DNA methylation profiling identifies epigenetic differences between diabetes patients with ESRD and diabetes patients without nephropathy.

We identified potential epigenetic biomarkers for chronic kidney disease progression by comparing site-specific DNA methylation levels in more than 14,000 genes between African American and Hispanic diabetes patients with end stage renal disease (ESRD) and diabetes patients without nephropathy. We identified 187 genes that are differentially methylated between the two groups on at least two CpG sites in each gene in DNA extracted from saliva. Of the 187 genes whose mean methylation levels differed between the two groups, 39 genes, or closely related gene family members, have been reported to be involved in kidney development or diabetic nephropathy, per se, or have been associated with dialysis-induced changes in gene expression in peripheral blood cells. The fact that such a substantial fraction (21%) of the 187 candidate genes have been implicated previously through genome association or transcription profiling studies suggests strongly that the DNA methylation differences we observe are associated with disease predisposition and/or treatment. The fact that these nephropathy and/or dialysis-associated differences between patients were identified in DNA extracted from saliva offers proof-of-principle that inter-individual epigenetic differences may prove useful as predictive biomarkers of disease susceptibility.

DNA methylation and gene expression differences in children conceived in vitro or in vivo.

Epidemiological data indicate that children conceived in vitro have a greater relative risk of low birth-weight, major and minor birth defects, and rare disorders involving imprinted genes, suggesting that epigenetic changes may be associated with assisted reproduction. We examined DNA methylation at more than 700 genes (1536 CpG sites) in placenta and cord blood and measured gene expression levels of a subset of genes that differed in methylation levels between children conceived in vitro versus in vivo. Our results suggest that in vitro conception is associated with lower mean methylation at CpG sites in placenta and higher mean methylation at CpG sites in cord blood. We also find that in vitro conception-associated DNA methylation differences are associated with gene expression differences at both imprinted and non-imprinted genes. The range of inter-individual variation in gene expression of the in vitro and in vivo groups overlaps substantially but some individuals from the in vitro group differ from the in vivo group mean by more than two standard deviations. Several of the genes whose expression differs between the two groups have been implicated in chronic metabolic disorders, such as obesity and type II diabetes. These findings suggest that there may be epigenetic differences in the gametes or early embryos derived from couples undergoing treatment for infertility. Alternatively, assisted reproduction technology may have an effect on global patterns of DNA methylation and gene expression. In either case, these differences or changes may affect long-term patterns of gene expression.