Russell/Engleman Rheumatology Research Center, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA.
Nat Commun. 2019 Aug 29;10(1):3902. doi: 10.1038/s41467-019-11845-y.
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.
系统性红斑狼疮（SLE）是一种异质性自身免疫性疾病，不同种族群体的结局存在差异。在这里，我们旨在使用基于美国风湿病学会（ACR）分类标准的无监督聚类方法在多民族队列中识别 SLE 亚组。我们根据疾病严重程度确定了三个患者聚类。甲基化关联分析确定了一组跨越聚类的 256 个差异甲基化 CpG，包括 I 型干扰素途径中基因的 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基因座分析确定了 744 个显著的 CpG-SNP 对。甲基化特征富含与种族相关的 CpG，表明遗传和非遗传因素可能会影响结局和与种族相关的甲基化差异。我们的计算方法强调了与聚类相关的分子差异，而不是单一的结果衡量标准。这项工作表明，在多因素多民族疾病环境中应用综合方法解决临床异质性具有实用性。
