Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn's disease
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摘要
AIM To investigate genetic factors that might help define which Crohn's disease(CD) patients are likely to benefit from anti-tumor necrosis factor(TNF) therapy. METHODS This was a prospective cohort study. Patients wererecruited from a university digestive disease practice database. We included CD patients who received antiTNF therapy,had available medical records(with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood,and 7 single nucleotide polymorphisms(SNPs) were assessed. The main outcome measure(following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age,gender,race,and socioeconomic status disease,as well as disease characteristics(such as Montreal criteria). RESULTS121 patients were included. Twenty-one were nonresponders,and 100 were ever-responders. Fas ligand SNP(rs763110) genotype frequencies,TNF gene-308 SNP(rs1800629) genotype frequencies,and their combination,were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype(P = 0.009,OR = 4.30,95%CI: 1.45-12.80). The presence of the A(minor) TNF gene-308 allele correlated with three-fold higher odds of being a non-responder(P = 0.049,OR = 2.88,95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF-308 A allele had nearly five-fold higher odds of being a non-responder(P = 0.015,OR = 4.76,95%CI: 1.35-16.77). No difference was seen for the remaining SNPs.CONCLUSION The Fas-ligand SNP and TNF gene-308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.
AIM To investigate genetic factors that might help define which Crohn's disease(CD) patients are likely to benefit from anti-tumor necrosis factor(TNF) therapy. METHODS This was a prospective cohort study. Patients wererecruited from a university digestive disease practice database. We included CD patients who received antiTNF therapy,had available medical records(with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood,and 7 single nucleotide polymorphisms(SNPs) were assessed. The main outcome measure(following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age,gender,race,and socioeconomic status disease,as well as disease characteristics(such as Montreal criteria). RESULTS121 patients were included. Twenty-one were nonresponders,and 100 were ever-responders. Fas ligand SNP(rs763110) genotype frequencies,TNF gene-308 SNP(rs1800629) genotype frequencies,and their combination,were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype(P = 0.009,OR = 4.30,95%CI: 1.45-12.80). The presence of the A(minor) TNF gene-308 allele correlated with three-fold higher odds of being a non-responder(P = 0.049,OR = 2.88,95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF-308 A allele had nearly five-fold higher odds of being a non-responder(P = 0.015,OR = 4.76,95%CI: 1.35-16.77). No difference was seen for the remaining SNPs.CONCLUSION The Fas-ligand SNP and TNF gene-308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.
AIM To investigate genetic factors that might help define which Crohn's disease(CD) patients are likely to benefit from anti-tumor necrosis factor(TNF) therapy. METHODS This was a prospective cohort study. Patients wererecruited from a university digestive disease practice database. We included CD patients who received antiTNF therapy,had available medical records(with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood,and 7 single nucleotide polymorphisms(SNPs) were assessed. The main outcome measure(following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age,gender,race,and socioeconomic status disease,as well as disease characteristics(such as Montreal criteria). RESULTS121 patients were included. Twenty-one were nonresponders,and 100 were ever-responders. Fas ligand SNP(rs763110) genotype frequencies,TNF gene-308 SNP(rs1800629) genotype frequencies,and their combination,were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype(P = 0.009,OR = 4.30,95%CI: 1.45-12.80). The presence of the A(minor) TNF gene-308 allele correlated with three-fold higher odds of being a non-responder(P = 0.049,OR = 2.88,95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF-308 A allele had nearly five-fold higher odds of being a non-responder(P = 0.015,OR = 4.76,95%CI: 1.35-16.77). No difference was seen for the remaining SNPs.CONCLUSION The Fas-ligand SNP and TNF gene-308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.
引文
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8 Bonafede MM,Gandra SR,Watson C,Princic N,Fox KM.Cost per treated patient for etanercept,adalimumab,and infliximab across adult indications:a claims analysis.Adv Ther 2012;29:234-248[PMID:22411424 DOI:10.1007/s12325-012-0007-y]
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18 Income by zip codes(database online),Cubit Planning Inc 2016.Available from:URL:https://www.incomebyzipcode.com
19 Satsangi J,Silverberg MS,Vermeire S,Colombel JF.The Montreal classification of inflammatory bowel disease:controversies,consensus,and implications.Gut 2006;55:749-753[PMID:16698746DOI:10.1136/gut.2005.082909]
20 GE Healthcare.Illustra Genomiphi V2 protocol,25-6600-30WP Rev B,2006.Available from:URL:http://www.gelifesciences.com/webapp/wcs/stores/servlet/product By Id/en/GELife Sciencesus/25660030
21 Life technologies.Taq Man?SNP Genotyping Assays user guide,2014.Available from:URL:https://tools.thermofisher.com/content/sfs/manuals/Taq Man_SNP_Genotyping_Assays_man.pdf
