Department of Pathology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China.
Front Immunol. 2024 Oct 7;15:1448476. doi: 10.3389/fimmu.2024.1448476. eCollection 2024.
Beta-2 microglobulin (β2M) is acknowledged as a prognostic biomarker for B-cell malignancies. However, insights into the impact of β2M on B-cell malignancy risk, and vice versa, are limited.
We conducted a genome-wide meta-analysis (GWMA), bidirectional two-sample Mendelian randomization (TSMR) analysis, and pathway enrichment analysis to explore the causal relationship between β2M and B-cell malignancies and the underlying biological processes.
The GWMA identified 55 lead SNPs across five genomic regions (three novel: WDR72, UMOD, and NLRC5) associated with β2M. In the UKB, genetically predicted β2M showed a positive association with diffuse large B-cell lymphoma (DLBCL; odds ratio [OR]: 1.742 per standard deviation increase in β2M; 95% confidence interval [CI]: 1.215-2.498; = 3.00 × 10; FDR = 7.50× 10) and Hodgkin lymphoma (HL; OR: 2.270; 95% CI: 1.525-3.380; = 5.15 × 10; FDR =2.58 × 10). However, no associations were found with follicular lymphoma (FL), chronic lymphoid leukemia (CLL), or multiple myeloma (MM). Reverse TSMR analysis revealed no association between genetically predicted B-cell malignancies and β2M. In FinnGen, β2M was found to be associated with an increased risk of DLBCL (OR: 2.098; 95% CI: 1.358-3.242; = 8.28 × 10; FDR = 4.14 × 10), HL (OR: 1.581; 95% CI: 1.167-2.142; = 3.13 × 10; FDR = 5.22 × 10), and FL (OR: 2.113; 95% CI: 1.292-3.455; = 2.90 × 10; FDR = 5.22 × 10). However, no association was found with CLL or MM. Reverse TSMR analysis indicated that genetically predicted DLBCL, FL, and MM may perturb β2M levels. Pathway enrichment analysis suggested that the innate immune system represents a convergent biological process underlying β2M, DLBCL, and HL.
Our findings suggested that elevated levels of β2M were associated with an increased risk of DLBCL and HL, which is potentially linked to dysfunction of the innate immune system.
β2-微球蛋白（β2M）被认为是 B 细胞恶性肿瘤的预后生物标志物。然而，β2M 对 B 细胞恶性肿瘤风险的影响，反之亦然，目前了解有限。
我们进行了全基因组荟萃分析（GWMA）、双向两样本 Mendelian 随机化（TSMR）分析和途径富集分析，以探讨β2M 与 B 细胞恶性肿瘤之间的因果关系以及潜在的生物学过程。
GWMA 在五个基因组区域（三个新区域：WDR72、UMOD 和 NLRC5）中确定了 55 个与β2M 相关的 lead SNPs。在 UKB 中，遗传预测的β2M 与弥漫性大 B 细胞淋巴瘤（DLBCL；β2M 每标准偏差增加的优势比[OR]：1.742；95%置信区间[CI]：1.215-2.498； = 3.00 × 10；FDR = 7.50× 10）和霍奇金淋巴瘤（HL；OR：2.270；95%CI：1.525-3.380； = 5.15 × 10；FDR =2.58 × 10）呈正相关。然而，与滤泡性淋巴瘤（FL）、慢性淋巴细胞白血病（CLL）或多发性骨髓瘤（MM）均无关联。反向 TSMR 分析显示，遗传预测的 B 细胞恶性肿瘤与β2M 之间无关联。在 FinnGen 中，β2M 与 DLBCL（OR：2.098；95%CI：1.358-3.242； = 8.28 × 10；FDR = 4.14 × 10）、HL（OR：1.581；95%CI：1.167-2.142； = 3.13 × 10；FDR = 5.22 × 10）和 FL（OR：2.113；95%CI：1.292-3.455； = 2.90 × 10；FDR = 5.22 × 10）的风险增加相关。然而，与 CLL 或 MM 无关联。反向 TSMR 分析表明，遗传预测的 DLBCL、FL 和 MM 可能会改变β2M 水平。途径富集分析表明，固有免疫系统是β2M、DLBCL 和 HL 潜在的共同生物学过程。
我们的研究结果表明，β2M 水平升高与 DLBCL 和 HL 风险增加相关，这可能与固有免疫系统功能障碍有关。
