ABCB1/MDR1 gene determines susceptibility and phenotype in ulcerative colitis:: discrimination of critical variants using a gene-wide haplotype tagging approach
ABCB1/MDR1 gene determines susceptibility and phenotype in ulcerative colitis:: discrimination of critical variants using a gene-wide haplotype tagging approach
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DOI：
10.1093/hmg/ddi494
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发表时间：
2006-03-01
影响因子：
3.5
通讯作者：
Satsangi, J
中科院分区：
文献类型：
--
作者：
Ho, GT;Soranzo, N;Satsangi, J
一些证据表明，多药耐药基因(ABCB1/MDR1)及其产物P-糖蛋白170在炎症性肠病(IBD)的发病机制中发挥了作用。此外，P-糖蛋白活性决定了在许多医学专业中经常使用的许多药物的生物利用度，而ABCB/MDR1变异似乎是一个关键的药物遗传学决定因素。我们使用了全基因单倍型标记方法来进一步确定ABCB1/MDR1基因中导致IBD易感性的胚系变异的身份。通过对24个高加索人种ABCB1/mdr1基因单倍型结构的分析，初步鉴定出6个代表该基因单倍型变异的单倍型标记单核苷酸多态(TSNPs)。对249例溃疡性结肠炎(UC)、179例克罗恩病(CD)患者和260例健康对照进行了基因分型。使用对数似然分析，我们发现常见的单倍型与UC(P=4.22x10(-7))有非常显著的相关性，但与CD(P=0.22)无关。这种显著的关联严重依赖于一个tSNP，内含子变体rs3789243。具有该变异的所有单倍型均保持高度相关(P=3.2x10(-7)-3.6x10(-12))，但当rs3789243在系统单倍型分析中缺失时就失去了显著性。此tSNP的作用不依赖于C3435T SNP，C3435T SNP以前被认为是疾病易感性和药物转运的关键变异。UC与广泛性疾病表型的相关性最强(P=1.7×10(-7))。这种“候选基因”方法提供了令人信服的证据，支持ABCB1/MDR1基因在确定UC而不是CD的风险方面的贡献，并为关键易感决定因素在基因内的定位提供了新的见解。此外，这些发现对药物遗传学在包括艾滋病毒、癫痫和结直肠癌在内的一系列常见疾病中的应用具有潜在的重要影响。
Several lines of evidence suggest a role for the multidrug resistance gene (ABCB1/MDR1) and its product, P-glycoprotein 170, in the pathogenesis of inflammatory bowel disease (IBD). In addition, P-glycoprotein activity determines bioavailability of many drugs used regularly in many medical specialities, and ABCB/MDR1 variation appears to be a critical pharmacogenetic determinant. We have utilized a gene-wide haplotype tagging approach to further define the identity of germ-line variations in the ABCB1/MDR1 gene contributing to IBD susceptibility. Six haplotype tagging single nucleotide polymorphisms (tSNPs) representing the haplotypic variations of the ABCB1/MDR1 gene were identified initially following the characterization of the haplotype structure of this gene in 24 Centre d'Etude du Polymorphisme Humain Caucasian trios. Genotyping was performed in 249 ulcerative colitis (UC) and 179 Crohn's disease (CD) patients and 260 healthy controls. Using log-likelihood analysis, we observed a highly significant association between the common haplotypes and UC (P=4.22x10(-7)) but not CD (P=0.22). This significant association was critically dependent on one tSNP, intronic variant rs3789243. All haplotypes with this variant retained a highly significant association (P=3.2x10(-7)-3.6x10(-12)), whereas significance was lost when rs3789243 was dropped in systematic haplotypic analysis. The effect of this tSNP was independent of C3435T SNP, previously suggested to be the critical variant in disease susceptibility and drug transport. The association with UC was shown to be strongest with the phenotype of extensive disease (P=1.7x10(-7)). This 'candidate gene' approach provides compelling evidence to support the contribution of the ABCB1/MDR1 gene in determining risk to UC but not to CD and provides new insights into the localization of the critical susceptibility determinants within the gene. In addition, these findings have potentially important implications in the application of pharmacogenetics across a range of common diseases, including HIV, epilepsy and colorectal cancer.