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.

基于常见单核苷酸多态性 （SNP） 的全基因组关联研究 （GWAS） 已经确定了与意义不明的单克隆丙种球蛋白病 （MGUS） 风险相关的几个基因座，MGUS 是多发性骨髓瘤 （MM） 的前体疾病。我们假设分析单倍型可能比分析单个 SNP 更有用，因为它可以识别共同导致 MGUS 风险的功能性染色体单位。为了检验这一假设，我们使用了之前 GWAS 的数据，涉及来自 3 个欧洲人群的 992 例 MGUS 病例和 2910 例对照。我们确定了 23 个在全基因组显著性水平上与 MGUS 风险相关的单倍型 （p < 5 × 10⁻⁸），并在所有三个人群中显示出一致的结果。在 10 个基因组区域中，强启动子、增强子和调节元件相关的组蛋白标记及其与靶基因的联系以及基因组分割数据支持这些区域在 MGUS 易感性中的重要性。几种相关的单倍型影响了对 MM 细胞存活很重要的通路，例如泛素-蛋白酶体系统 （RNF186， OTUD3）、PI3K/AKT/mTOR （HINT3）、先天免疫 （SEC14L1， ZBP1）、细胞死亡调节 （BID） 和 NOTCH 信号转导 （RBPJ）。这些途径是 MM 当前重要的治疗靶点，这可能突出了单倍型方法归巢到功能单位的优势。