The Prognostic Power of the NOD2 Genotype for Complicated Crohn's Disease: A Meta-Analysis

被引:145
作者
Adler, Jeremy [1 ]
Rangwalla, Sujal C. [1 ]
Dwamena, Ben A. [2 ]
Higgins, Peter D. R. [3 ]
机构
[1] Univ Michigan Hlth Syst, Div Gastroenterol, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA
[2] Univ Michigan Hlth Syst, Div Nucl Med, Dept Radiol, Ann Arbor, MI 48109 USA
[3] Univ Michigan Hlth Syst, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA
关键词
INFLAMMATORY-BOWEL-DISEASE; NOD2/CARD15 GENE POLYMORPHISMS; CARD15; GENE; PHENOTYPE ANALYSIS; FRAMESHIFT MUTATION; SUSCEPTIBILITY LOCI; INSERTION MUTATION; RISK-FACTORS; 1ST SURGERY; RECEPTOR;
D O I
10.1038/ajg.2011.19
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
OBJECTIVES: Crohn's disease is often purely inflammatory at presentation, but most patients develop strictures and fistulae over time (complicated disease). Many studies have suggested that nucleotide-binding oligomerization domain 2 (NOD2) mutations are associated with a varying but increased risk of complicated disease. An accurate and sufficiently powerful predictor of complicated disease could justify the early use of biological therapy in high-risk individuals. We performed a systematic review and meta-analysis to obtain accurate estimates of the predictive power of the identified mutations (such as p.R702W, P.G908R, and p.Leu1007fsX1008) in NOD2 for the risk of complicated disease. METHODS: An electronic search of MEDLINE, Embase, and Web of Science identified 917 relevant papers. Inclusion required specification of genetic mutations at the individual level and disease phenotypes by Vienna classification (inflammatory (B1), stricturing (B2), and fistulizing (B3)). A total of 49 studies met these criteria, which included 8,893 subjects, 2,897 of whom had NOD2 mutations. Studies were weighted by median disease duration. Studies not providing duration data were weighted at the level of the study with the shortest disease duration (3.9 years). RESULTS: The relative risk (RR) of the presence of any NOD2 mutant allele for complicated disease (B2 or B3) was 1.17 (95% confidence interval (95 % CI) 1.10-1.24; P < 0.001). P.G908R was associated with an RR of complicated disease of 1.33 (95 % CI 1.11-1.60; P = 0.002). NOD2 did not predict perianal disease (P = 0.4). The RR of surgery was 1.58 (95 % CI 1.38-1.80; P < 0.001). There was substantial heterogeneity across all studies (I-2 = 66.7 %). On the basis of logistic regression of these data, the sensitivity of any mutation in predicting complicated disease was 36% and specificity was 73 %, with the area under the receiver operating characteristic curve 0.56. CONCLUSIONS: The presence of a single NOD2 mutation predicted an 8 % increase in the risk for complicated disease (B2 or B3), and a 41 % increase with 2 mutations. Surgery risk is increased by 58 % with any NOD2 mutation, whereas perianal disease was unchanged. The predictive power associated with a single NOD2 mutation is weak. The RR of any NOD2 mutations for complicated disease was only 17 % across 36 studies. However, the presence of two NOD2 mutations had 98 % specificity for complicated disease. These data provide insufficient evidence to support top-down therapy based solely on single NOD2 mutations, but suggest that targeted early-intensive therapy for high-risk patients with two NOD2 mutations might be beneficial, if prospective trials can demonstrate changes in the natural history in this subset of patients.
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页码:699 / 712
页数:14
相关论文
共 86 条
[1]   Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease [J].
Abreu, MT ;
Taylor, KD ;
Lin, YC ;
Hang, T ;
Gaiennie, J ;
Landers, CJ ;
Vasiliauskas, EA ;
Kam, LY ;
Rojany, M ;
Papadakis, KA ;
Rotter, JI ;
Targan, SR ;
Yang, HY .
GASTROENTEROLOGY, 2002, 123 (03) :679-688
[2]   The molecular classification of the clinical manifestations of Crohn's disease [J].
Ahmad, T ;
Armuzzi, A ;
Bunce, M ;
Mulcahy-Hawes, K ;
Marshall, SE ;
Orchard, TR ;
Crawshaw, J ;
Large, O ;
De Silva, A ;
Cook, JT ;
Barnardo, M ;
Cullen, S ;
Welsh, KI ;
Jewell, DP .
