PO.PS01.07 · 人群科学

多发性骨髓瘤多基因风险评分（PRS）对MGUS的意义

Implications of multiple myeloma polygenic risk scores (PRS) for MGUS

编号 3603 展板 21 时间 4/20 02:00–05:00 区域 Section 35 主讲 Alyssa Clay-Gilmour, PhD

分会场 Genetic Epidemiology 1: GxE, GWAS, Polygenic Risk Scores, and Post-GWAS

查看 PDF 下载 PDF 🔒 查看 / 下载完整 PDF 需登录并开通下载套餐 · 查看套餐 / 开通 AACR 官方页面

作者与单位 Authors & Affiliations

Alyssa Ione Clay-Gilmour¹, Angelica Macauda², Cristine Allmer², Danelle Moonen², Aaron D. Norman², Nicholas Boddicker², Janet E. Olson², Elizabeth E. Brown³, Vincent S. Rajkumar², Esteban Braggio⁴, David Murray², Susan Slager², Shaji Kunnathu Kumar⁵, Celine Vachon⁶

¹University of South Carolina, Columbia, SC,²Mayo Clinic, Rochester, MN,³University Alabama Birmingham, Birmingham, AL,⁴Mayo Clinic Arizona, Scottsdale, AZ,⁵Professor of Medicine, Dept. of Hematology, Mayo Clinic, Rochester, MN,⁶Mayo Clinic College of Medicine and Science, Rochester, MN

摘要 Abstract

中文摘要

背景。全基因组关联研究（GWAS）已在欧洲血统（EA）个体中鉴定出35个多发性骨髓瘤（MM）遗传易感单核苷酸多态性（SNP），并显示MM与其前体病变意义未明的单克隆丙种球蛋白病（MGUS）之间存在强遗传相关性。我们评估了这35个MM变异对MGUS易感性的总体贡献及按预后亚组的贡献。方法。该研究纳入来自Mayo Clinic的20,756名参与者（14,486例对照，1,883例MGUS，2,163例MM）。采用假设加性模型的Logistic回归估计单个SNP及MM-PRS的比值比（OR）和95%置信区间（CI），并对年龄、性别、研究和主成分进行校正。PRS为35个SNP的加权总和，其效应估计来自最大规模的MM GWAS，并按连续变量（每个SD）和五分位（Q1-Q5）建模。SNPnexus对在MGUS中得到重复验证（P<0.05且OR>1.01）与未得到验证（P>0.05且OR<1.01）的变异进行了注释。结果。35-SNP的MM-PRS与MM风险强相关，与MGUS则呈中等程度关联。与中间五分位（Q3）相比，MM的比值比从Q1的OR=0.55（CI=0.46-0.65，P=2.2e⁻¹¹）升至Q5的OR=1.82（CI=1.59-2.09，P=6.2e⁻¹⁸）。MGUS呈现相似但减弱的模式（Q1 OR=0.74，CI=0.64-0.84，P=6.4e⁻⁶／Q5 OR=1.36，CI=1.21-1.53，P=3.4e⁻⁷）。PRS每增加一个SD，MM对应OR=1.52（CI=1.45-1.59，P=1.3e⁻⁶⁶），MGUS对应OR=1.22（CI=1.18-1.27，P=1.0e⁻²³）。较高的PRS值与较大的M蛋白（0.1-1.5 g/dL：OR=1.40，CI=1.18-1.65，P=5.8e⁻¹² 对比 <0.1 g/dL：OR=1.19，CI=1.13-1.24，P=5.8e⁻¹²）以及异常游离轻链（FLC）比值（OR=1.33，CI=1.21-1.46，P=1.0e⁻⁹ 对比正常比值 OR=1.19，CI=1.14-1.25，P=1.4e⁻¹³）相关。10个风险位点在MGUS中得到重复验证，映射到参与浆细胞功能、免疫调节和DNA修复的基因，并在Rho GTP酶信号、NF-κB介导的凋亡和RNA聚合酶II转录中富集，提示浆细胞早期活化和转录调控的参与。12个未获重复验证的位点，包括PHC3、ATG5和NFIC，映射到参与染色质重塑、自噬和SUMO化的基因，提示其在应激反应和基因组维护中的作用。结论。MM-PRS捕捉到MM与MGUS之间共享的遗传率，并与MGUS的亚型和严重程度相关。得到重复验证的变异凸显了与MGUS发病相关的免疫和细胞周期通路，而未获验证的位点则聚集于DNA修复和应激反应过程，凸显其在疾病进展中的潜在作用。

