Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. It has a strong genetic basis, showing a ~ 8-fold increased risk of CLL in first-degree relatives. Genome-wide association studies (GWAS) have identified 41 risk variants across 41 loci. However, for a majority of the loci, the functional variants and the mechanisms underlying their causal roles remain undefined. Here, we examined the genetic and epigenetic features associated with 12 index variants, along with any correlated (r² ≥ 0.5) variants, at the CLL risk loci located outside of gene promoters. Based on publicly available ChIP-seq and chromatin accessibility data as well as our own ChIP-seq data from CLL patients, we identified six candidate functional variants at six loci and at least two candidate functional variants at each of the remaining six loci. The functional variants are predominantly located within enhancers or super-enhancers, including bi-directionally transcribed enhancers, which are often restricted to immune cell types. Furthermore, we found that, at 78% of the functional variants, the alternative alleles altered the transcription factor binding motifs or histone modifications, indicating the involvement of these variants in the change of local chromatin state. Finally, the enhancers carrying functional variants physically interacted with genes enriched in the type I interferon signaling pathway, apoptosis, or TP53 network that are known to play key roles in CLL. These results support the regulatory roles for inherited noncoding variants in the pathogenesis of CLL.

中文翻译：

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慢性淋巴细胞白血病 (CLL) 风险由 CLL 风险位点内的多个增强子变异介导。

慢性淋巴细胞白血病 (CLL) 是西方国家最常见的成人白血病。它具有强大的遗传基础，一级亲属患 CLL 的风险增加了约 8 倍。全基因组关联研究 (GWAS) 已在 41 个基因座中确定了 41 个风险变异。然而，对于大多数基因座，功能变异及其因果作用的机制仍未确定。在这里，我们检查了与 12 个索引变异相关的遗传和表观遗传特征，以及任何相关的 (r ² ≥ 0.5) 变异，位于基因启动子之外的 CLL 风险位点。基于公开可用的 ChIP-seq 和染色质可及性数据以及我们自己来自 CLL 患者的 ChIP-seq 数据，我们在六个基因座上确定了六个候选功能变异，并在其余六个基因座中的每一个上确定了至少两个候选功能变异。功能变体主要位于增强子或超级增强子内，包括双向转录的增强子，通常仅限于免疫细胞类型。此外，我们发现，在 78% 的功能变体中，替代等位基因改变了转录因子结合基序或组蛋白修饰，表明这些变体参与了局部染色质状态的变化。最后，携带功能变异的增强子与富含 I 型干扰素信号通路、细胞凋亡或 TP53 网络的基因发生物理相互作用，这些基因已知在 CLL 中起关键作用。这些结果支持遗传非编码变异在 CLL 发病机制中的调节作用。