Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.
Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
Ann Rheum Dis. 2018 Jul;77(7):1078-1084. doi: 10.1136/annrheumdis-2018-213093. Epub 2018 Apr 6.
Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. Through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. This study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning.
We conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning.
We identified three novel loci that surpassed genome-wide significance, including (rs13238909, p=4.40E-08), (rs2428, p=1.17E-08) and (rs2731783, p=1.08E-09). We also confirmed the association of locus with SLE (rs763361, p=2.45E-08). Fine-mapping and functional analyses indicated that the putative causal variants in locus reside in an enhancer and are associated with expression of in B-lymphocytes, suggesting a potential mechanism of association. In addition, we demonstrated that SLE risk genes were more likely to be interacting proteins with targets of approved SLE drugs (OR=2.41, p=1.50E-03) which supports the role of genetic studies to repurpose drugs approved for other diseases for the treatment of SLE.
This study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.
系统性红斑狼疮（SLE）是一种具有强烈遗传成分的自身免疫性疾病。通过全基因组关联研究（GWAS），我们最近确定了 10 个与 SLE 相关的新位点，并发现了一些需要进一步验证的提示性位点。本研究旨在独立队列中验证这些位点，并评估 SLE 遗传学在药物重定位中的作用。
我们进行了 GWAS 和复制研究，共纳入 12280 例 SLE 病例和 18828 例对照，并进行精细映射分析，以确定新确定的位点内可能的因果变异。我们进一步扫描药物靶点数据库，以评估 SLE 遗传学在药物重定位中的作用。
我们确定了三个新的超过全基因组显著水平的位点，包括 （rs13238909，p=4.40E-08）， （rs2428，p=1.17E-08）和 （rs2731783，p=1.08E-09）。我们还证实了 位点与 SLE 的关联（rs763361，p=2.45E-08）。精细映射和功能分析表明， 位点的假定因果变异位于增强子中，与 B 淋巴细胞中 的表达相关，提示潜在的关联机制。此外，我们证明了 SLE 风险基因更有可能与已批准的 SLE 药物的靶点相互作用蛋白（OR=2.41，p=1.50E-03），这支持了遗传研究在为治疗 SLE 而重新定位其他疾病批准药物中的作用。
本研究确定了三个与 SLE 相关的新位点，并证明了 SLE GWAS 发现在药物重定位中的作用。
