Combining Genetics and Epigenetics Will Yield New Insights into Kidney Diseases

Understanding DNA has helped science make major strides in understanding and treating disease.

But “we [still] can’t explain most of the variability leading to most human disease,” said Andrew Feinberg, MD, MPH, director of the Center for Epigenetics at Johns Hopkins University in Baltimore. Changes in the genetic code explain only about 20% of disease risk, noted Feinberg, who presented a State-of-the-Art lecture at Kidney Week 2017.

Epigenetic studies may help unravel how the environment and gene–environment interactions contribute to that remaining disease risk. Already there is emerging evidence that epigenetic changes may contribute to kidney disease. Feinberg and others in the field are optimistic that further study of the role that these epigenetic changes play in the development of kidney disease and other ailments may lead to new treatments.

Epigenetic variability

Epigenetic variability is likely a major contributor to health and disease from the very earliest stages of development, Feinberg said.

The DNA found in the precursor cells of the heart and kidney is identical yet these two types of cells develop into vastly different organs. Their paths diverge because of epigenetic modifications, or chemical changes to the DNA that alter the expression of the genes.

“It’s the grammar on top of the words of the DNA sequence,” Feinberg said.

The addition of methyl groups to a stretch of DNA, for example, can act as a switch that turns on or off the expression of a gene or genes. These types of epigenetic changes underlie the characteristics that differentiate different organs as well as those that differentiate cancer cells from normal ones, he said.

There is variation in the methylation patterns among humans, just as there is variation in human genetics. Feinberg’s work suggests that epigenetic variation is a driving force in evolution (Feinberg AP and Irizarry RA. Proc Natl Acad Sci USA 2010; 107 Suppl 1:1757–1764).

Having such variability may make it easier for organisms to adapt to changing environments.

“Different variants would be beneficial or harmful depending on the environment,” he said.

These epigenetic variations may also contribute to disease risk. For example, Feinberg noted that a lot of cell death occurs during the early development of the kidneys. There may also be a good deal of variability in the process, he said. These differences could contribute to kidney resilience or vulnerability to kidney injury later in life.

“There is very good epidemiological data that epigenetics might play a role in kidney disease,” said Katalin Susztak, MD, PhD, a professor of medicine and genetics at the University of Pennsylvania’s Perelman School of Medicine.

Environmental exposures can alter a person’s epigenetics and may explain these observational findings, Susztak said. For example, maternal over- or under-nutrition could cause epigenetic changes that make a child’s kidneys more susceptible to kidney diseases or vulnerable to faster progression. In diabetic kidney disease, there is also evidence that a history of poor diabetes control may have lasting effects on outcomes even if an individual later achieves better control. These persistent effects might be explained by epigenetic changes.

“The epigenome is essentially the footprint of all the environmental changes that affect a human being from conception to death,” she said.

Kidney clues

By tapping a large bank of kidney tissue samples, Susztak and her colleagues have identified epigenetic changes in patients with chronic kidney disease and diabetic kidney disease. She presented some preliminary findings from the studies at Kidney Week.

“The bigger question is, can we show a causal relationship between changes and disease development,” she said.

To do that, she and her colleagues must next turn to cell and animal studies in which they will replicate these kidney disease–linked epigenetic changes and determine their physiological effects. Fortunately, new gene-editing technology called CRISPR CAS 9 technology can be used to make epigenetic changes as well as genetic ones.

So far, her work and that of others suggests that epigenetic changes play an important role in gene expression. Interestingly, genomewide association studies (GWAS) have suggested that genes linked to disease risk also play a role in regulating gene expression.

“There is a certain convergence between epigenome-wide association studies (EWAS) and GWAS changes,” Susztak said.

This convergence has led Feinberg to propose that scientists combine EWAS and GWAS studies, along with environmental exposures that might cause epigenetic changes in order to better understand how these factors together may contribute to disease.

“We could save a fortune of National Institutes of Health money by combining these things,” Feinberg said.

Both Susztak and Feinberg are optimistic that understanding how epigenetics contributes to disease may one day lead to new treatments that target disease-linked epigenetic changes.

“It would be very, very exciting if we could interfere with epigenetic changes and modify it and develop new therapies for kidney disease,” Susztak said.

January 2018 (Vol. 10, Number 1)