目的:在骨髓增殖性肿瘤(MPN)的发病机制中,炎症起着重要作用。然而,目前尚不清楚炎症与MPN之间是否存在因果关系.我们使用了双向的,双样本孟德尔随机化(MR)方法研究全身性炎性细胞因子与骨髓增殖性肿瘤之间的因果关系。
方法:对8293名欧洲参与者进行的全基因组关联研究(GWAS)确定了循环细胞因子和生长因子的遗传工具变量。MPN的汇总统计数据来自GWAS,包括1086例欧洲血统的病例和407,155例对照。逆方差加权方法主要用于计算比值比(OR)和95%置信区间(Cl)。
结果:我们的结果表明,较高的白细胞介素-2受体,α亚基(IL-2rα)水平,和较高的干扰素γ诱导蛋白10(IP-10)水平与MPN的风险增加有关(OR=1.36,95CI=1.03-1.81,P=0.032;OR=1.5,95CI=1.09-2.22,P=0.015;分别)。此外,遗传预测MPN促进炎性细胞因子白细胞介素-10(IL-10)的表达(BETA=0.033,95%CI=0.003~0.064,P=0.032)和干扰素-γ(MIG)诱导的单核因子(BETA=0.052,95%CI=0.002~0.102,P=0.043),在激活时,正常T细胞表达和分泌RANTES(BETA=0.055,95%CI=0.0090.1,P=0.018)。
结论:我们的研究结果表明,细胞因子对MPN的病理生理学至关重要。如果这些生物标志物可用于预防和治疗MPN,则需要更多的研究。
OBJECTIVE: In the pathogenesis of myeloproliferative neoplasms (MPN), inflammation plays an important role. However, it is unclear whether there is a causal link between inflammation and MPNs. We used a bidirectional, two-sample Mendelian randomization (MR) approach to investigate the causal relationship between systemic inflammatory cytokines and myeloproliferative neoplasms.
METHODS: A genome-wide association
study (GWAS) of 8293 European participants identified genetic instrumental variables for circulating cytokines and growth factors. Summary statistics of MPN were obtained from a GWAS including 1086 cases and 407,155 controls of European ancestry. The inverse-variance-weighted method was mainly used to compute odds ratios (OR) and 95% confidence intervals (Cl).
RESULTS: Our results showed that higher Interleukin-2 receptor, alpha subunit (IL-2rα) levels, and higher Interferon gamma-induced protein 10 (IP-10) levels were associated with an increased risk of MPN (OR = 1.36,95%CI = 1.03-1.81, P = 0.032; OR = 1.55,95%CI = 1.09-2.22, P = 0.015; respectively).In addition, Genetically predicted MPN promotes expression of the inflammatory cytokines interleukin-10 (IL-10) (BETA = 0.033, 95% CI = 0.003 ~ 0.064, P = 0.032) and monokine induced by interferon-gamma (MIG) (BETA = 0.052, 95% CI = 0.002-0.102, P = 0.043) and, on activation, normal T cells express and secrete RANTES (BETA = 0.055, 95% CI = 0.0090.1, P = 0.018).
CONCLUSIONS: Our findings suggest that cytokines are essential to the pathophysiology of MPN. More research is required if these biomarkers can be used to prevent and treat MPN.