91种炎症蛋白水平与急性髓系白血病发病风险相关的孟德尔随机化研究

doi:10.16150/j.1671-2870.2024.05.007

摘要/Abstract

摘要：

目的：分析循环炎症蛋白与急性髓系白血病（acute myeloid leukemia，AML）发生风险间的相关性。方法：从FinnGen联盟获取AML数据，以91种循环炎症蛋白的全基因组关联研究（Genome-Wide Association Studies，GWAS）数据作为暴露因素，使用孟德尔随机化（Mendelian randomization，MR）分析评估91种循环炎症蛋白对AML发生风险的影响。采用逆方差加权法（Inverse Variance Weighted，IVW）作为主要分析方法，用MR-Egger和加权中位数（Weighted Median，WM）方法进一步强化结果。此外，用敏感性分析评估结果的稳定性和可靠性。结果：91种循环炎症蛋白中有8种与AML的发生有因果关联（P<0.05）。其中，神经鞘胚素（artemin，ARTN）(OR=0.458 3，95%CI为0.219 0~0.959 1)、白细胞介素（interleukin, IL）-2受体β(OR=0.2347，95%CI为0.094 1~0.585 3)、沉默蛋白2（sirtuin-2，SIRT2）(OR=0.310 4，95%CI为0.138 0~0.698 2)、信号转导接头分子结合蛋白（signal-transducing adaptor mo-lecule binding protein，STAMPB） (OR=0.289 0，95%CI为0.104 9~0.796 1)水平升高与AML发生风险降低相关；而CD6(OR=3.269 3，95%CI为1.285 3~8.315 9)、趋化因子配体5（C-X-C motif chemokine ligand 5，CXCL5）(OR=1.694 6，95%CI为1.013 4~2.833 6)、IL-15受体α (OR=1.572 9，95%CI为1.050 0~2.344 8)、基质金属蛋白酶（matrix metalloproteinase，MMP）-10(OR=1.882 0，95%CI为1.061 4~3.337 1)水平升高与AML发生风险升高相关。使用Cochran’s Q检验（P>0.05）和MR-Egger回归检验（P>0.05）进行敏感性分析，结果显示炎症蛋白的单核苷酸多态性（singlenucleotide polymorphisms，SNP)之间没有异质性和多效性。结论：基于MR研究提示，循环炎症蛋白ARTN、IL-2RB、SIRT2和STAMPB水平与AML发生风险呈负相关，CD6、CXCL5、IL-15RA和MMP-10水平与AML发生风险呈正相关，为今后AML的病理机制研究提供一定的参考信息。

关键词: 急性髓系白血病, 孟德尔随机化分析, 全基因组关联研究, 细胞免疫治疗

Abstract:

Objective The study aims to analyze the correlation between circulating inflammatory proteins and the risk of acute myeloid leukemia (AML). Methods AML data were obtained from the FinnGen alliance as the outcome. The Genome-wide Association Studies (GWAS) data of 91 circulating inflammatory proteins were used as exposure factors. Mendelian randomization (MR) analysis was conducted to evaluate the effects of 91 circulating inflammatory proteins on the risk of AML. Inverse Variance Weighted (IVW) was used as the main analysis method, and the MR-Egger and Weighted Median (WM) methods were used to further strengthen the results. In addition, sensitivity analysis was used to evaluate the stability and reliability of the results. Results Among the 91 circulating inflammatory proteins, 8 were causally associated with the occurrence of AML (P<0.05). Specifically, higher levels of artemin (ARTN) (OR=0.458 3, 95% CI: 0.219 0-0.959 1), interleukin (IL)-2 receptor β (OR=0.2347, 95% CI: 0.094 1-0.585 3), sirtuin-2 (SIRT2) (OR=0.310 4, 95%CI: 0.138 0-0.698 2), and signal-transducing adaptor molecule binding protein (STAMPB) (OR=0.289 0, 95% CI: 0.104 9-0.796 1) were associated with a reduced risk of AML. In contrast, higher levels of CD6 (OR=3.269 3, 95% CI: 1.285 3-8.315 9), C-X-C motif chemokine ligand 5 (CXCL5) (OR=1.694 6, 95% CI: 1.013 4-2.833 6), IL-15 receptor α (OR=1.572 9, 95% CI: 1.050 0-2.344 8), and matrix metalloproteinase (MMP)-10 (OR=1.882 0, 95% CI: 1.061 4-3.337 1) were associated with an increased risk of AML. Sensitivity analysis using Cochran’s Q test (P>0.05) and MR-Egger regression test (P>0.05) showed no heterogeneity or pleiotropy in the single nucleotide polymorphisms (SNPs) of inflammatory proteins. Conclusions The Mendelian randomization study suggests that circulating inflammatory proteins ARTN, IL-2β, SIRT2, STAMPB, CD6, CXCL-5, IL-15α, and MMP-10 are causally associated with the risk of AML, which provides valuable insights for future research on the pathological mechanism of AML.

