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
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
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.
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.
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.
Last updated Friday, August 18, 2023