A phenotypic and genomics approach in a multi-ethnic cohort to subtype systemic lupus erythematosus
A phenotypic and genomics approach in a multi-ethnic cohort to subtype systemic lupus erythematosus
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DOI：
10.1038/s41467-019-11845-y
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发表时间：
2019-08-29
影响因子：
16.6
通讯作者：
Criswell, Lindsey A.
中科院分区：
文献类型：
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作者：
Lanata, Cristina M.;Paranjpe, Ishan;Criswell, Lindsey A.
系统性红斑狼疮(SLE)是一种异质性自身免疫性疾病，不同种族的预后不同。在这里，我们的目标是使用基于美国风湿病学会(ACR)分类标准的无监督聚类方法来识别多种族队列中的SLE亚组。我们确定了三个根据疾病严重程度而不同的患者群。甲基化关联分析确定了一组256个跨簇的差异甲基化CPG，包括I型干扰素途径基因中的101个CPG，我们在外部队列中验证了这些关联。顺式甲基化数量性状分析确定了744对有意义的CpG-SNP。种族相关CPGS的甲基化特征被丰富，这表明遗传和非遗传因素可能驱动结果和种族相关的甲基化差异。我们的计算方法强调了与集群相关的分子差异，而不是单一结果衡量标准。这项工作证明了在多因素、多种族疾病环境中应用综合方法来解决临床异质性的实用性。
Systemic lupus erythematous (SLE) is a heterogeneous autoimmune disease in which outcomes vary among different racial groups. Here, we aim to identify SLE subgroups within a multiethnic cohort using an unsupervised clustering approach based on the American College of Rheumatology (ACR) classification criteria. We identify three patient clusters that vary according to disease severity. Methylation association analysis identifies a set of 256 differentially methylated CpGs across clusters, including 101 CpGs in genes in the Type I Interferon pathway, and we validate these associations in an external cohort. A cis-methylation quantitative trait loci analysis identifies 744 significant CpG-SNP pairs. The methylation signature is enriched for ethnic-associated CpGs suggesting that genetic and non-genetic factors may drive outcomes and ethnic-associated methylation differences. Our computational approach highlights molecular differences associated with clusters rather than single outcome measures. This work demonstrates the utility of applying integrative methods to address clinical heterogeneity in multifactorial multi-ethnic disease settings.