Immune cells mediate the effect of plasma lipidomes on IgA nephropathy: a Mendelian randomization study

IgA nephropathy (IgAN) is a leading cause of chronic kidney disease, often associated with dyslipidemia and immune dysfunction. This study employs Mendelian randomization (MR) to investigate the causal relationship between plasma lipidomes and IgAN, with a focus on the potential mediating role of immune cells. We analyzed the 179 genetically predicted plasma lipidomes and the IgAN gene using two-sample Mendelian randomization (TSMR) and multivariable MR based on summary-level data from a genome-wide association study, and the results were validated by liquid chromatography-mass spectrometry. Furthermore, we quantified the proportional effect of immune cell-mediated lipidomes on IgAN using TSMR. This study identified significant causal relationships of 3 lipidomes on IgAN risk by examining 179 lipidome traits as exposures. To investigate whether the impact of the 3 lipid groups on IgAN is specific, we performed TSMR analyses using 3 lipidomes as exposure factors and 4 nephritides as outcomes. Specifically, only phosphatidylinositol (18:1_20:4) was found to have a significant negative relationship with IgAN incidence (IVW method, <i>p</i> = 0.01, OR = 0.71, 95% CI = 0.55 - 0.92). Our further analysis focused on 8 immune cells associated with IgAN. We identified 2 immune cell phenotypes that may contribute to phosphatidylinositol (18:1_20:4)-mediated IgAN by careful screening. Our findings provide robust genetic evidence supporting a causal link between plasma lipidomes and IgAN, with immune cells acting as potential mediators. Phosphatidylinositol (18:1_20:4) emerges as a promising biomarker for IgAN risk stratification, early detection, and therapeutic intervention. Modulating its plasma levels may offer novel avenues for IgAN management.

IgA肾病（IgAN）是慢性肾脏病的主要病因之一，常与血脂异常及免疫功能障碍相关。本研究采用孟德尔随机化（MR）方法探究血浆脂质组与IgAN之间的因果关联，重点关注免疫细胞的潜在中介作用。基于全基因组关联研究（genome-wide association study）的汇总水平数据，我们对179个遗传预测的血浆脂质组与IgAN相关基因进行分析，采用两样本孟德尔随机化（TSMR）及多变量MR方法，结果经液相色谱-质谱联用技术（liquid chromatography-mass spectrometry）验证。此外，我们通过TSMR量化了免疫细胞介导的脂质组对IgAN的比例效应。本研究以179个脂质组特征为暴露因素开展分析，发现其中3个脂质组与IgAN风险存在显著因果关联。为探究这3个脂质组对IgAN的影响是否具有特异性，我们以其为暴露因素、4种肾炎为结局指标进行TSMR分析。具体而言，仅磷脂酰肌醇（18:1_20:4）与IgAN发病率呈显著负相关（IVW法，p=0.01，OR=0.71，95%置信区间（CI）=0.55-0.92）。我们进一步针对8种与IgAN相关的免疫细胞开展分析，通过精细筛选发现2种免疫细胞表型可能参与磷脂酰肌醇（18:1_20:4）介导的IgAN发病过程。本研究结果为血浆脂质组与IgAN之间的因果关联提供了可靠的遗传学证据，且免疫细胞可能发挥中介作用。磷脂酰肌醇（18:1_20:4）有望成为IgAN风险分层、早期诊断及治疗干预的潜在生物标志物（biomarker）。调节其血浆水平或可为IgAN的临床管理提供新方向。