背景:免疫球蛋白A肾病(IgAN)是一种自身免疫性疾病,其特征是产生半乳糖缺陷型IgA1(Gd‑IgA1)并在肾脏中沉积免疫复合物。探索IgAN中免疫失调的景观对于发病机理和疾病治疗具有重要意义。我们进行了孟德尔随机化(MR)来评估炎症和IgAN之间的因果关系。
方法:基于可用的遗传数据集,我们使用双样本MR研究了炎症与IgAN风险之间的潜在因果关系.我们使用全基因组关联研究(GWAS)汇总统计5个典型的炎症标志物,41种炎性细胞因子,和731个免疫细胞特征,从公共GWAS目录访问。用于MR分析的主要方法是逆方差加权(IVW)。为了确认结果的一致性,还进行了四种补充MR方法:MR-Egger,加权中位数,加权模式,和简单的模式。为了评估多效性,我们使用了MR-Egger回归截距检验和孟德尔随机偏导和离群值(MR-PRESSO)检验.应用Cochrane的Q统计量来评估异质性。此外,通过留一法敏感性分析验证了MR结果的稳定性.
结果:这项研究表明,根据IVW方法,白细胞介素-7(IL-7)和干细胞生长因子β(SCGF-β)可能与IgAN的风险有关,估计比值比(OR)为1.059(95%置信区间[CI]1.015至1.104,P=0.008)和1.043(95%CI1.002至1.085,P=0.037)。五个免疫特征被确定可能与IgAN风险有关,每个P值低于0.01,包括自然杀伤T%T细胞(OR=1.058,95%CI:1.020至1.097,P=0.002),自然杀伤T%淋巴细胞(OR=1.055,95%CI:1.016至1.096,P=0.006),CD25+CD8+T细胞%T细胞(OR=1.057,95%CI:1.016~1.099,P=0.006),CD3对效应记忆性CD4+T细胞的影响(OR=1.045,95%CI:1.019~1.071,P=0.001),CD28+CD45RA+CD8+T细胞上的CD3(OR=1.042,95%CI:1.016~1.068,P=0.001)。中枢记忆CD4+T细胞上的CD4可能是IgAN的保护因子(OR=0.922,95%CI:0.875~0.971,P=0.002)。此外,IgAN可能与粒细胞集落刺激因子(G-CSF)升高的高风险有关(OR=1.114,95%CI1.002至1.239,P=0.046)。
结论:我们的研究揭示了典型炎症标志物的暴露,炎性细胞因子,以及通过MR分析可能与IgAN风险相关的免疫细胞特征。这种见解可能会促进我们对IgAN病因的理解,并支持靶向治疗策略的发展。
BACKGROUND: Immunoglobulin A nephropathy (IgAN) is an autoimmune disease characterized by the production of galactose‑deficient IgA1 (Gd‑IgA1) and the deposition of immune complexes in the kidney. Exploring the landscape of immune dysregulation in IgAN is valuable for pathogenesis and disease treatment. We conducted Mendelian randomization (MR) to assess the causal correlations between inflammation and IgAN.
METHODS: Based on available genetic datasets, we investigated potential causal links between inflammation and the risk of IgAN using two-sample MR. We used genome-wide association study (GWAS) summary statistics of 5 typical inflammation markers, 41 inflammatory cytokines, and 731 immune cell signatures, accessed from the public GWAS Catalog. The primary method employed for MR analysis was Inverse Variance Weighted (IVW). To confirm consistency across results, four supplementary MR methods were also conducted: MR-Egger, Weighted Median, Weighted Mode, and Simple Mode. To assess pleiotropy, we used the MR-Egger regression intercept test and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. Cochrane\'s Q statistic was applied to evaluate heterogeneity. Additionally, the stability of the MR findings was verified through the leave-one-out sensitivity analysis.
RESULTS: This study revealed that interleukin-7 (IL-7) and stem cell growth factor beta (SCGF-β) were possibly associated with the risk of IgAN according to the IVW approach, with estimated odds ratios (OR) of 1.059 (95 % confidence interval [CI] 1.015 to 1.104, P = 0.008) and 1.043 (95 % CI 1.002 to 1.085, P = 0.037). Five immune traits were identified that might be linked to IgAN risk, each with P-values below 0.01, including natural killer T %T cell (OR = 1.058, 95 % CI: 1.020 to 1.097, P = 0.002), natural killer T %lymphocyte (OR = 1.055, 95 % CI: 1.016 to 1.096, P = 0.006), CD25++ CD8+ T cell %T cell (OR = 1.057, 95 % CI: 1.016 to 1.099, P = 0.006), CD3 on effector memory CD4+ T cell (OR = 1.045, 95 % CI: 1.019 to 1.071, P = 0.001), and CD3 on CD28+ CD45RA+ CD8+ T cell (OR = 1.042, 95 % CI: 1.016 to 1.068, P = 0.001). CD4 on central memory CD4+ T cell might be a protective factor for IgAN (OR = 0.922, 95 % CI: 0.875 to 0.971, P = 0.002). Moreover, IgAN may be implicated in a high risk of elevated granulocyte colony-stimulating factor (G-CSF) (OR = 1.114, 95 % CI 1.002 to 1.239, P = 0.046).
CONCLUSIONS: Our study revealed exposures among typical inflammation markers, inflammatory cytokines, and immune cell signatures that may potentially linked to IgAN risk by MR analysis. This insight may advance our understanding of the etiology of IgAN and support the development of targeted therapeutic strategies.