Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, , Alicante, Spain.
Gut. 2014 Feb;63(2):272-80. doi: 10.1136/gutjnl-2012-303557. Epub 2013 Feb 1.
The aetiology of Crohn's disease (CD) has been related to nucleotide-binding oligomerisation domain containing 2 (NOD2) and ATG16L1 gene variants. The observation of bacterial DNA translocation in patients with CD led us to hypothesise that this process may be facilitated in patients with NOD2/ATG16L1-variant genotypes, affecting the efficacy of anti-tumour necrosis factor (TNF) therapies.
179 patients with Crohn's disease were included. CD-related NOD2 and ATG16L1 variants were genotyped. Phagocytic and bactericidal activities were evaluated in blood neutrophils. Bacterial DNA, TNFα, IFNγ, IL-12p40, free serum infliximab/adalimumab levels and antidrug antibodies were measured.
Bacterial DNA was found in 44% of patients with active disease versus 23% of patients with remitting disease (p=0.01). A NOD2-variant or ATG16L1-variant genotype was associated with bacterial DNA presence (OR 4.8; 95% CI 1.1 to 13.2; p=0.001; and OR 2.4; 95% CI 1.4 to 4.7; p=0.01, respectively). This OR was 12.6 (95% CI 4.2 to 37.8; p=0.001) for patients with a double-variant genotype. Bacterial DNA was associated with disease activity (OR 2.6; 95% CI 1.3 to 5.4; p=0.005). Single and double-gene variants were not associated with disease activity (p=0.19). Patients with a NOD2-variant genotype showed decreased phagocytic and bactericidal activities in blood neutrophils, increased TNFα levels in response to bacterial DNA and decreased trough levels of free anti-TNFα. The proportion of patients on an intensified biological therapy was significantly higher in the NOD2-variant groups.
Our results characterise a subgroup of patients with CD who may require a more aggressive therapy to reduce the extent of inflammation and the risk of relapse.
克罗恩病（CD）的病因与核苷酸结合寡聚化结构域包含蛋白 2（NOD2）和 ATG16L1 基因变异有关。在 CD 患者中观察到细菌 DNA 易位，这促使我们假设该过程可能在 NOD2/ATG16L1 变异基因型的患者中更容易发生，从而影响抗肿瘤坏死因子（TNF）治疗的疗效。
纳入了 179 名克罗恩病患者。对 CD 相关的 NOD2 和 ATG16L1 变异进行基因分型。评估血液中性粒细胞的吞噬和杀菌活性。测量细菌 DNA、TNFα、IFNγ、IL-12p40、游离血清英夫利昔单抗/阿达木单抗水平和抗药物抗体。
在活动期疾病患者中发现 44%存在细菌 DNA，而缓解期疾病患者中为 23%（p=0.01）。NOD2 变异或 ATG16L1 变异基因型与细菌 DNA 存在相关（比值比 4.8；95%置信区间 1.1 至 13.2；p=0.001；比值比 2.4；95%置信区间 1.4 至 4.7；p=0.01）。双变异基因型患者的比值比为 12.6（95%置信区间 4.2 至 37.8；p=0.001）。细菌 DNA 与疾病活动相关（比值比 2.6；95%置信区间 1.3 至 5.4；p=0.005）。单基因和双基因变异与疾病活动无关（p=0.19）。NOD2 变异基因型患者血液中性粒细胞的吞噬和杀菌活性降低，对细菌 DNA 反应的 TNFα 水平升高，游离抗 TNFα 的谷底水平降低。NOD2 变异组中接受强化生物治疗的患者比例显著更高。
我们的研究结果描述了一组可能需要更积极治疗以减轻炎症程度和复发风险的 CD 患者。
