Abstract
BackgroundGenetic 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.ResultsImpressive 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 similarly 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.ConclusionEthnicity-specific inherited epigenetic susceptibility loci in CD4+ T cells provide clues to explain differences in the susceptibility to autoimmunity and possibly other T cell-related diseases between populations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-015-0037-1) contains supplementary material, which is available to authorized users.
Highlights
Genetic and epigenetic variability contributes to the susceptibility and pathogenesis of autoimmune diseases
Applying a threshold of |Δβ| > 0.1 and false discovery rate (FDR)-adjusted P value ≤0.05, we found 306 hypomethylated CpG sites associated with 144 genes and 375 hypermethylated CpG sites associated with 164 genes in naïve CD4+ T cells isolated from African-Americans compared to European -Americans (Additional file 1: Table S1)
Hypomethylated genes in African‐Americans are enriched in genes related to autoimmunity and are hypomethylated in lupus patients As pro-apoptotic gene ontologies were associated with hypomethylated genes in African-Americans, and because autoimmune diseases such as lupus tend to be more common and more severe in African-Americans, we investigated if hypomethylated genes in naïve CD4+
Summary
Genetic and epigenetic variability contributes to the susceptibility and pathogenesis of autoimmune diseases. Differences in DNA methylation contribute to the phenotypic variation present between individuals and ethnicities. Previous studies of the DNA methylation patterns in different ethnicities revealed that peripheral blood cells from non-Hispanic African-Americans display. DNA methylation differences seen in individuals of African-American, European-American, and Han Chinese ancestry were associated with genes related to xenobiotic metabolism and immune system function, among others [5]. These examples of epigenetic variation between ethnicities may provide answers as to what contribution inherent epigenetic differences make to the development and progression of autoimmune diseases
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