22 The SAS System(Computer program)V9.Cary,SAS Institute Inc,2003.
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24 Agresti A.Categorical Data Analysis.3rd ed.Hoboken,New Jersey:John Wiley and Sons,2013
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2 Danese S,Vuitton L,Peyrin-Biroulet L.Biologic agents for IBD:practical insights.Nat Rev Gastroenterol Hepatol 2015;12:537-545[PMID:26284562 DOI:10.1038/nrgastro.2015.135]
3 Yanai H,Hanauer SB.Assessing response and loss of response to biological therapies in IBD.Am J Gastroenterol 2011;106:685-698[PMID:21427713 DOI:10.1038/ajg.2011.103]
4 Ford AC,Peyrin-Biroulet L.Opportunistic infections with antitumor necrosis factor-αtherapy in inflammatory bowel disease:meta-analysis of randomized controlled trials.Am J Gastroenterol2013;108:1268-1276[PMID:23649185 DOI:10.1038/ajg.2013.138]
5 Singh S,Nagpal SJ,Murad MH,yadav S,Kane SV,Pardi DS,Talwalkar JA,Loftus EV.Inflammatory bowel disease is associated with an increased risk of melanoma:a systematic review and metaanalysis.Clin Gastroenterol Hepatol 2014;12:210-218[PMID:23644389 DOI:10.1016/j.cgh.2013.04.033]
6 Siegel CA,Marden SM,Persing SM,Larson RJ,Sands BE.Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn’s disease:a meta-analysis.Clin Gastroenterol Hepatol 2009;7:874-881[PMID:19558997 DOI:10.1016/j.cgh.2009.01.004]
7 Wu N,Lee y C,Shah N,Harrison DJ.Cost of biologics per treated patient across immune-mediated inflammatory disease indications in a pharmacy benefit management setting:a retrospective cohort study.Clin Ther 2014;36:1231-1241,1241.e1-3[PMID:25062652DOI:10.1016/j.clinthera.2014.06.014]
8 Bonafede MM,Gandra SR,Watson C,Princic N,Fox KM.Cost per treated patient for etanercept,adalimumab,and infliximab across adult indications:a claims analysis.Adv Ther 2012;29:234-248[PMID:22411424 DOI:10.1007/s12325-012-0007-y]
9 Singh S,Pardi DS.Update on anti-tumor necrosis factor agents in Crohn disease.Gastroenterol Clin North Am 2014;43:457-478[PMID:25110253 DOI:10.1016/j.gtc.2014.05.008]
10 Siegel CA,Melmed Gy.Predicting response to Anti-TNF Agents for the treatment of crohn’s disease.Therap Adv Gastroenterol2009;2:245-251[PMID:21180547 DOI:10.1177/1756283x09336364]
11 Louis E,Vermeire S,Rutgeerts P,De Vos M,Van Gossum A,Pescatore P,Fiasse R,Pelckmans P,Reynaert H,D’Haens G,Malaise M,Belaiche J.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;37:818-824[PMID:12190096]
12 Mc Govern DP,Kugathasan S,Cho JH.Genetics of Inflammatory Bowel Diseases.Gastroenterology 2015;149:1163-1176.e2[PMID:26255561 DOI:10.1053/j.gastro.2015.08.001]
13 Ananthakrishnan AN.Epidemiology and risk factors for IBD.Nat Rev Gastroenterol Hepatol 2015;12:205-217[PMID:25732745DOI:10.1038/nrgastro.2015.34]
14 Mascheretti S,Schreiber S.The role of pharmacogenomics in the prediction of efficacy of anti-TNF therapy in patients with Crohn’s disease.Pharmacogenomics 2004;5:479-486[PMID:15212584DOI:10.1517/14622416.5.5.479]
15 Little J,Higgins JP,Ioannidis JP,Moher D,Gagnon F,von Elm E,Khoury MJ,Cohen B,Davey-Smith G,Grimshaw J,Scheet P,Gwinn M,Williamson RE,Zou Gy,Hutchings K,Johnson Cy,Tait V,Wiens M,Golding J,van Duijn C,Mc Laughlin J,Paterson A,Wells G,Fortier I,Freedman M,Zecevic M,King R,InfanteRivard C,Stewart A,Birkett N.STrengthening the REporting of Genetic Association Studies(STREGA):an extension of the STROBE statement.PLo S Med 2009;6:e22[PMID:19192942DOI:10.1371/journal.pmed.1000022]
