti P: Variants of CARD15 are associated with an aggressive clinical course of Crohn’s disease–an IG-IBD study. Am J Gastroenterol 2005, 100(1):84-92.
• [33]Kugathasan S, Collins N, Maresso K, Hoffmann RG, Stephens M, Werlin SL, Rudolph C, Broeckel U: CARD15 gene mutations and risk for early surgery in pediatric-onset Crohn’s disease. Clin Gastroenterol Hepatol 2004, 2(11):1003-1009.
• [34]Issenman RM, Atkinson SA, Radoja C, Fraher L: Longitudinal assessment of growth, mineral metabolism, and bone mass in pediatric Crohn’s disease. J Pediatr Gastroenterol Nutr 1993, 17(4):401-406.
• [35]Herzog D, Bishop N, Glorieux F, Seidman EG: Interpretation of bone mineral density values in pediatric Crohn’s disease. Inflamm Bowel Dis 1998, 4(4):261-267.
• [36]Harpavat M, Greenspan SL, O’Brien C, Chang CC, Bowen A, Keljo DJ: Altered bone mass in children at diagnosis of Crohn disease: a pilot study. J Pediatr Gastroenterol Nutr 2005, 40(3):295-300.
• [37]von Tirpitz C, Steder-Neukamm U, Glas K, Sander S, Ring C, Klaus J, Reinshagen M: [Osteoporosis in inflammatory bowel disease - results of a survey among members of the German Crohn’s and Ulcerative Colitis Association]. Z Gastroenterol 2003, 41(12):1145-1150.
• [38]Paganelli M, Albanese C, Borrelli O, Civitelli F, Canitano N, Viola F, Passariello R, Cucchiara S: Inflammation is the main determinant of low bone mineral density in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2007, 13(4):416-423.
• [39]Leonard MB: Glucocorticoid-induced osteoporosis in children: impact of the underlying disease. Pediatrics 2007, 119(Suppl 2):S166-S174.
• [40]Inohara N, Nunez G: NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 2003, 3(5):371-382.
• [41]Nemetz A, Toth M, Garcia-Gonzalez MA, Zagoni T, Feher J, Pena AS, Tulassay Z: Allelic variation at the interleukin 1beta gene is associated with decreased bone mass in patients with inflammatory bowel diseases. Gut 2001, 49(5):644-649.
• [42]Niess JH, Klaus J, Stephani J, Pfluger C, Degenkolb N, Spaniol U, Mayer B, Lahr G, von Boyen GB: NOD2 Polymorphism Predicts Response to Treatment in Crohn’s Disease-First Steps to a Personalized Therapy. Dig Dis Sci 2011, 57(4):879-886.
• [43]Weiss B, Lebowitz O, Fidder HH, Maza I, Levine A, Shaoul R, Reif S, Bujanover Y, Karban A: Response to medical treatment in patients with Crohn’s disease: the role of NOD2/CRAD15, disease phenotype, and age of diagnosis. Dig Dis Sci 2010, 55(6):1674-1680.
• [44]Louis E, Vermeire S, Rutgeerts P, De Vos M, Van Gossum A, Pescatore P, Fiasse R, Pelckmans P, Reynaert H, D’Haens G: A positive response to infliximab in Crohn disease: association with a higher systemic inflammation before treatment but not with −308 TNF gene polymorphism. Scand J Gastroenterol 2002, 37(7):818-824.
• [45]Vermeire S, Louis E, Rutgeerts P, De Vos M, Van Gossum A, Belaiche J, Pescatore P, Fiasse R, Pelckmans P, Vlietinck R: NOD2/CARD15 does not influence response to infliximab in Crohn’s disease. Gastroenterology 2002, 123(1):106-111.
• [46]Abreu MT, Geller JL, Vasiliauskas EA, Kam LY, Vora P, Martyak LA, Yang H, Hu B, Lin YC, Keenan G: Treatment with infliximab is associated with increased markers of bone formation in patients with Crohn’s disease. J Clin Gastroenterol 2006, 40(1):55-63.