Clinical and Molecular Hepatology Laboratory, Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Argentina.
Pharmacogenet Genomics. 2010 Jan;20(1):1-8. doi: 10.1097/FPC.0b013e328333a1dd.
To explore the contribution of gene variants and derived haplotypes of the pregnane X receptor (NR1I2) to the severity of nonalcoholic fatty liver disease (NAFLD).
A total of 290 individuals were evaluated in a case-control association study, including 188 NAFLD patients with different stages of disease severity and 102 healthy individuals. Four tag single nucleotide polymorphisms (SNPs; rs12488820 C/T, rs2472671 C/T, rs2461823 A/G, and rs1054191 A/G) encompassing 36 kb in chromosome 3 and representing 33 polymorphic sites (r2>0.8) were genotyped. Four additional SNPs (rs3814055, rs3814057, rs6785049, and rs7643645) were also included because they showed earlier evidence of functionality.
Genotypic tests for single SNPs showed that rs7643645 and rs2461823 were significantly associated with disease severity by ordinal multinomial analysis (P<0.0015 and 0.039, respectively). A significant association was also observed under the additive model for both variants (P<0.00038 and 0.012, respectively). Consistent with the analysis of individual markers, we observed that the multimarker composed of rs2461823/A-rs7643645/G was significantly associated with disease severity (P<6.9 x 10(-5), beta: 0.45). In addition, the rs7643645/G variant was significantly associated with ALT level (P<0.026), a surrogate marker of severe liver injury. Finally, in univariate analysis rs7643645/G was significantly associated with fatty liver disease (P<0.04), with an odds ratio of 1.457 (95% confidence interval: 1.018-2.086).
Our study suggests that pregnane X receptor polymorphisms and related haplotypes may contribute to disease severity in NAFLD by influencing the individual susceptibility to progress to more severe stages of the disease.
探讨孕烷 X 受体（NR1I2）基因变异及其衍生单倍型对非酒精性脂肪性肝病（NAFLD）严重程度的影响。
在一项病例对照关联研究中，共评估了 290 人，包括 188 名不同疾病严重程度的 NAFLD 患者和 102 名健康个体。对包含染色体 3 上 36 kb 并代表 33 个多态性位点（r2>0.8）的 4 个标签单核苷酸多态性（SNP；rs12488820 C/T、rs2472671 C/T、rs2461823 A/G 和 rs1054191 A/G）进行了基因分型。还包括 4 个额外的 SNP（rs3814055、rs3814057、rs6785049 和 rs7643645），因为它们具有更早的功能证据。
单 SNP 的基因型检验表明，rs7643645 和 rs2461823 通过有序多项分类分析与疾病严重程度显著相关（P<0.0015 和 0.039，分别）。两种变体在加性模型下也观察到显著关联（P<0.00038 和 0.012，分别）。与个体标记的分析一致，我们观察到由 rs2461823/A-rs7643645/G 组成的多标记与疾病严重程度显著相关（P<6.9 x 10(-5)，β：0.45）。此外，rs7643645/G 变体与 ALT 水平显著相关（P<0.026），ALT 是严重肝损伤的替代标志物。最后，在单变量分析中，rs7643645/G 与脂肪肝显著相关（P<0.04），优势比为 1.457（95%置信区间：1.018-2.086）。
我们的研究表明，孕烷 X 受体多态性及其相关单倍型可能通过影响个体进展为疾病更严重阶段的易感性，导致 NAFLD 的疾病严重程度。
