Research Centre, Ste-Justine Hospital, Montreal, Quebec, Canada.
Inflamm Bowel Dis. 2011 Nov;17(11):2308-17. doi: 10.1002/ibd.21608. Epub 2011 Jan 6.
Corticosteroids (CS) effectively induce remission in patients with moderate to severe Crohn's disease (CD). However, CS dependence in children is a significant clinical problem associated with numerous side effects. Identification of molecular markers of CS dependence is of paramount importance. The ABCB1 gene codes for P-glycoprotein, a transporter involved in the metabolism of CS. We examined whether DNA variation in the ABCB1 gene was associated with CS dependency in children with CD.
A retrospective study was carried out in two Canadian tertiary pediatric gastroenterology centers. Clinical information was abstracted from medical charts of CD patients (N = 260) diagnosed with CD prior to age 18 and administered a first course of CS during the 1 year since diagnosis. Patients were classified as CS-dependent if they relapsed during drug tapering or after the end of therapy. DNA was extracted from blood or saliva. Thirteen tagging single nucleotide polymorphisms (tag-SNPs) and a synonymous variation (C3435T) in the ABCB1 gene were genotyped. Allelic, genotype, and haplotype associations were examined using logistic regression and Haploview.
Tag-SNP rs2032583 was statistically significantly associated with CS dependency. The rare C allele of this SNP (odds ratio [OR] = 0.56, 95% confidence interval [CI]: 0.34-0.95, P = 0.029) and heterozygous genotype TC (OR = 0.52, 95% CI: 0.28-0.95, P = 0.035) conferred protection from CS dependency. A three-marker haplotype was significantly associated with CS dependence (multiple comparison corrected P-value = 0.004).
Our results suggest that the ABCB1 gene may be associated with CS dependence in pediatric CD patients.
皮质类固醇（CS）可有效诱导中重度克罗恩病（CD）患者缓解。然而，儿童 CS 依赖性是一个严重的临床问题，与许多副作用相关。鉴定 CS 依赖性的分子标志物至关重要。ABCB1 基因编码 P-糖蛋白，一种参与 CS 代谢的转运蛋白。我们研究了 ABCB1 基因中的 DNA 变异是否与 CD 患儿 CS 依赖性相关。
在加拿大两个三级儿科胃肠病学中心进行了回顾性研究。从诊断为 CD 且年龄在 18 岁之前、诊断后 1 年内接受首剂 CS 治疗的 CD 患者（N=260）的病历中提取临床信息。如果患者在药物减量期间或治疗结束后复发，则将其归类为 CS 依赖性。从血液或唾液中提取 DNA。对 ABCB1 基因中的 13 个标记单核苷酸多态性（tag-SNP）和同义变异（C3435T）进行基因分型。使用逻辑回归和 Haploview 检查等位基因、基因型和单倍型关联。
tag-SNP rs2032583 与 CS 依赖性具有统计学显著相关性。该 SNP 的罕见 C 等位基因（比值比[OR] = 0.56，95%置信区间[CI]：0.34-0.95，P=0.029）和杂合基因型 TC（OR=0.52，95%CI：0.28-0.95，P=0.035）可降低 CS 依赖性的风险。一个三标记单倍型与 CS 依赖性显著相关（多重比较校正 P 值=0.004）。
我们的研究结果表明，ABCB1 基因可能与儿科 CD 患者 CS 依赖性相关。