Key words: Acute myeloid leukemia, Mendelian randomization analysis, Genome-wide association study, Cellular immunotherapy

中图分类号:

安慧慧, 吴涛, 刘文慧, 田思锐. 91种炎症蛋白水平与急性髓系白血病发病风险相关的孟德尔随机化研究[J]. 诊断学理论与实践, 2024, 23(05): 509-516.

AN Huihui, WU Tao, LIU Wenhui, TIAN Sirui. A Mendelian randomized study on the correlation between 91 inflammatory protein levels and the risk of acute myeloid leukemia[J]. Journal of Diagnostics Concepts & Practice, 2024, 23(05): 509-516.

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Exposure	Outcomes	SNPs	IVW			MR-Egger			Weighted median
Exposure	Outcomes	SNPs	SE	OR (95%CI)	P	SE	OR (95%CI)	P	SE	OR (95%CI)	P
ARTN	AML	14	0.3768	0.4583（0.2190-0.9591）	0.0384	0.8732	0.3252（0.0587-1.8007）	0.2226	0.5050	0.3688（0.1371-0.9922）	0.0482
CD6	AML	6	0.4763	3.2693(1.2853-8.3159)	0.0129	1.7673	2.4846(0.0778-79.3565)	0.6337	0.5444	3.1903(1.0975-9.2740)	0.0331
CXCL5	AML	11	0.2623	1.6946(1.0134-2.8336)	0.0443	0.3990	1.5728(0.7196-3.4377)	0.2857	0.2694	1.7337(1.0224-2.9397)	0.0411
IL-15RA	AML	9	0.2037	1.5729(1.0550-2.3448)	0.0262	0.3623	0.8618(0.4237-1.7531)	0.6937	0.2276	1.4059(0.9000-2.1962)	0.1344
IL-2RB	AML	11	0.4662	0.2347(0.0941-0.5853)	0.0019	0.9384	0.5465(0.0869-3.4385)	0.5357	0.6405	0.3298(0.0940-1.1573)	0.0833
MMP-10	AML	11	0.2922	1.8820(1.0614-3.3371)	0.0305	0.4725	1.6175(0.6407-4.0836)	0.3354	0.3657	1.7830(0.8707-3.6512)	0.1138
SIRT2	AML	11	0.4136	0.3104(0.1380-0.6982)	0.0047	0.8396	0.1697(0.0327-0.8798)	0.0638	0.5670	0.2611(0.0859-0.7935)	0.0179
STAMPB	AML	10	0.5171	0.2890(0.1049-0.7961)	0.0164	1.5349	0.2560(0.0126-5.1855)	0.4006	0.7170	0.2570(0.0630-1.0477)	0.0581

exposure	Outcomes	SNPs	Cochran’s Q test		MR-Egger intercept		MR-Presso
exposure	Outcomes	SNPs	IVW	MR Egger	Egger intercept	P	Global Test RSSobs	P
ARTN	AML	14	10.7366	10.5471	0.0349	0.6711	12.2728	0.6667
CD6	AML	6	1.4264	1.4004	0.0242	0.8797	0.9447	0.9447
CXCL5	AML	11	12.5723	12.4797	0.0170	0.8019	13.4745	0.4093
IL-15RA	AML	9	7.0478	3.0151	0.1516	0.0846	16.1052	0.4327
IL-2RB	AML	11	7.7765	6.6991	-0.1012	0.3264	9.3245	0.6887
MMP-10	AML	11	10.1907	9.9951	0.0315	0.6845	11.2204	0.5253
SIRT2	AML	11	10.4870	9.7401	0.0838	0.4276	12.7845	0.4190
STAMPB	AML	10	8.5948	8.5872	0.0148	0.9350	10.8371	0.4917