Ethnicity-specific epigenetic variation in naïve CD4+ T cells and the susceptibility to autoimmunity

Background: Genetic and epigenetic variability contributes to the susceptibility and pathogenesis of autoimmune diseases. T cells play an important role in several autoimmune conditions, including lupus, which is more common and more severe in people of African descent. To investigate inherent epigenetic differences in T cells between ethnicities, we characterized genome-wide DNA methylation patterns in naïve CD4+ T cells in healthy African-Americans and European-Americans, and then confirmed our findings in lupus patients. Results: Impressive ethnicity-specific clustering of DNA methylation profiling in naïve CD4+ T cells was revealed. Hypomethylated loci in healthy African-Americans were significantly enriched in pro-apoptotic and pro-inflammatory genes. We also found hypomethylated genes in African-Americans to be disproportionately related to autoimmune diseases including lupus. We then confirmed that these genes, such as IL32, CD226, CDKN1A, and PTPRN2 were simi‑ larly hypomethylated in lupus patients of African-American compared to European-American descent. Using patch DNA methylation and luciferase reporter constructs, we showed that methylation of the IL32 promoter region reduces gene expression in vitro. Importantly, bisulfite DNA sequencing demonstrated that cis-acting genetic variants within and directly disrupting CpG sites account for some ethnicity-specific variability in DNA methylation. A total of 66 healthy female individuals (21 African-Americans and 45 European-Americans) were recruited for our studies. There was no significant difference in age between the African-American (mean age = 39.3 years) and European-American (mean age  =  42.5  years) groups (P value = 0.34). All study participants signed an informed consent prior to enrollment into the study. The institutional review boards at the University of Michigan and the Henry Ford Health System approved this study. To validate the relevance of detected ethnicity-specific DNA methylation differences in an autoimmune disease, a group of age-matched 21 African-American and 42 European-American female lupus patients were studied. All patients met the American College of Rheumatology classification criteria for SLE. This series includes only the healthy control samples.