Polymorphism of receptor-type tyrosine-protein phosphatase delta gene in the development of non-alcoholic fatty liver disease
Polymorphism of receptor-type tyrosine-protein phosphatase delta gene in the development of non-alcoholic fatty liver disease
复制标题
DOI：
10.1111/jgh.13820
复制
发表时间：
2018-01-01
影响因子：
4.1
通讯作者：
Okumura, Toshikatsu
中科院分区：
文献类型：
--
作者：
Nakajima, Shunsuke;Tanaka, Hiroki;Okumura, Toshikatsu
背景与目的一些单核苷酸多态性(SNPs)与非酒精性脂肪性肝病(NAFLD)的发生有关。PNPLA3 rs738409(I148M)基因作为NAFLD的遗传因素之一，在NAFLD的发病机制中起重要作用。由于其他SNP在日本尚不清楚，我们进行了针对1000多个基因的高通量测序，以确定日本NAFLD患者中的一种新的基因变异。方法本研究对36名NAFLD患者和27名健康志愿者进行了研究。使用高通量测序仪检测基因变异。对53例NAFLD患者和41例健康志愿者的候选基因进行TaqMan SNP基因分型。结果EXO1 rs1047840、PTPRD rs35929428、IFNAR2 rs2229207、CPOX rs1131857、IL23R rs1884444、IL10RA rs2228055和FAM3B rs111988437被鉴定为候选遗传变异，而PTPRD rs35929428仅被提取为预测蛋白质功能障碍的SNP。在验证性分析中，PTPRD rs35929428与NAFLD的发生相关(P=0.015，优势比=5.00，95%可信区间：1.33~18.70)。此外，PTPRD rs35929428与Fib-4指数和肝脂肪滴相关。生化分析表明PTPRD rs35929428可促进肝细胞酪氨酸705信号转导和转录激活子3(Tyr 705)的去磷酸化。PTPRD rs35929428可能通过加剧肝细胞信号转导和转录激活子3(Tyr705)的去磷酸化，在肝脏脂质堆积和纤维化中发挥作用，进而导致NAFLD的发生。
Background and AimSome single-nucleotide polymorphisms (SNPs) are associated with the development of non-alcoholic fatty liver disease (NAFLD). As one of the genetic factors, PNPLA3 rs738409 (I148M) is important to associate with pathogenesis of NAFLD. Because other SNPs remain unclear in Japan, we performed a high-throughput sequencing that targeted more than 1000 genes to identify a novel genetic variant in Japanese patients with NAFLD.MethodsThe present study in 36 NAFLD patients and 27 healthy volunteers was performed. A high-throughput sequencer was used to detect the gene variations. Candidate genes were validated by TaqMan SNP genotyping assay in 53 NAFLD patients and 41 healthy volunteers. To investigate the function of candidate gene, we performed biochemical analyses in cultured hepatocytes and liver tissues.ResultsEXO1 rs1047840, PTPRD rs35929428, IFNAR2 rs2229207, CPOX rs1131857, IL23R rs1884444, IL10RA rs2228055, and FAM3B rs111988437 were identified as candidate genetic variants, and PTPRD rs35929428 was only extracted as a SNP predicting to cause protein dysfunction. In validation analysis, PTPRD rs35929428 associated with the development of NAFLD (P=0.015, odds ratio=5.00, 95% confidence interval: 1.33-18.70). In addition, PTPRD rs35929428 was associated with Fib-4 index and with hepatic fat droplets. Biochemical analyses indicated that PTPRD rs35929428 promoted dephosphorylation of tyrosine 705 signal transducer and activator of transcription 3 (Tyr 705) in hepatocytes.ConclusionPTPRD rs35929428 was a novel SNP in patients with NAFLD. Through exacerbation of the dephosphorylation of signal transducer and activator of transcription 3 (Tyr 705) in hepatocytes, PTPRD rs35929428 might play a role in hepatic lipid accumulation and fibrosis, followed by the development of NAFLD.