Background/Purpose:  Systemic lupus erythematosus (SLE) is a multi-system, complex disease believed to be triggered by gene-environment interactions. While we have made considerable progress in investigation of genetic risk for SLE, there remains much to learn about how the environment and genetic variation interact to create that genetic risk. Over 80% of the human genome is believed to express non-coding sequences. Of 46 single nucleotide polymorphisms (SNPs) shown to confer genetic risk for SLE in recent genome-wide association studies, 30 lie within non-coding regions of the human genome. We therefore sought to identify and describe the functional elements (aside from genes) located within these regions of interest.

Methods:  We used a next-generation sequencing approach (chromatin immunoprecipitation (ChIP) followed by sequencing) to identify epigenetic marks associated with enhancer function (H3K4me1/H3K4me3/H3K27ac) in adult neutrophils to determine whether enhancer-associated histone marks were enriched within the linkage disequilibrium (LD) blocks encompassing the 46 SNPs of interest. We also interrogated available data in Roadmap Epigenomics for CD4+ T cells and CD19+ B cells to identify these same elements in lymphoid cells.

Results:  All three cell types demonstrated enrichment of enhancer-associated histone marks compared to genomic background within LD blocks encoded by SLE-associated SNPs. In addition, within the promoter regions of these LD blocks, all three cell types demonstrated enrichment for transcription factor binding sites above genomic background. In CD19+ B cells, all but one of the LD blocks of interest were also enriched for enhancer-associated histone marks.

Conclusion:  Regions of genetic risk for SLE contain functional genomic elements that are involved in the regulation and coordination of transcription on a genome-wide basis. These regions specifically are enriched for epigenetic marks associated with enhancer function, and appear to be correlated with active, dynamic regions of the genome as evidenced by the abundance of transcription factor binding in these regions of interest. Elucidating the specific roles of these non-coding elements within these cell-type-specific genomes will be crucial to our understanding of SLE pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-non-coding-genome-and-the-genetics-of-systemic-lupus/