基因多态性可预测克罗恩病患者对抗肿瘤坏死因子治疗的反应。
Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn's disease.
作者信息
Netz Uri, Carter Jane Victoria, Eichenberger Maurice Robert, Dryden Gerald Wayne, Pan Jianmin, Rai Shesh Nath, Galandiuk Susan
机构信息
Uri Netz, Jane Victoria Carter, Maurice Robert Eichenberger, Susan Galandiuk, Price Institute of Surgical Research, the Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, United States.
出版信息
World J Gastroenterol. 2017 Jul 21;23(27):4958-4967. doi: 10.3748/wjg.v23.i27.4958.
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 were recruited from a university digestive disease practice database. We included CD patients who received anti-TNF 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).
RESULTS
121 patients were included. Twenty-one were non-responders, 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 ( = 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 ( = 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 ( = 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 gene -308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.
目的
研究可能有助于确定哪些克罗恩病（CD）患者可能从抗肿瘤坏死因子（TNF）治疗中获益的遗传因素。
方法
这是一项前瞻性队列研究。患者从大学消化系统疾病实践数据库中招募。我们纳入了接受抗TNF治疗、有可用病历（包含治疗持续时间和疗效信息）且同意参与的CD患者。排除有过敏反应的患者。患者被分为持续应答者或无应答者。从外周血中提取基因组DNA，并评估7个单核苷酸多态性（SNP）。主要结局指标（在接触药物后）是对治疗的反应。将患者基因型评估为结局的预测因素。可能的混杂因素和效应修饰因素包括年龄、性别、种族、社会经济状况疾病以及疾病特征（如蒙特利尔标准）。
结果
纳入121例患者。21例为无应答者，100例为持续应答者。在控制蒙特利尔疾病行为和肛周疾病的多变量分析中，Fas配体SNP（rs763110）基因型频率、TNF基因 -308 SNP（rs1800629）基因型频率及其组合在两组之间存在显著差异。与TC或TT基因型相比，Fas配体CC基因型患者成为无应答者的几率高四倍（P = 0.009，OR = 4.30，95%CI：1.45 - 12.80）。TNF基因 -308 A（次要）等位基因的存在与成为无应答者的几率高三倍相关（P = 0.049，OR = 2.88，95%CI：1.01 - 8.22）。具有Fas配体CC基因型和TNF -308 A等位基因组合的患者成为无应答者的几率几乎高五倍（P = 0.015，OR = 4.76，95%CI：1.35 - 16.77）。其余SNP未见差异。
结论
Fas配体SNP和TNF基因 -308 SNP与CD患者抗TNF治疗反应相关，可能有助于选择可能从治疗中获益的患者。
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