Renal Division, Department of Medicine, Peking University First Hospital, No.8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, China.
Institute of Nephrology, Peking University, Beijing, China.
Mol Genet Genomics. 2021 Jul;296(4):1017-1026. doi: 10.1007/s00438-021-01798-7. Epub 2021 Jun 2.
An autoimmune component has been suggested to play a role in pathogenesis of IgA nephropathy (IgAN). And genetic studies have reported the shared susceptibility loci between IgAN and the prototype autoimmune disease systemic lupus erythematosus (SLE). This study was designed to systemically identify and annotate the shared susceptibility genes between IgAN and SLE. We first conducted an imputation-based genome-wide association analysis in 1180 IgAN cases and 899 controls, 1639 SLE cases and 2410 controls. Then we integrated blood expression quantitative trait loci (eQTL) databases and gene expression data to prioritize the potentially functional genes. The results showed that a total of 1928 SNPs mapping to 14 loci were identified to be shared genes between IgAN and SLE. Conditional analysis prioritized 18 independent SNPs, among which alleles of 4 SNPs in HLA and 7 SNPs in non-HLA loci were risk for SLE were protective alleles for IgAN. Most of the shared SNPs and their proxies (r ≥ 0.8 in Asians) (181/184, 98.37%) in non-HLA loci were located in non-coding regions. By analyzing two publicly independent blood-eQTL databases, four genes UBE2L3, FCGR2B, ANXA6, and BLK, which seemed to be restricted to PBMC or its subsets were prioritized. Among them only UBE2L3 showed consistent direction between SLE and IgAN, while the others showed opposite directions. Differential gene analysis showed that UBE2L3 was highly expressed in both SLE and IgAN, while FCGR2B and BLK showed marginal significance in SLE and IgAN, respectively. By exploring the pleiotropy of shared genes between IgAN and SLE, our results provide important clues for understanding the shared role of plasmablasts but the distinct role of B cells in pathogenesis of these two diseases.
自身免疫成分被认为在 IgA 肾病（IgAN）的发病机制中起作用。遗传研究报告了 IgAN 与原型自身免疫性疾病系统性红斑狼疮（SLE）之间的共同易感基因座。本研究旨在系统地鉴定和注释 IgAN 和 SLE 之间的共同易感基因。我们首先在 1180 例 IgAN 病例和 899 例对照、1639 例 SLE 病例和 2410 例对照中进行了基于 imputation 的全基因组关联分析。然后，我们整合了血液表达数量性状基因座（eQTL）数据库和基因表达数据，以优先考虑潜在的功能基因。结果表明，共鉴定出 1928 个 SNP 映射到 14 个基因座，这些 SNP 是 IgAN 和 SLE 之间的共同基因。条件分析优先考虑了 18 个独立的 SNP，其中 HLA 中的 4 个 SNP 和非 HLA 基因座中的 7 个 SNP 的等位基因是 SLE 的风险等位基因，而 IgAN 的等位基因为保护性等位基因。大多数非 HLA 基因座中的共享 SNP 及其近因（在亚洲人中 r≥0.8）（181/184，98.37%）位于非编码区。通过分析两个公开的独立血液-eQTL 数据库，优先考虑了四个似乎局限于 PBMC 或其亚群的基因 UBE2L3、FCGR2B、ANXA6 和 BLK。其中只有 UBE2L3 在 SLE 和 IgAN 之间表现出一致的方向，而其他基因则表现出相反的方向。差异基因分析表明，UBE2L3 在 SLE 和 IgAN 中均高度表达，而 FCGR2B 和 BLK 分别在 SLE 和 IgAN 中均有边缘意义。通过探索 IgAN 和 SLE 之间共享基因的多效性，我们的结果为理解浆母细胞在这两种疾病发病机制中的共同作用以及 B 细胞的独特作用提供了重要线索。
