Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Key Laboratory of Respiratory Diseases, National Health Commission of China, Wuhan, China.
Front Immunol. 2024 Aug 16;15:1371662. doi: 10.3389/fimmu.2024.1371662. eCollection 2024.
The relationship between peripheral immune cells and immunoglobulin A nephropathy (IgAN) is widely known; however, causal evidence of this link is lacking. Here, we aimed to determine the causal effect of peripheral immune cells, specifically total white blood cells, lymphocytes, monocytes, basophils, eosinophils, and neutrophils, as well as lymphocyte subset traits, on the IgAN risk using a Mendelian randomization (MR) analysis.
The inverse-variance weighted (IVW) method was used for the primary analysis. We applied three complementary methods, including the weighted median, MR-Egger regression, and MR-PRESSO, to detect and correct for the effect of horizontal pleiotropy. Additionally, we performed a multivariable MR (MVMR) analysis, adjusting for the effects of C-reactive protein (CRP) levels. The roles of specific lymphocyte subtypes and their significance have garnered interest. Bidirectional two-sample MR analysis was performed to test the potential causal relationships between immune traits, including median fluorescence intensities (MFIs) and the relative cell count (AC), and IgAN.
The IVW-MR analysis suggested a potential causal relationship between lymphocyte counts and IgAN in Europe (OR per 1-SD increase: 1.43, 95% CI: 1.08-1.88, = 0.0123). The risk effect of lymphocytes remained even after adjusting for CRP levels using the MVMR method (OR per 1-SD increase: 1.44, 95% CI: 1.05-1.96, = 0.0210). The other sensitivity analyses showed a consistent trend. The largest GWAS published to date was used for peripheral blood immunophenotyping to explore the potential causal relationship between peripheral immune cell subsets and IgAN. Six AC-IgAN and 14 MFI-IgAN pairs that reached statistical significance ( < 0.05) were detected. Notably, CD3, expressed in eight subsets of T cells, consistently showed a positive correlation with IgAN. The bidirectional MR analysis did not reveal any evidence of reverse causality. According to the sensitivity analysis, horizontal pleiotropy was unlikely to distort the causal estimates.
Genetically determined high lymphocyte counts were associated with IgAN, supporting that high lymphocyte counts is causal risk factor for IgAN.
外周免疫细胞与 IgA 肾病（IgAN）之间的关系已广为人知，但缺乏这种关联的因果证据。在这里，我们旨在使用孟德尔随机化（MR）分析来确定外周免疫细胞（尤其是总白细胞、淋巴细胞、单核细胞、嗜碱性粒细胞、嗜酸性粒细胞和中性粒细胞）以及淋巴细胞亚群特征对 IgAN 风险的因果影响。
主要分析采用逆方差加权（IVW）法。我们应用了三种互补方法，包括加权中位数、MR-Egger 回归和 MR-PRESSO，以检测和纠正水平多效性的影响。此外，我们进行了多变量 MR（MVMR）分析，调整了 C 反应蛋白（CRP）水平的影响。特定淋巴细胞亚群的作用及其意义引起了关注。进行了双向两样本 MR 分析，以测试免疫特征（包括中荧光强度（MFI）和相对细胞计数（AC））与 IgAN 之间潜在的因果关系。
IVW-MR 分析表明，在欧洲，淋巴细胞计数与 IgAN 之间存在潜在的因果关系（每增加 1-SD：1.43，95%CI：1.08-1.88， = 0.0123）。使用 MVMR 方法调整 CRP 水平后，淋巴细胞的风险效应仍然存在（每增加 1-SD：1.44，95%CI：1.05-1.96， = 0.0210）。其他敏感性分析显示出一致的趋势。使用迄今为止发表的最大 GWAS 进行外周血免疫表型分析，以探索外周免疫细胞亚群与 IgAN 之间潜在的因果关系。检测到六个 AC-IgAN 和 14 个 MFI-IgAN 对达到统计学意义（<0.05）。值得注意的是，表达在八个 T 细胞亚群中的 CD3 与 IgAN 呈一致的正相关。双向 MR 分析没有发现任何反向因果关系的证据。根据敏感性分析，水平多效性不太可能扭曲因果估计。
遗传决定的高淋巴细胞计数与 IgAN 相关，支持高淋巴细胞计数是 IgAN 的因果危险因素。
