Tang Wenhao, Li Qiu, Yang Xueying, Yang Haiping
Department of Nephrology Children's Hospital of Chongqing Medical University, Chongqing, China; National Clinical Research Center for Child Health and Disorders, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China.
Clin Kidney J. 2025 Feb 24;18(3):sfaf057. doi: 10.1093/ckj/sfaf057. eCollection 2025 Mar.
Primary glomerular diseases (PGDs), including nephrotic syndrome (NS), membranous nephropathy (MN), and IgA nephropathy (IgAN), are complex renal conditions influenced by immune system dysregulation. Although associations between immune cell phenotypes and PGDs have been observed, the precise causal relationships have not been fully elucidated.
Utilizing genetic association data from genome-wide association studies (GWASs), we investigated 731 immunophenotypes in relation to PGDs. A bidirectional two-sample Mendelian randomization (MR) approach, primarily employing inverse variance weighting (IVW), was conducted to establish causality. MR-Egger, weighted median, simple mode, and weighted mode were used as complementary methods to reinforce the robustness and validity of the results. Sensitivity analyses further validated the sensitivity and stability of our results.
We identified 38 immunophenotypes suggestively related to IgAN, with 20 as risk factors and 18 as protective effects. Six immunophenotypes remained significant after Bonferroni correction: The percentage of CD25hi among T cells; the percentage of CD25hi CD45RA CD4 not T regulatory (Treg) among T cells; the percentage of CD25hi CD45RA CD4 not Treg within the CD4 T cell population; CX3CR1 expression on monocytes; CD40 expression on monocytes; and CD64 expression on CD14 CD16 monocytes. In the validation analysis of IgAN, CD3 expression on effector memory CD4 T cells further confirmed the predisposing risk role of effector memory T cells in the development of IgAN. Additionally, the MR analysis demonstrated suggestive associations between 25 immunophenotypes and MN (8 risk factors and 17 protective factors), as well as between 22 immunophenotypes and NS (10 risk factors and 12 protective factors). Last, by intersecting the immunophenotypes showing suggestive associations with PGDs, we identified two common immunophenotypes shared by IgAN and MN, three by IgAN and NS, and one by MN and NS.
This genetic-level investigation uncovers causal associations between immunophenotypes and PGDs, providing valuable insights into the immunological underpinnings of PGDs. Our findings suggest potential targets for treatment strategies, thereby facilitating more personalized and effective therapeutic approaches in PGDs management.
原发性肾小球疾病（PGDs），包括肾病综合征（NS）、膜性肾病（MN）和IgA肾病（IgAN），是受免疫系统失调影响的复杂肾脏疾病。尽管已观察到免疫细胞表型与PGDs之间的关联，但确切的因果关系尚未完全阐明。
利用全基因组关联研究（GWASs）的遗传关联数据，我们研究了731种与PGDs相关的免疫表型。采用双向两样本孟德尔随机化（MR）方法，主要采用逆方差加权（IVW）来确定因果关系。MR-Egger、加权中位数、简单模式和加权模式用作补充方法，以加强结果的稳健性和有效性。敏感性分析进一步验证了我们结果的敏感性和稳定性。
我们确定了38种与IgAN可能相关的免疫表型，其中20种为危险因素，18种为保护因素。经Bonferroni校正后，六种免疫表型仍具有显著性：T细胞中CD25hi的百分比；T细胞中CD25hi CD45RA CD4非调节性T细胞（Treg）的百分比；CD4 T细胞群体中CD25hi CD45RA CD4非Treg的百分比；单核细胞上CX3CR1的表达；单核细胞上CD40的表达；以及CD14 CD16单核细胞上CD64的表达。在IgAN的验证分析中，效应记忆CD4 T细胞上的CD3表达进一步证实了效应记忆T细胞在IgAN发生发展中的易患风险作用。此外，MR分析表明25种免疫表型与MN之间存在可能的关联（8种危险因素和17种保护因素），以及22种免疫表型与NS之间存在可能的关联（10种危险因素和12种保护因素）。最后，通过交叉分析显示与PGDs存在可能关联的免疫表型，我们确定了IgAN和MN共有的两种常见免疫表型，IgAN和NS共有的三种，以及MN和NS共有的一种。
这项基因水平的研究揭示了免疫表型与PGDs之间的因果关联，为PGDs的免疫学基础提供了有价值的见解。我们的研究结果提示了治疗策略的潜在靶点，从而有助于在PGDs管理中采用更个性化和有效的治疗方法。