查看英文原文 English abstract

Background. Genome-wide association studies (GWAS) have identified 35 genetic susceptibility single-nucleotide polymorphisms (SNPs) for multiple myeloma (MM) in individuals of European ancestry (EA) and shown strong genetic correlation between MM and its precursor, monoclonal gammopathy of undetermined significance (MGUS). We evaluate the contribution of the 35 MM variants to MGUS susceptibility overall and by prognostic subgroups. Methods. The study included 20,756 participants (14,486 controls, 1,883 with MGUS, and 2,163 with MM) from the Mayo Clinic. Logistic regression assuming an additive model estimated odds ratios (ORs) and 95% confidence intervals (CIs) for individual SNPs and for the MM-PRS, adjusted for age, sex, study, and principal components. The PRS was a weighted sum of 35 SNPs with effect estimates from the largest MM GWAS and was modeled continuously (per SD) and by quintiles (Q1-Q5). SNPnexus annotated variants that replicated in MGUS (P < 0.05 and OR > 1.01) versus those that did not (P > 0.05 and OR < 1.01). Results. The 35-SNP MM-PRS was strongly associated with MM risk and modestly with MGUS. Compared with the middle quintile (Q3), MM odds rose from OR=0.55 (CI=0.46-0.65, P=2.2e⁻¹¹) in Q1 to OR = 1.82 (CI=1.59-2.09, P=6.2e⁻¹⁸) in Q5. MGUS showed a similar, attenuated pattern (Q1 OR = 0.74, CI=0.64-0.84, P=6.4e⁻⁶ / Q5 OR=1.36, CI=1.21-1.53, P=3.4e⁻⁷). Each SD increase in PRS corresponded to OR=1.52 (CI=1.45-1.59, P=1.3e⁻⁶⁶) for MM and OR = 1.22 (CI=1.18-1.27, P=1.0e⁻²³) for MGUS. Higher PRS values were linked to larger M-protein ((0.1-1.5 g/dL: OR=1.40, CI=1.18-1.65, P=5.8e⁻¹²) vs <0.1 g/dL: OR = 1.19, CI=1.13-1.24, P=5.8e⁻¹²)) and abnormal free light chain (FLC) ratio ((OR = 1.33, CI=1.21-1.46, P=1.0e⁻⁹) vs normal ratio (OR=1.19, CI=1.14-1.25, P=1.4e⁻¹³)). Ten risk loci replicated in MGUS, mapping to genes involved in plasma-cell function, immune regulation, and DNA repair and enriched for Rho GTPase signaling, NF-κB-mediated apoptosis, and RNA polymerase II transcription, implicating early plasma-cell activation and transcriptional control. The 12 non-replicating loci, including PHC3 , ATG5 , and NFIC , mapped to genes involved in chromatin remodeling, autophagy, and SUMOylation, suggesting roles in stress response and genomic maintenance. Conclusions. The MM-PRS captures shared heritability between MM and MGUS and correlates with MGUS subtype and severity. Replicating variants highlight immune and cell-cycle pathways relevant to MGUS onset, whereas non-replicating loci cluster in DNA-repair and stress-response processes, underscoring their potential role in progression.

利益披露 Disclosure

A. I. Clay-Gilmour, None.. C. Allmer, None.. D. Moonen, None.. E. E. Brown, None.. V. S. Rajkumar, None.. D. Murray, None.. S. Slager, None.

← 返回 AACR 2026 检索