Posted August 18, 2023

Carl Langefeld, Ph.D., Wake Forest University Health Sciences

Systemic lupus erythematosus (SLE) is the most common presentation of the autoimmune disease Lupus, affecting around 70% of all lupus patients, 90% of which are female. SLE is associated with a higher risk of renal disease, cardiovascular disease, stroke, breast and cervical cancer, and even premature death.¹ Symptoms vary greatly from person to person, and there are few treatments available. While SLE can run in families, which suggests genetics contribute to the disease, genetic factors do not account for the total risk of developing SLE. Epigenetic and environmental factors also contribute to SLE. Epigenetic mechanisms, such as DNA methylation (the transfer of a methyl group onto the DNA bases), cause alterations that can change gene expression without changing the DNA sequence. Research has indicated the methylation status of autoimmune-related genes correlates with SLE disease severity, with the majority of the genes being undermethylated in lupus cells.² Methylation of CpG sites, specific regions of DNA, is of particular significance to SLE severity.

With funding from a Fiscal Year 2019 Lupus Research Program Impact Award, Dr. Langefeld and his team, including investigators from RILITE (Re-Imagine Lupus Investigation, Treatment and Education) and the Medical University of South Carolina, aimed to investigate epigenetic risk factors for SLE to identify pathogenic mechanisms and therapeutics to target and treat the disease. They hypothesized that epigenetic factors significantly contribute to the development of SLE. To test this hypothesis, researchers analyzed genomic DNA extracted from whole blood from sets of monozygotic (identical) twins discordant for SLE (only one twin has SLE) to control for the impact of genetic factors. The healthy twins acted as controls in the study. Because lupus disproportionately affects females, this research used female subjects.

For a genome-wide analysis, the study utilized two cohorts of monozygotic twins discordant for SLE. The discovery cohort consisted of three sets of twins enrolled into the Lupus Family Registry and Repository, and a replication cohort containing DNA methylation data from four sets of twins downloaded from the Gene Expression Omnibus. With a genome-wide DNA methylation assay, researchers evaluated 485,500 CpG sites to identify regions of differential DNA methylation in affected twins when compared to unaffected twins. From this, 59 sites across 33 genes were identified as statistically significant, and the 59 sites then were validated with the replication cohort. Statistical analysis revealed CpG sites with differential DNA methylation were within genes of the nucleic acid-sensing pathway and the type I interferon pathway. Both pathways are essential for recognition and defense against pathogens. Nucleic acid-sensing triggers for an immune response and type I interferons modulate those responses. As knowledge of these pathways remains vital to discovering potential therapeutics to treat SLE, researchers investigated genes involved in both pathways for potential gene-drug interactions using the Search Tool for Interactions of Chemicals, Ingenuity Pathway Analysis, and the Drug–Gene Interaction public database. This research generated a list of 41 compounds that are candidates to serve as therapeutics in future trials for SLE. More importantly, researchers selected compounds already approved by the U.S. Food and Drug Administration, or compounds in ongoing clinical trials, which allows for a shorter timeline in moving drugs from bench to bedside.

Dr. Langefeld and his team utilized methylation, gene expression, and pathway analyses to discover two complimentary molecular pathways involved with SLE severity. They were able to analyze epigenetic factors by controlling for genetic factors in using data from monozygotic twins discordant for SLE. Findings strongly suggest there are opportunities to repurpose drugs as treatments for SLE. By providing a list of previously approved drugs, Dr. Langefeld and his team have built the foundation for future clinical trials. Building upon this research, future directions include generating additional drug target lists and developing methods for drug-target prioritization. The research team also suggests the necessity of cell- and tissue-specific analyses. Because there are so few treatments available for SLE, this work has the potential to influence the quality of life for individuals with SLE.

Publication:
Marion MC, Ramos PS, Bachali P, et al. 2021. Nucleic acid-sensing and interferon-inducible pathways show differential methylation in MZ twins discordant for Lupus and overexpression in independent Lupus samples: Implications for pathogenic mechanism and drug targeting. Genes 12(12):1898.

References:
¹Lupus Foundation of America. 2021. What is systemic lupus erythematosus (SLE)? https://www.lupus.org/resources/what-is-systemic-lupus-erythematosus-sle.

²Jeffries M, Dozmorov M, Tang Y, et al. 2011. Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus. Epigenetics 6(5):593-601.

Link:
Public and Technical Abstracts: Multiancestral Genomic Approach to SLE Precision Medicine

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Last updated Friday, August 18, 2023