A phenotypic and genomics approach in a multi-ethnic cohort to subtype systemic lupus erythematosus

Abstract

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.

Ethnicity-specific transcriptomic variation in immune cells and correlation with disease activity in systemic lupus erythematosus

“…Interestingly, from this correlation analysis, we noted a similar relationship for the transcriptomic clusters of CD4 + T cells and the clinical K-means clusters previously identi ed by our group solely using ACR clinical criteria 12 (Fig. 2C).…”

“…In our own previous work, unsupervised clustering of the 18 American College of Rheumatology (ACR) classi cation criteria on an ethnically diverse lupus cohort revealed three stable clusters, characterized by signi cant differences in several SLE features as well as the lupus severity index 12 . Following up on the clinical clustering study, the objective of the current study which leverages the same cohort is to use large-scale transcriptomic data from diverse ethnic population to identify transcriptomic signature in SLE relating various clinical and demographic factors and better sub-classify SLE patients into more clinically actionable groups.…”

A longitudinal and transancestral analysis of DNA methylation patterns and disease activity in lupus patients

“…potential mechanism by which risk alleles contribute to disease susceptibility in lupus (13)(14)(15). Lupus susceptibility is significantly higher in patients of non-European ancestry, who are also more likely to develop more severe disease, even after accounting for the influence of social and environmental factors (16).…”

The DNA methylation Profile of Undifferentiated Arthritis Patients Anticipates their Subsequent Differentiation to Rheumatoid Arthritis

“…Those alterations, which occur in regions that are functionally associated with inflammatory pathways, are common to those previously observed in other inflammatory diseases. In particular, enriched functional categories of inflammation, immune cell activation and cytokine signalling are also found in RA [6,28,29], SLE [30,31], asthma [32] and IBD [33] in comparable studies, supporting the idea that UA shares epigenetic similarities with other inflammatory diseases and thus can be molecularly considered as such. Furthermore, the identification of vast DNA methylation differences at the TNF locus as well as alterations at several CpGs within the HLA class II region (both at the DMP and DVP level) reasserts UA as an arthritide, such as RA, with which shares clinical characteristics [7,34–36]…”