Department of Genetics, Ribeirão Preto Medical School, USP, Ribeirão Preto, SP, Brazil.
Department of Medical Genetics, Faculty of Medical Sciences, UNICAMP, Campinas, SP, Brazil.
PLoS One. 2018 Nov 28;13(11):e0206683. doi: 10.1371/journal.pone.0206683. eCollection 2018.
Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic component and etiology characterized by chronic inflammation and autoantibody production. The purpose of this study was to ascertain copy number variation (CNV) in SLE using a case-control design in an admixed Brazilian population. The whole-genome detection of CNV was performed using Cytoscan HD array in SLE patients and healthy controls. The best CNV candidates were then evaluated by quantitative real-time PCR in a larger cohort or validated using droplet digital PCR. Logistic regression models adjusted for sex and ancestry covariates was applied to evaluate the association between CNV with SLE susceptibility. The data showed a synergistic effect between the FCGR3B and ADAM3A loci with the presence of deletions in both loci significantly increasing the risk to SLE (5.9-fold) compared to the deletion in the single FCGR3B locus (3.6-fold). In addition, duplications in these genes were indeed more frequent in healthy subjects, suggesting that high FCGR3B/ADAM3A gene copy numbers are protective factors against to disease development. Overall, 21 rare CNVs were identified in SLE patients using a four-step pipeline created for identification of rare variants. Furthermore, heterozygous deletions overlapping the CFHR4, CFHR5 and HLA-DPB2 genes were described for the first time in SLE patients. Here we present the first genome-wide CNV study of SLE patients in a tri-hybrid population. The results show that novel susceptibility loci to SLE can be found once the distribution of structural variants is analyzed throughout the whole genome.
系统性红斑狼疮（SLE）是一种具有强烈遗传成分和病因学特征的自身免疫性疾病，其特征为慢性炎症和自身抗体产生。本研究旨在采用混合巴西人群的病例对照设计，确定 SLE 中的拷贝数变异（CNV）。使用 Cytoscan HD 阵列在 SLE 患者和健康对照中进行全基因组 CNV 检测。然后，通过更大的队列进行定量实时 PCR 评估或使用液滴数字 PCR 进行验证，评估最佳 CNV 候选物。应用逻辑回归模型调整性别和祖源协变量，评估 CNV 与 SLE 易感性之间的关联。数据显示 FCGR3B 和 ADAM3A 基因座之间存在协同作用，两个基因座缺失均显著增加 SLE 风险（与单个 FCGR3B 基因座缺失相比增加 5.9 倍）。此外，这些基因的重复在健康受试者中确实更为频繁，这表明高 FCGR3B/ADAM3A 基因拷贝数是疾病发展的保护因素。总体而言，通过创建用于鉴定罕见变异的四步流程，在 SLE 患者中鉴定出 21 个罕见 CNV。此外，首次在 SLE 患者中描述了重叠 CFHR4、CFHR5 和 HLA-DPB2 基因的杂合性缺失。本研究首次在三杂交人群中进行了 SLE 患者的全基因组 CNV 研究。结果表明，一旦分析整个基因组中的结构变异分布，就可以发现 SLE 的新易感基因座。
