Udomsinprasert Wanvisa, Kitkumthorn Nakarin, Mutirangura Apiwat, Chongsrisawat Voranush, Poovorawan Yong, Honsawek Sittisak
Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.
Department of Oral and Biology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand.
Sci Rep. 2016 May 31;6:26969. doi: 10.1038/srep26969.
Alu and LINE-1 elements are retrotransposons with a ubiquitous presence in the human genome that can cause genomic instability, specifically relating to telomere length. Genotoxic agents may induce methylation of retrotransposons, in addition to oxidative DNA damage in the form of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Methylation of retrotransposons induced by these agents may contribute to biliary atresia (BA) etiology. Here, we investigated correlations between global methylation, 8-OHdG, and relative telomere length, as well as reporting on Alu and LINE-1 hypomethylation in BA patients. Alu and LINE-1 hypomethylation were found to be associated with elevated risk of BA (OR = 4.07; 95% CI: 2.27-7.32; P < 0.0001 and OR = 3.51; 95% CI: 1.87-6.59; P < 0.0001, respectively). Furthermore, LINE-1 methylation was associated with liver stiffness in BA patients (β coefficient = -0.17; 95% CI: -0.24 to -0.10; P < 0.0001). Stratified analysis revealed negative correlations between Alu and LINE-1 methylation and 8-OHdG in BA patients (P < 0.0001). In contrast, positive relationships were identified between Alu and LINE-1 methylation and relative telomere length in BA patients (P < 0.0001). These findings suggest that retrotransposon hypomethylation is associated with plasma 8-OHdG and telomere length in BA patients.
Alu元件和LINE-1元件是逆转录转座子，在人类基因组中普遍存在，可导致基因组不稳定，特别是与端粒长度有关。除了以8-羟基-2'-脱氧鸟苷（8-OHdG）形式存在的氧化性DNA损伤外，基因毒性剂可能会诱导逆转录转座子的甲基化。这些剂诱导的逆转录转座子甲基化可能与胆道闭锁（BA）的病因有关。在这里，我们研究了整体甲基化、8-OHdG和相对端粒长度之间的相关性，并报告了BA患者中Alu元件和LINE-1元件的低甲基化情况。发现Alu元件和LINE-1元件的低甲基化与BA风险升高相关（OR = 4.07；95% CI：2.27 - 7.32；P < 0.0001和OR = 3.51；95% CI：1.87 - 6.59；P < 0.0001）。此外，LINE-1甲基化与BA患者的肝脏硬度相关（β系数 = -0.17；95% CI：-0.24至-0.10；P < 0.0001）。分层分析显示，BA患者中Alu元件和LINE-1甲基化与8-OHdG之间存在负相关（P < 0.0001）。相反，在BA患者中，Alu元件和LINE-1甲基化与相对端粒长度之间存在正相关（P < 0.0001）。这些发现表明，逆转录转座子低甲基化与BA患者的血浆8-OHdG和端粒长度相关。