16 Kopylov U,Al-Taweel T,yaghoobi M,Nauche B,Bitton A,Lakatos PL,Ben-Horin S,Afif W,Seidman EG.Adalimumab monotherapy versus combination therapy with immunomodulators in patients with Crohn’s disease:a systematic review and metaanalysis.J Crohns Colitis 2014;8:1632-1641[PMID:25067824DOI:10.1016/j.crohns.2014.07.003]
17 Sandborn WJ,Hanauer SB,Rutgeerts P,Fedorak RN,Lukas M,Mac Intosh DG,Panaccione R,Wolf D,Kent JD,Bittle B,Li J,Pollack PF.Adalimumab for maintenance treatment of Crohn’s disease:results of the CLASSIC II trial.Gut 2007;56:1232-1239[PMID:17299059 DOI:10.1136/gut.2006.106781]
18 Income by zip codes(database online),Cubit Planning Inc 2016.Available from:URL:https://www.incomebyzipcode.com
19 Satsangi J,Silverberg MS,Vermeire S,Colombel JF.The Montreal classification of inflammatory bowel disease:controversies,consensus,and implications.Gut 2006;55:749-753[PMID:16698746DOI:10.1136/gut.2005.082909]
20 GE Healthcare.Illustra Genomiphi V2 protocol,25-6600-30WP Rev B,2006.Available from:URL:http://www.gelifesciences.com/webapp/wcs/stores/servlet/product By Id/en/GELife Sciencesus/25660030
21 Life technologies.Taq Man?SNP Genotyping Assays user guide,2014.Available from:URL:https://tools.thermofisher.com/content/sfs/manuals/Taq Man_SNP_Genotyping_Assays_man.pdf
22 The SAS System(Computer program)V9.Cary,SAS Institute Inc,2003.
23 Fleiss JL,Levin LB,Paik MC.Statistical Methods for Rates and Proportions.3rd ed.Hoboken,New Jersey:John Wiley&Sons,2003
24 Agresti A.Categorical Data Analysis.3rd ed.Hoboken,New Jersey:John Wiley and Sons,2013
25 Vermeulen K,Van Bockstaele DR,Berneman ZN.Apoptosis:mechanisms and relevance in cancer.Ann Hematol 2005;84:627-639[PMID:16041532 DOI:10.1007/s00277-005-1065-x]
26 Chen L,Park SM,Turner JR,Peter ME.Cell death in the colonic epithelium during inflammatory bowel diseases:CD95/Fas and beyond.Inflamm Bowel Dis 2010;16:1071-1076[PMID:20049945 DOI:10.1002/ibd.21191]
27 ?lebioda TJ,Kmie?Z.Tumour necrosis factor superfamily members in the pathogenesis of inflammatory bowel disease.Mediators Inflamm 2014;2014:325129[PMID:25045210 DOI:10 .1155/2014/325129]
28 Xu L,Zhou X,Jiang F,Qiu MT,Zhang Z,yin R,Xu L.FASL rs763110 polymorphism contributes to cancer risk:an updated meta-analysis involving 43,295 subjects.PLo S One 2013;8:e74543[PMID:24086353 DOI:10.1371/journal.pone.0074543]
29 Wu J,Metz C,Xu X,Abe R,Gibson AW,Edberg JC,Cooke J,Xie F,Cooper GS,Kimberly RP.A novel polymorphic CAAT/enhancer-binding protein beta element in the Fas L gene promoter alters Fas ligand expression:a candidate background gene in African American systemic lupus erythematosus patients.J Immunol 2003;170:132-138[PMID:12496392]
30 Levin AD,Wildenberg ME,van den Brink GR.Mechanism of Action of Anti-TNF Therapy in Inflammatory Bowel Disease.J Crohns Colitis 2016;10:989-997[PMID:26896086 DOI:10.1093/ecco-jcc/jjw053]
31 Hlavaty T,Pierik M,Henckaerts L,Ferrante M,Joossens S,van Schuerbeek N,Noman M,Rutgeerts P,Vermeire S.Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn’s disease.Aliment Pharmacol Ther 2005;22:613-626[PMID:16181301 DOI:10.1111/j.1365-2036.2005.02635.x]
32 López-Hernández R,Valdés M,Campillo JA,Martínez-Garcia P,Salama H,Salgado G,Boix F,Moya-Quiles MR,Minguela A,Sánchez-Torres A,Miras M,Garcia A,Carballo F,álvarezLópez MR,Muro M.Genetic polymorphisms of tumour necrosis factor alpha(TNF-α)promoter gene and response to TNF-αinhibitors in Spanish patients with inflammatory bowel disease.Int J Immunogenet 2014;41:63-68[PMID:23590430 DOI:10.1111/iji.12059]
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