Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning
Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning
复制标题
鉴定 ST3AGL4、MFHAS1、CSNK2A2 和 CD226 作为与系统性红斑狼疮 (SLE) 相关的基因座，并评估药物重新定位中的 SLE 遗传学
DOI：
10.1136/annrheumdis-2018-213093
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发表时间：
2018-07-01
影响因子：
27.4
通讯作者：
Yang, Wanling
中科院分区：
文献类型：
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作者：
Wang, Yong-Fei;Zhang, Yan;Yang, Wanling
目的系统性红斑狼疮（SLE）是一种遗传因素参与的自身免疫性疾病。通过全基因组关联研究（GWAS），我们最近发现了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。本研究的目的是在独立的队列中验证这些位点，并评估SLE遗传学在药物重新定位中的作用。方法对12 280例SLE患者和18 828例对照者进行了GWAS和复制研究，并进行了精细定位分析，以确定新发现的基因座中可能的致病变异。我们进一步扫描药物靶点数据库，以评估SLE遗传学在药物重新定位中的作用。结果筛选出3个具有全基因组显著性的新基因座：ST 3AGL 4（rs 13238909，pmeta=4.40E-08）、MFHAS 1（rs 2428，pmeta=1.17E-08）和CSNK 2A 2（rs 2731783，pmeta=1.08E-09）。CD 226位点与SLE的相关性（rs763361，pmeta=2.45E-08）。精细定位和功能分析表明，CSNK 2A 2基因座的推定致病变异体位于增强子中，并与B淋巴细胞中CSNK 2A 2的表达相关，提示了潜在的关联机制。此外，我们证明了SLE风险基因更可能是与已批准的SLE药物靶点相互作用的蛋白质（OR=2.41，p=1.50E-03），这支持了遗传研究的作用，以重新利用已批准用于其他疾病的药物治疗SLE。结论本研究发现了3个与SLE相关的新位点，并证实了SLE GWAS在药物定位中的作用。
Objectives 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. Methods 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. Results We identified three novel loci that surpassed genome-wide significance, including ST3AGL4 (rs13238909, pmeta=4.40E-08), MFHAS1 (rs2428, pmeta=1.17E-08) and CSNK2A2 (rs2731783, pmeta=1.08E-09). We also confirmed the association of CD226 locus with SLE (rs763361, pmeta=2.45E-08). Fine-mapping and functional analyses indicated that the putative causal variants in CSNK2A2 locus reside in an enhancer and are associated with expression of CSNK2A2 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. Conclusion This study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.