Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis
Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis
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DOI：
10.1053/j.gastro.2004.11.019
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发表时间：
2005-02-01
期刊：
影响因子：
29.4
通讯作者：
Satsangi, J
中科院分区：
文献类型：
--
作者：
Ho, GT;Nimmo, ER;Satsangi, J
背景与目的：MDR 1基因编码的P-糖蛋白170是一种在肠上皮细胞中高度表达的外排转运蛋白。MDR 1外显子单核苷酸多态性（SNP）C3435 T和G2677 T已被证明与P-糖蛋白1.70的活性/表达相关。研究方法：这是在一个大型的充分表征的苏格兰白色队列（335例溃疡性结肠炎[UC]，268例克罗恩病[CD]和370例健康对照）中对MDR 1 C3435 T和G2677 T SNP进行的病例对照分析。我们进行了2位点单倍型和详细的单变量和多变量基因型表型分析。结果如下：MDR 1 3435 TT基因型（34.6% vs 26.5%; P = 0.04;比值比[OR]，1.60; 95%置信区间[95% CI]，1.04-2.44）和T等位基因频率（58.2% vs 52.8%; P = 0.02; OR，1.28; 95% CI，1.03-1.58），UC患者显著高于对照组。未发现与CD相关。与广泛UC的相关性最强（TT基因型：42.4% vs 26.5%; P = 0.003; OR，2.64; 95% CI，1.34-4.99; T等位基因：63.9% vs 52.8%; P = 0.009; OR，1.70; 95%CI，1.24-2.29），这也在多变量分析中得到证实（P = .007）。G2677 T SNP与UC或CD无关。这2个SNP在我们的群体中处于连锁不平衡（D '，.8-.9; r（2），.7-.8）。双位点单倍型显示与UC的正相关（3435 T/G2677单倍型：P = .03; OR，：1.44）和负相关（C3435/2677 T单倍型：P = .002; OR，.35）。单倍型3435 T/G2677的纯合子在UC中显著增加（P = 0.017; OR，8.88; 95%CI，1.10-71.45）。结论：MDR 1基因的等位基因变异决定了苏格兰人群UC的疾病程度和易感性。目前的数据强烈暗示C3435 T SNP，虽然2位点单倍型数据强调需要进一步详细的单倍型研究。
Background & Aims: The MDR1 gene encodes P-glycoprotein 170, an efflux transporter that is highly expressed in intestinal epithelial cells. The MDR1 exonic single nucleotide polymorphisms (SNPs) C3435T and G2677T have been shown to correlate with activity/expression of P-glycoprotein 1.70. Methods: This was a case-control analysis of MDR1 C3435T and G2677T SNPs in a large well-characterized Scottish white cohort (335 with ulcerative colitis [UC], 268 with Crohn's disease [CD], and 370 healthy controls). We conducted 2-locus haplotype and detailed univariate and multivarlate genotypic-phenotypic analyses. Results: The MDR1 3435 TT genotype (34.6% vs 26.5%; P = .04; odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.04-2.44) and T-allelic frequencies (58.2% vs 52.8%; P = .02; OR, 1.28; 95% CI, 1.03-1.58) were significantly higher in patients with UC compared with controls. No association was seen with CD. The association was strongest with extensive UC (TT genotype: 42.4% vs 26.5%; P = .003; OR, 2.64; 95% CI, 1.34-4.99; and T allele: 63.9% vs 52.8%; P = .009; OR, 1.70; 95% CI, 1.24-2.29), and this was also confirmed on multivariate analysis (P = .007). The G2677T SNP was not associated with UC or CD. These 2 SNPs lie in linkage disequilibrium in our population (D', .8-.9; r(2), .7-.8). Two-locus haplotypes showed both positive (3435T/G2677 haplotype: P = .03; OR, :1.44) and negative (C3435/2677T haplotype: P = .002; OR, .35) associations with UC. Homozygotes for the haplotype 3435T/G2677 were significantly increased in UC (P = .017; OR, 8.88; 95% CI, 1.10-71.45). Conclusions: Allelic variations of the MDR1 gene determine disease extent as well as susceptibility to UC in the Scottish population. The present data strongly implicate the C3435T SNP, although the 2-locus haplotype data underline the need for further detailed haplotypic studies.