Lee Matthew A, Burley Kate L, Hazelwood Emma L, Moore Sally, Lewis Sarah J, Goudswaard Lucy J
Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organisation, Lyon, France.
Population Health Sciences, University of Bristol, Bristol, UK.
Sci Rep. 2025 Jan 30;15(1):3752. doi: 10.1038/s41598-025-86222-5.
Multiple myeloma (MM) is an incurable blood cancer with unclear aetiology. Proteomics is a valuable tool in exploring mechanisms of disease. We investigated the causal relationship between circulating proteins and MM risk, using two of the largest cohorts with proteomics data to-date. We performed bidirectional two-sample Mendelian randomization (MR; forward MR = causal effect estimation of proteins and MM risk; reverse MR = causal effect estimation of MM risk and proteins). Summary statistics for plasma proteins were obtained from genome-wide association studies performed using SomaLogic (N = 35,559; deCODE) and Olink (N = 34,557; UK Biobank; UKB) proteomic platforms and for MM risk from a meta-analysis of UKB and FinnGen (case = 1649; control = 727,247) or FinnGen only (case = 1085; control = 271,463). Cis-SNPs associated with protein levels were used to instrument circulating proteins. We evaluated proteins for the consistency of directions of effect across MR analyses (with 95% confidence intervals not overlapping the null) and corroborating evidence from genetic colocalization. In the forward MR, 994 (SomaLogic) and 1570 (Olink) proteins were instrumentable. 440 proteins were analysed in both deCODE and UKB; 302 (69%) of these showed consistent directions of effect in the forward MR. Seven proteins had 95% confidence intervals (CIs) that did not overlap the null in both forward MR analyses and did not have evidence for an effect in the reverse direction: higher levels of dermatopontin (DPT), beta-crystallin B1 (CRYBB1), interleukin-18-binding protein (IL18BP) and vascular endothelial growth factor receptor 2 (KDR) and lower levels of odorant-binding protein 2b (OBP2B), glutamate-cysteine ligase regulatory subunit (GCLM) and gamma-crystallin D (CRYGD) were implicated in increasing MM risk. Evidence from genetic colocalization did not meet our threshold for a shared causal signal between any of these proteins and MM risk (h4 < 0.8). Our results highlight seven circulating proteins which may be involved in MM risk. Although evidence from genetic colocalization suggests these associations may not be robust to the effects of horizontal pleiotropy, these proteins may be useful markers of MM risk. Future work should explore the utility of these proteins in disease prediction or prevention using proteomic data from patients with MM or precursor conditions.
多发性骨髓瘤（MM）是一种病因不明的无法治愈的血癌。蛋白质组学是探索疾病机制的一种有价值的工具。我们利用两个迄今为止最大的拥有蛋白质组学数据的队列，研究了循环蛋白与MM风险之间的因果关系。我们进行了双向两样本孟德尔随机化（MR；正向MR = 蛋白质与MM风险的因果效应估计；反向MR = MM风险与蛋白质的因果效应估计）。血浆蛋白的汇总统计数据来自使用SomaLogic（N = 35,559；deCODE）和Olink（N = 34,557；英国生物银行；UKB）蛋白质组学平台进行的全基因组关联研究，以及来自UKB和芬兰基因库（病例 = 1649；对照 = 727,247）或仅芬兰基因库（病例 = 1085；对照 = 271,463）的MM风险的荟萃分析。与蛋白水平相关的顺式单核苷酸多态性（Cis-SNPs）被用作循环蛋白的工具变量。我们评估了蛋白质在MR分析中的效应方向的一致性（95%置信区间不与无效值重叠），并从基因共定位中获得了确证证据。在正向MR中，994种（SomaLogic）和1570种（Olink）蛋白质是可作为工具变量的。在deCODE和UKB中都对440种蛋白质进行了分析；其中302种（69%）在正向MR中显示出一致的效应方向。七种蛋白质在两个正向MR分析中的95%置信区间（CIs）都不与无效值重叠，并且在反向方向上没有效应的证据：皮肤桥蛋白（DPT）、β-晶状体蛋白B1（CRYBB1）、白细胞介素-18结合蛋白（IL18BP）和血管内皮生长因子受体2（KDR）水平较高，以及气味结合蛋白2b（OBP2B）、谷氨酸-半胱氨酸连接酶调节亚基（GCLM）和γ-晶状体蛋白D（CRYGD）水平较低与MM风险增加有关。基因共定位的证据未达到我们对于这些蛋白质与MM风险之间共享因果信号的阈值（h4 < 0.8）。我们的结果突出了七种可能与MM风险相关的循环蛋白。尽管基因共定位的证据表明这些关联可能对水平多效性的影响不稳健，但这些蛋白质可能是MM风险的有用标志物。未来的工作应该利用MM患者或前驱疾病患者的蛋白质组学数据，探索这些蛋白质在疾病预测或预防中的效用。
