文章：

单倍型分析鉴定意义未明的单克隆丙种球蛋白病中的功能元件

Haplotype analysis identifies functional elements in monoclonal gammopathy of unknown significance

原文发布日期：2024-08-20

DOI: 10.1038/s41408-024-01121-8

类型: Article

开放获取: 是

英文摘要：

Genome-wide association studies (GWASs) based on common single nucleotide polymorphisms (SNPs) have identified several loci associated with the risk of monoclonal gammopathy of unknown significance (MGUS), a precursor condition for multiple myeloma (MM). We hypothesized that analyzing haplotypes might be more useful than analyzing individual SNPs, as it could identify functional chromosomal units that collectively contribute to MGUS risk. To test this hypothesis, we used data from our previous GWAS on 992 MGUS cases and 2910 controls from three European populations. We identified 23 haplotypes that were associated with the risk of MGUS at the genome-wide significance level (p < 5 × 10−8) and showed consistent results among all three populations. In 10 genomic regions, strong promoter, enhancer and regulatory element-related histone marks and their connections to target genes as well as genome segmentation data supported the importance of these regions in MGUS susceptibility. Several associated haplotypes affected pathways important for MM cell survival such as ubiquitin-proteasome system (RNF186, OTUD3), PI3K/AKT/mTOR (HINT3), innate immunity (SEC14L1, ZBP1), cell death regulation (BID) and NOTCH signaling (RBPJ). These pathways are important current therapeutic targets for MM, which may highlight the advantage of the haplotype approach homing to functional units.
 

摘要翻译： 

基于常见单核苷酸多态性（SNP）的全基因组关联研究（GWAS）已发现多个与意义未明的单克隆免疫球蛋白病（MGUS）风险相关的基因位点，MGUS是多发性骨髓瘤（MM）的前期病变。我们假设分析单倍型可能比分析单个SNP更有价值，因为单倍型能够识别共同影响MGUS风险的功能性染色体单元。为验证这一假设，我们利用先前对来自三个欧洲人群的992例MGUS患者和2910例对照者进行的GWAS数据，识别出23个在全基因组显著性水平（p < 5 × 10⁻⁸）上与MGUS风险相关的单倍型，且在三个群体中结果一致。在10个基因组区域中，强启动子、增强子及调控元件相关的组蛋白修饰标记、它们与靶基因的关联以及基因组分割数据均支持这些区域对MGUS易感性的重要性。若干相关单倍型影响了MM细胞存活的关键通路，例如泛素-蛋白酶体系统（RNF186、OTUD3）、PI3K/AKT/mTOR（HINT3）、天然免疫（SEC14L1、ZBP1）、细胞死亡调控（BID）以及NOTCH信号通路（RBPJ）。这些通路是当前MM治疗的重要靶点，这可能凸显了单倍型分析方法聚焦于功能单元的优势。

原文链接：

Haplotype analysis identifies functional elements in monoclonal gammopathy of unknown significance