以色列魏茨曼科学研究所Eran Hornstein团队发现，白细胞介素18受体辅助蛋白3'UTR中的变体可预防肌萎缩侧索硬化 (ALS) 。该项研究成果于2022年3月31日在线发表在《自然—神经科学》杂志上。

研究人员对6,139个ALS全基因组和70,403个非ALS对照全基因组的非翻译区域中的25,000余个变体进行了基于区域的罕见变异关联分析。研究人员确定白细胞介素18受体辅助蛋白（IL18RAP）3'非翻译区（3'UTR）变体在非ALS基因组中显著富集，并且与患ALS的风险降低五倍相关，这在一个独立的队列中得到了重复。IL18RAP 3'UTR中的这些变体降低了mRNA稳定性和双链RNA（dsRNA）结合蛋白的结合。

最后，IL18RAP 3'UTR的变体赋予运动神经元生存优势，因为它们抑制了人类诱导多能干细胞（iPSC）衍生的小胶质细胞在C9orf72中具有ALS相关扩增的神经毒性，这取决于NF-κB信号传导。这项研究揭示了通过减少神经炎症来预防ALS的遗传变异，并强调了非编码遗传关联研究的重要性。

据介绍，非编码基因组比蛋白质编码基因组大得多，但遗传关联研究在很大程度上尚未探索。

附：英文原文

Title: Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3′UTR protect against ALS

Author: Eitan, Chen, Siany, Aviad, Barkan, Elad, Olender, Tsviya, van Eijk, Kristel R., Moisse, Matthieu, Farhan, Sali M. K., Danino, Yehuda M., Yanowski, Eran, Marmor-Kollet, Hagai, Rivkin, Natalia, Yacovzada, Nancy Sarah, Hung, Shu-Ting, Cooper-Knock, Johnathan, Yu, Chien-Hsiung, Louis, Cynthia, Masters, Seth L., Kenna, Kevin P., van der Spek, Rick A. A., Sproviero, William, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Jones, Ashley R., Elbaz-Alon, Yael, Cohen, Yahel, Chapnik, Elik, Rothschild, Daphna, Weissbrod, Omer, Beck, Gilad, Ainbinder, Elena, Ben-Dor, Shifra, Werneburg, Sebastian, Schafer, Dorothy P., Brown, Robert H., Shaw, Pamela J., Van Damme, Philip, van den Berg, Leonard H., Phatnani, Hemali, Segal, Eran, Ichida, Justin K., Al-Chalabi, Ammar, Veldink, Jan H., Hornstein, Eran

Issue&Volume: 2022-03-31

Abstract: The noncoding genome is substantially larger than the protein-coding genome but has been largely unexplored by genetic association studies. Here, we performed region-based rare variant association analysis of >25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole genomes and the whole genomes of 70,403 non-ALS controls. We identified interleukin-18 receptor accessory protein (IL18RAP) 3′ untranslated region (3′UTR) variants as significantly enriched in non-ALS genomes and associated with a fivefold reduced risk of developing ALS, and this was replicated in an independent cohort. These variants in the IL18RAP 3′UTR reduce mRNA stability and the binding of double-stranded RNA (dsRNA)-binding proteins. Finally, the variants of the IL18RAP 3′UTR confer a survival advantage for motor neurons because they dampen neurotoxicity of human induced pluripotent stem cell (iPSC)-derived microglia bearing an ALS-associated expansion in C9orf72, and this depends on NF-κB signaling. This study reveals genetic variants that protect against ALS by reducing neuroinflammation and emphasizes the importance of noncoding genetic association studies.

DOI: 10.1038/s41593-022-01040-6

Source: https://www.nature.com/articles/s41593-022-01040-6