Single-nucleotide polymorphism analysis of the multidrug resistance protein 3 gene for the detection of clinical progression in Japanese patients with primary biliary cirrhosis
Single-nucleotide polymorphism analysis of the multidrug resistance protein 3 gene for the detection of clinical progression in Japanese patients with primary biliary cirrhosis
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DOI：
10.1002/hep.22382
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发表时间：
2008-09-01
期刊：
影响因子：
13.5
通讯作者：
Tsukamoto, Kazuhiro
中科院分区：
文献类型：
--
作者：
Ohishi, Yuki;Nakamura, Minoru;Tsukamoto, Kazuhiro
原发性胆汁性肝硬化（PBC）是一种多因素的疾病，其中遗传因素而不是环境因素可能占主导地位的发病机制。为了确定PBC疾病严重程度和进展的遗传决定因素，我们研究了148名日本PBC患者和150名年龄和性别匹配的健康对照者的多药耐药蛋白3（MDR 3/ABCB 4）基因中7个标签单核苷酸多态性（SNP）的相关性。通过聚合酶链反应（PCR）限制性片段长度多态性和PCR直接DNA测序方法检测SNPs。随后，从与PBC进展显著相关的三个标签SNP（rs31658、rs31672和rs 1149222）构建单倍型。逻辑回归分析显示，MDR 3中的Hap 2单倍型及其纯合双倍型Hap 2/Hap 2与PBC黄疸型进展的易感性密切相关[P = 0.004，比值比（OR）3.93，95%置信区间（0）1.56-9.90和P = 0.0003，OR 17-73，95% CI 3.77-83.42]。相反，另一种单倍型Hap 1及其纯合双倍型Hap 1/Hap 1与进展为晚期PBC的不易感性相关（分别为P = 0.021，OR 0.55，95%CI 0.33-0.91和P = 0.011，OR 0.24，95%CI 0.08-0.71）。结论：本研究首次报道了MDR 3单倍型和双倍型与PBC进展的关系。因此，Hap 2/Hap 2双倍型MDR 3可能应用于日本PBC患者的DNA诊断，作为预测PBC进展和预后的强有力的遗传生物标志物。
Primary biliary cirrhosis (PBC) is a multifactorial disease in which genetic factors rather than environmental factors may predominantly contribute to the pathogenesis. In order to identify the genetic determinants of the disease severity and progression of PBC, we examined an association of seven tag single-nucleotide polymorphisms (SNPs) in the multidrug resistance protein 3 (MDR3/ABCB4) gene in 148 Japanese PBC patients and 150 age- and sex-matched healthy control subjects. SNPs were detected via polymerase chain reaction (PCR) restriction fragment length polymorphism and PCR direct DNA sequencing methods. Subsequently, haplotypes were constructed from three tag SNPs (rs31658, rs31672, and rs1149222) that were significantly associated with progression of PBC. Logistic regression analyses revealed that a Hap 2 haplotype and its homozygous diplotype, Hap 2/Hap 2, in MDR3 were closely associated with the susceptibility to jaundice-type progression of PBC [P = 0.004, odds ratio (OR) 3.93, 95% confidence interval (0) 1.56-9.90 and P = 0.0003, OR 17-73, 95% CI 3.77-83.42, respectively]. Conversely, another haplotype, Hap 1, and its homozygous diplotype, Hap 1/Hap 1, were associated with the insusceptibility to the progression to late-stage PBC (P = 0.021, OR 0.55, 95% CI 0.33-0.91 and P = 0.011, OR 0.24, 95% CI 0.08-0.71, respectively). Conclusion: The present study is the first report of an association of MDR3 haplotypes and diplotypes with progression of PBC. The Hap 2/Hap 2 diplotype in MDR3 could therefore be potentially applied to DNA-based diagnosis in Japanese patients with PBC as a strong genetic biomarker for predicting the progression and prognosis of PBC.