循环炎性细胞因子与冠状动脉粥样硬化的因果关系:双向孟德尔随机化研究OA
Causal relationship between circulating inflammatory cytokines and coronary atherosclerosis:a bidirectional Mendelian randomization study
目的 采用双向孟德尔随机化(MR)分析探讨循环炎性细胞因子与冠状动脉粥样硬化之间的因果关系.方法 炎性细胞因子数据来源于GWAS Catalog数据库中的欧洲人群全基因组蛋白质定量性状位点(pQTL)研究(n=14 824),冠状动脉粥样硬化数据来源于芬兰基因(FinnGen)联盟(n=434 704).采用逆方差加权法(IVW)、共定位分析和反向MR分析,结合MR-Egger和加权中位数等多种分析方法,全面评估炎性细胞因子与冠状动脉粥样硬化之间的双向因果关系.结果 白细胞介素-17C(IL-17C,OR=1.062,95%CI 1.002～1.126,P=0.044)、白细胞介素-22受体亚基A1(IL-22RA1,OR=1.115,95%CI 1.004～1.239,P=0.042)及基质金属蛋白酶-1(MMP-1,OR=1.071,95%CI 1.000～1.147,P=0.049)水平升高与冠状动脉粥样硬化风险增加相关;而可溶性CD40L(sCD40L,OR=0.967,95%CI 0.937～0.998,P=0.036)、白细胞介素-24(IL-24,OR=0.912,95%CI 0.832～0.999,P=0.048)及尿激酶型纤溶酶原激活剂(uPA,OR=0.934,95%CI 0.874～0.999,P=0.045)水平升高则与冠状动脉粥样硬化风险降低相关.此外,冠状动脉粥样硬化的发生与血管内皮生长因子-A(VEGF-A,OR=0.946,95%CI 0.899～0.996,P=0.036)、巨噬细胞集落刺激因子-1(CSF-1,OR=0.948,95%CI 0.902～0.996,P=0.033)、T细胞表面糖蛋白CD5(OR=0.918,95%CI 0.872～0.966,P=0.001)及嗜酸性粒细胞趋化因子(CCL11,OR=0.952,95%CI 0.908～0.988,P=0.040)水平降低相关.结论 IL-17C、IL-22RA1、MMP-1水平升高可增加冠状动脉粥样硬化风险,而sCD40L、IL-24、uPA水平升高则可降低冠状动脉粥样硬化风险.冠状动脉粥样硬化本身也会降低CCL11、CD5、CSF-1和VEGF-A的水平.
Objective To explore the causal relationship between circulating inflammatory cytokines and coronary atherosclerosis through bidirectional Mendelian randomization(MR)analysis.Methods The inflammatory cytokine data were sourced from the European population genome-wide protein quantitative trait locus(pQTL)study in the GWAS Catalog database(n=14 824),and the coronary atherosclerosis data were obtained from the FinnGen consortium(n=434 704).Methods including inverse variance weighted(IVW),colocalization analysis,and reverse MR analysis were employed,complemented by MR-Egger and weighted median methods,to comprehensively assess the bidirectional causal relationship between inflammatory cytokines and coronary atherosclerosis.Results Higher levels of interleukin-17C(IL-17C)(OR=1.062,95%CI 1.002-1.126,P=0.044),interleukin-22 receptor subunit A1(IL-22RA1)(OR=1.115,95%CI 1.004-1.239,P=0.042),and matrix metalloproteinase-1(MMP-1)(OR=1.071,95%CI 1.000-1.147,P=0.049)were associated with an increased risk of coronary atherosclerosis.Conversely,higher levels of soluble CD40L(sCD40L)(OR=0.967,95%CI 0.937-0.998,P=0.036),interleukin-24(IL-24)(OR=0.912,95%CI 0.832-0.999,P=0.048),and urokinase-type plasminogen activator(uPA)(OR=0.934,95%CI 0.874-0.999,P=0.045)were associated with a reduced risk of coronary atherosclerosis.Furthermore,the occurrence of coronary atherosclerosis was associated with lower levels of vascular endothelial growth factor-A(VEGF-A)(OR=0.946,95%CI 0.899-0.996,P=0.036),macrophage colony-stimulating factor-1(CSF-1)(OR=0.948,95%CI 0.902-0.996,P=0.033),T-cell surface glycoprotein CD5(OR=0.918,95%CI 0.872-0.966,P=0.001),and eosinophil chemotactic factor(CCL11)(OR=0.952,95%CI 0.908-0.988,P=0.040).Conclusions Elevated levels of IL-17C,IL-22RA1,and MMP-1 are associated with an increased risk of coronary atherosclerosis,whereas elevated levels of sCD40L,IL-24,and uPA are associated with a reduced risk.Moreover,coronary atherosclerosis itself can lower the levels of VEGF-A,CSF-1,CD5,and CCL11.
闫浩杰;史树锦;韩帆;宿俊杰;徐帅;衣慧;岳帅;张然
解放军总医院第六医学中心心血管病医学部,北京 100853||解放军医学院研究生院,北京 100853解放军总医院第六医学中心心血管病医学部,北京 100853||解放军医学院研究生院,北京 100853解放军总医院第六医学中心心血管病医学部,北京 100853||解放军医学院研究生院,北京 100853解放军总医院第六医学中心心血管病医学部,北京 100853||解放军医学院研究生院,北京 100853解放军总医院第六医学中心心血管病医学部,北京 100853||解放军医学院研究生院,北京 100853解放军总医院第六医学中心心血管病医学部,北京 100853||解放军医学院研究生院,北京 100853||解放军总医院第七医学中心儿科医学部小儿心脏内科,北京 100700解放军总医院第六医学中心心血管病医学部,北京 100853||解放军医学院研究生院,北京 100853解放军总医院第六医学中心心血管病医学部,北京 100853||解放军医学院研究生院,北京 100853
医药卫生
炎症细胞因子冠状动脉粥样硬化孟德尔随机化
inflammationcirculating inflammatory cytokinescoronary atherosclerosisMendelian randomization
《解放军医学杂志》 2026 (2)
155-163,9
This work was supported by the National Key Research and Development Program of China(2021YFC2701700,2021YFC2701703),and the National Natural Science Foundation of China(82171857) 国家重点研发计划(2021YFC2701700,2021YFC2701703)国家自然科学基金(82171857)
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