Genomes of identical twins reveal epigenetic changes that may play role in lupus

Because the genetic makeup of monozygotic twins (commonly known as identical twins) is nearly identical, phenotypic traits and heritable diseases are often concordant, manifesting in both siblings. However, some phenotypes and diseases such as autoimmune disease can arise in only one sibling, suggesting other factors such as environment likely play a role in determining phenotypic differences.

Epigenetic modifications, cellular changes that can influence expression of genes, are now widely recognized to influence phenotype and frequently occur in disease. Furthermore, environmental factors such as diet and chemical exposure can change the epigenetic status of genes. Recent research has identified epigenetic modifications at several aberrantly regulated genes in autoimmune diseases such as systemic lupus erythematosus (SLE), and other studies have suggested that epigenetic differences are associated with phenotypic discordance between identical twins.

In this work, researchers from Spain and the United States performed the first genome-wide high-throughput analysis of a specific epigenetic modification, DNA methylation, in the context of autoimmune disease. Taking advantage of the identical genetic background in monozygotic twins, the group directly compared DNA methylation in healthy twins and twins discordant for autoimmune diseases, including SLE, looking for changes that could be related to pathogenesis in one sibling and not the other.

In the case of SLE, the group found widespread changes in DNA methylation status at a significant number of genes. Dr. Esteban Ballestar, senior author of the study, noted that this is the largest number of genes exhibiting DNA methylation changes observed in an autoimmune disease to date, and includes genes previously implicated in SLE pathogenesis. Importantly, Ballestar's team found that a significant number of the novel differentially methylated genes are related to multiple immune system functions and are potentially linked to SLE.

"Our study suggests that the effect of the environment or differences in lifestyle may leave a molecular mark in key genes for immune function that contributes to the differential onset of the disease in twins," Ballestar said. Most studies of DNA methylation and human disease have been in the context of cancer research, Ballestar noted, and he hopes that this work will attract more researchers to also investigate DNA methylation alterations in autoimmune disease and other disorders for the development of therapies.

Scientists from Bellvitge Biomedical Research Institute (Barcelona, Spain), Christian-Albrechts-University Kiel (Kiel, Germany), Centro de Investigacion Principe Felipe (Valencia, Spain), the Broad Institute of MIT and Harvard (Cambridge, MA), Brigham and Women's Hospital (Brookline, MA), the National Institute of Environmental Health Sciences (Bethesda, MD), Gregorio Marañon Hospital (Madrid, Spain), ISCIII Center for Biomedical Research on Rare Diseases (Valencia, Spain), Institut de Medicina Predictiva i Personalitzada del Càncer (Badalona, Spain), and the University of Oklahoma Health Sciences Center (Oklahoma City, OK) contributed to this study.

This work was supported by the Spanish Ministry of Science and Innovation, the National Institute of Environmental Health Sciences, the National Institutes of Health, the Alliance for Lupus Research, the US Department of Veterans Affairs, and a BEFI Predoctoral Fellowship from the Carlos III Health Institute, Spain.