Division of Musculoskeletal and Dermatological Sciences, Centre for Genetics and Genomics Versus Arthritis, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, England, United Kingdom.
NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester,England, United Kingdom.
PLoS One. 2020 Mar 20;15(3):e0223939. doi: 10.1371/journal.pone.0223939. eCollection 2020.
Whilst susceptibility variants for many complex diseases, such as rheumatoid arthritis (RA), have been well characterised, the mechanism by which risk is mediated is still unclear for many loci. This is especially true for the majority of variants that do not affect protein-coding regions. lncRNA represent a group of molecules that have been shown to be enriched amongst variants associated with RA and other complex diseases, compared to random variants. In order to establish to what degree direct disruption of lncRNA may represent a potential mechanism for mediating RA susceptibility, we chose to further explore this overlap. By testing the ability of annotated features to improve a model of disease susceptibility, we were able to demonstrate a local enrichment of enhancers from immune-relevant cell types amongst RA susceptibility variants (log2 enrichment 3.40). This was not possible for lncRNA annotations in general, however a small, but significant enrichment was observed for immune-enriched lncRNA (log2 enrichment 0.867002). This enrichment was no longer apparent when the model was conditioned on immune-relevant enhancers (log2 enrichment -0.372734), suggesting that direct disruption of lncRNA sequence, independent of enhancer disruption, does not represent a major mechanism by which susceptibility to complex diseases is mediated. Furthermore, we demonstrated that, in keeping with general lncRNA characteristics, immune-enriched lncRNA are expressed at low levels that may not be amenable to functional characterisation.
虽然许多复杂疾病（如类风湿关节炎（RA））的易感性变异已经得到很好的描述，但对于许多位点，风险的介导机制仍然不清楚。对于大多数不影响蛋白质编码区域的变异来说，尤其如此。lncRNA 是一类已被证明在与 RA 和其他复杂疾病相关的变异中比随机变异更为丰富的分子。为了确定直接破坏 lncRNA 是否可能代表介导 RA 易感性的潜在机制，我们选择进一步探索这种重叠。通过测试注释特征对疾病易感性模型的改善能力，我们能够证明 RA 易感性变异体中免疫相关细胞类型的增强子具有局部富集（log2 富集 3.40）。对于一般的 lncRNA 注释来说，这是不可能的，但是对于免疫富集的 lncRNA 观察到了一个较小但显著的富集（log2 富集 0.867002）。当模型根据免疫相关增强子进行条件化时，这种富集不再明显（log2 富集-0.372734），这表明 lncRNA 序列的直接破坏，而不依赖于增强子的破坏，并不代表复杂疾病易感性的主要介导机制。此外，我们还证明，与一般 lncRNA 特征一致，免疫富集的 lncRNA 表达水平较低，可能不适于功能表征。
