Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn's disease
Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn's disease
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DOI：
10.1111/j.1365-2036.2005.02635.x
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发表时间：
2005-10-01
影响因子：
7.6
通讯作者：
Vermeire, S
中科院分区：
文献类型：
--
作者：
Hlavaty, T;Pierik, M;Vermeire, S
背景：英夫利西单抗治疗70-80%的难治性管腔型和瘘管型克罗恩病患者有效。英夫利西单抗的作用是归因于诱导apoptosis.Aim：To研究是否在凋亡基因多态性预测的反应英夫利西单抗和他们是否与临床predictors.Methods：队列的287例连续患者用英夫利西单抗治疗难治性管腔（n = 204）或fistulizing（n = 83）克罗恩病的21个基因多态性的凋亡基因进行了基因分型。在第4周（管腔型克罗恩病）或第10周（瘘管型克罗恩病）后，第一次英夫利西单抗infliximab infration.Results的短期临床反应进行了评估：反应率为69%，管腔型和瘘管型克罗恩病80%。在管腔型克罗恩病中，确定了两个遗传预测因子：（i）具有Fas配体-843 CC/CT基因型（n = 135）的患者在75%中应答，而TT基因型（n = 21）仅在38%中应答（P = 0.002; OR = 0.11; 95%CI：0.08-0.56）。(ii)caspase-9 93 TT基因型患者（n = 9）全部应答，而CC和CT基因型患者（n = 147）应答率为67%（P = 0.04; OR = 1.50; 95%CI：1.34-1.68）。伴随硫唑嘌呤/巯基嘌呤治疗克服了不利基因型的影响。在瘘管型克罗恩病队列中，相同的Fas配体-843 CC/CT基因型是缓解的唯一预测因子。（P = 0.002; OR = 1.66; 95%CI：1.21-2.29），与caspase-9 93多态性相互作用，但与硫唑嘌呤/巯基嘌呤无相互作用。我们观察到FasL/Fas系统和caspase-9的多态性影响了管腔型和瘘管型克罗恩病对英夫利西单抗的反应。Fas配体-843 TT基因型与无应答之间的关联最强。然而，伴随巯基嘌呤/硫唑嘌呤治疗能够克服不利基因型在管腔疾病中的作用。
Background: Infliximab treatment is effective in 70-80% of patients with refractory luminal and fistulizing Crohn's disease. The effect of infliximab is ascribed to induction of apoptosis.Aim: To study whether polymorphisms in apoptosis genes predict the response to infliximab and whether they interact with clinical predictors.Methods: Cohort of 287 consecutive patients treated with infliximab for refractory luminal (n = 204) or fistulizing (n = 83) Crohn's disease was genotyped for 21 polymorphisms in apoptosis genes. Short-term clinical response was assessed at week 4 (luminal Crohn's disease) or 10 (fistulizing Crohn's disease) after the first infliximab infusion.Results: The response rate was 69% in luminal and 80% in fistulizing Crohn's disease. In luminal Crohn's disease, two genetic predictors were identified: (i) patients with the Fas ligand -843 CC/CT genotype (n = 135) responded in 75%, with the TT genotype (n = 21) in 38% only (P = 0.002; OR = 0.11; 95% CI: 0.08-0.56). (ii) Patients with the caspase-9 93 TT (n = 9) genotype all responded, in contrast with 67% (n = 147) with the CC and CT genotype (P = 0.04; OR = 1.50; 95% CI: 1.34-1.68). Concomitant azathioprine/mercaptopurine therapy overcame the effect of unfavourable genotypes. In the fistulizing Crohn's disease cohort, the same Fas ligand -843 CC/CT genotype was the only predictor of response (P = 0.002; OR = 1.66; 95% CI: 1.21-2.29), interacting with caspase-9 93 polymorphism but not with azathioprine/mercaptopurine.Conclusion: We observed that polymorphisms in FasL/Fas system and caspase-9 influence the response to infliximab in luminal and fistulizing Crohn's disease. The strongest association was seen between the Fas ligand -843 TT genotype and non-response. Concomitant mercaptopurine/azathioprine therapy, however, was able to overcome the effect of unfavourable genotypes in luminal disease.