基于全基因组关联研究的 SNP 和基因方法，鉴定汉族人群狼疮肾炎易感性候选基因。

Genome-wide association study of SNP- and gene-based approaches to identify susceptibility candidates for lupus nephritis in the Han Chinese population.

机构信息

Department of Nephrology, The First Medical Centre, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China.

Institute of Dermatology and Department of Dermatology at No.1 Hospital, Anhui Medical University, Hefei, China.

出版信息

Front Immunol. 2022 Oct 3;13:908851. doi: 10.3389/fimmu.2022.908851. eCollection 2022.

DOI:10.3389/fimmu.2022.908851

PMID:36275661

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9580327/

Abstract

BACKGROUND

Lupus nephritis (LN) is one of the most common and serious complications of systemic lupus erythaematosus (SLE). Genetic factors play important roles in the pathogenesis of LN and could be used to predict who might develop LN. The purpose of this study was to screen for susceptible candidates of LN across the whole genome in the Han Chinese population.

METHODS

592 LN patients and 453 SLE patients without renal damage were genotyped at 492,970 single nucleotide polymorphisms (SNPs) in the genome-wide association study (GWAS). Fifty-six SNPs were selected for replication in an independent cohort of 188 LN and 171 SLE without LN patients. Further quantitative real-time (qRT) PCR was carried out in 6 LN patients and 6 healthy controls. Gene-based analysis was conducted using the versatile gene-based test for GWAS. Subsequently, enrichment and pathway analyses were performed in the DAVID database.

RESULTS

The GWAS analysis and the following replication research identified 9 SNPs showing suggestive correlation with LN (<10). The most significant SNP was rs12606116 (18p11.32), at =8.72×10. The qRT-PCR results verified the mRNA levels of LINC00470 and ADCYAP1, the closest genes to rs12606116, were significantly lower in LN patients. From the gene-based analysis, 690 genes had suggestive evidence of association (<0.05), including LINC00470. The enrichment analysis identified the involvement of transforming growth factor beta (TGF-β) signalings in the development of LN. Lower plasma level of TGF-β1 (<0.05) in LN patients and lower expression of transforming growth factor beta receptor 2 in lupus mice kidney (<0.05) futher indicate the involvement of TGF-β in LN.

CONCLUSIONS

Our analyses identified several promising susceptibility candidates involved in LN, and further verification of these candidates was necessary.

摘要

背景

狼疮肾炎（LN）是系统性红斑狼疮（SLE）最常见和最严重的并发症之一。遗传因素在 LN 的发病机制中起着重要作用，并可用于预测哪些人可能发展为 LN。本研究旨在筛选汉族人群中全基因组范围内的 LN 易感候选者。

方法

在全基因组关联研究（GWAS）中，对 592 例 LN 患者和 453 例无肾损害的 SLE 患者进行了 492970 个单核苷酸多态性（SNP）的基因分型。选择 56 个 SNP 在 188 例 LN 和 171 例无 LN 的 SLE 患者的独立队列中进行复制。进一步对 6 例 LN 患者和 6 例健康对照进行实时定量（qRT）PCR。使用 GWAS 的通用基因检测进行基因检测分析。随后，在 DAVID 数据库中进行了富集和通路分析。

结果

GWAS 分析和随后的复制研究确定了 9 个与 LN 呈提示性相关性的 SNP（<10）。最显著的 SNP 是 rs12606116（18p11.32），=8.72×10。qRT-PCR 结果验证了与 rs12606116 最接近的基因 LINC00470 和 ADCYAP1 的 mRNA 水平在 LN 患者中显著降低。从基因检测分析中，有 690 个基因有提示性证据（<0.05），包括 LINC00470。富集分析确定了转化生长因子β（TGF-β）信号在 LN 发展中的参与。LN 患者血浆 TGF-β1 水平降低（<0.05），狼疮小鼠肾脏转化生长因子β受体 2 表达降低（<0.05），进一步表明 TGF-β 在 LN 中的参与。