Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
Department of Legal Medicine, Asahikawa Medical University, Asahikawa, Japan.
J Gastroenterol Hepatol. 2018 Jan;33(1):283-290. doi: 10.1111/jgh.13820.
Some 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.
The 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.
EXO1 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.
PTPRD 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.
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。作为遗传因素之一，PNPLA3 rs738409（I148M）与 NAFLD 的发病机制密切相关。由于其他 SNPs 在日本尚未明确，我们进行了高通量测序，以鉴定日本 NAFLD 患者的新遗传变异。
本研究纳入 36 例 NAFLD 患者和 27 名健康志愿者。使用高通量测序仪检测基因变异。候选基因在 53 例 NAFLD 患者和 41 名健康志愿者中通过 TaqMan SNP 基因分型检测进行验证。为了研究候选基因的功能，我们在培养的肝细胞和肝组织中进行了生化分析。
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 仅被提取为预测导致蛋白质功能障碍的 SNP。在验证分析中，PTPRD rs35929428 与 NAFLD 的发生相关（P=0.015，比值比=5.00，95%置信区间：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 促进了肝细胞中信号转导和转录激活因子 3（Tyr 705）的酪氨酸 705 去磷酸化。
PTPRD rs35929428 是 NAFLD 患者的一个新 SNP。通过加重肝细胞中转录激活因子 3（Tyr 705）的去磷酸化，PTPRD rs35929428 可能在肝脂质堆积和纤维化中发挥作用，进而导致 NAFLD 的发生。