GASTROENTEROLOGY, 2002, 122 (04) :854-866
[3]   Combined type-1 plasminogen activator inhibitor and NOD2/CARD15 genotyping predicts complicated Crohn's disease behaviour [J].
Alvarez-Lobos, M. ;
Arostegui, J. I. ;
Sans, M. ;
Tassies, D. ;
Piu, J. ;
Reverter, J. C. ;
Pique, J. . M. ;
Yague, J. ;
Panes, J. .
ALIMENTARY PHARMACOLOGY & THERAPEUTICS, 2007, 25 (04) :429-440
[4]   Crohn's disease patients carrying Nod2/CARD15 gene variants have an increased and early need for first surgery due to stricturing disease and higher rate of surgical recurrence [J].
Alvarez-Lobos, M ;
Arostegui, JI ;
Sans, M ;
Tassies, D ;
Plaza, S ;
Delgado, S ;
Lacy, AM ;
Pique, JM ;
Yagüe, J ;
Panés, J .
ANNALS OF SURGERY, 2005, 242 (05) :693-700
[5]   Variants of CARD 15 are associated with an aggressive clinical course of Crohn's disease -: An IG-IBD study [J].
Annese, V ;
Lombardi, G ;
Perri, F ;
D'Incá, R ;
Ardizzone, S ;
Riegler, G ;
Giaccari, S ;
Vecchi, M ;
Castiglione, F ;
Gionchetti, P ;
Cocchiara, E ;
Vigneri, S ;
Latiano, A ;
Palmieri, O ;
Andriulli, A .
AMERICAN JOURNAL OF GASTROENTEROLOGY, 2005, 100 (01) :84-92
[6]  
[Anonymous], 2003, GUT
[7]  
[Anonymous], STAT US GROUP DC09 S
[8]   CARD15 and IL23R influences Crohn's disease susceptibility but not disease phenotype in a Brazilian population [J].
Baptista, Marcia Luiza ;
Amarante, Heda ;
Picheth, Geraldo ;
Sdepanian, Vera Lucia ;
Peterson, Nicholas ;
Babasukumar, Umesh ;
Lima, Hermenio C. ;
Kugathasan, Subra .
INFLAMMATORY BOWEL DISEASES, 2008, 14 (05) :674-679
[9]  
Barker Fred G 2nd, 2005, Neurosurg Focus, V19, pE5, DOI 10.3171/foc.2005.19.4.6
[10]   Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease [J].
Barrett, Jeffrey C. ;
Hansoul, Sarah ;
Nicolae, Dan L. ;
Cho, Judy H. ;
Duerr, Richard H. ;
Rioux, John D. ;
Brant, Steven R. ;
Silverberg, Mark S. ;
Taylor, Kent D. ;
Barmada, M. Michael ;
Bitton, Alain ;
Dassopoulos, Themistocles ;
Datta, Lisa Wu ;
Green, Todd ;
Griffiths, Anne M. ;
Kistner, Emily O. ;
Murtha, Michael T. ;
Regueiro, Miguel D. ;
Rotter, Jerome I. ;
Schumm, L. Philip ;
Steinhart, A. Hillary ;
Targan, Stephan R. ;
Xavier, Ramnik J. ;
Libioulle, Cecile ;
Sandor, Cynthia ;
Lathrop, Mark ;
Belaiche, Jacques ;
Dewit, Olivier ;
Gut, Ivo ;
Heath, Simon ;
Laukens, Debby ;
Mni, Myriam ;
Rutgeerts, Paul ;
Van Gossum, Andre ;
Zelenika, Diana ;
Franchimont, Denis ;
Hugot, Jean-Pierre ;
de Vos, Martine ;
Vermeire, Severine ;
Louis, Edouard ;
Cardon, Lon R. ;
Anderson, Carl A. ;
Drummond, Hazel ;
Nimmo, Elaine ;
Ahmad, Tariq ;
Prescott, Natalie J. ;
Onnie, Clive M. ;
Fisher, Sheila A. ;
Marchini, Jonathan ;
Ghori, Jilur .
NATURE GENETICS, 2008, 40 (08) :955-962