Few subjects in medical research are more vexing than lupus, a multifaceted chronic autoimmune disease that has no diagnostic test or cure. Yet in a June 11 Distinguished Lecture, Lindsey A. Criswell, M.D., M.P.H., D.Sc., director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and head of the Genomics of Autoimmune Rheumatic Disease Section at the National Human Genome Research Institute (NHGRI), highlighted promising steps forward in understanding the genetic and environmental causes of lupus.

Lisa Rider, M.D., head of the NIEHS Environmental Autoimmunity Group, hosted the lecture. During her NIEHS visit, Criswell and NIEHS Director Rick Woychik, Ph.D., also discussed opportunities to bolster collaborations across their respective institutes in areas of shared interest. Environmental contributions to autoimmune disease and the application of exposomics to studies of autoimmune disease and other chronic conditions are among topics of mutual interest.

The genetics of lupus

“Compared to other autoimmune diseases, lupus, overall, has a relatively strong genetic contribution,” Criswell said.

For example, risk factors for lupus and other autoimmune diseases have been identified on chromosome 6, particularly within the major histocompatibility complex, which contains genes important to the immune response.

Although a large number of genetic variants have been associated with lupus, Criswell said, more work is needed to understand the basic biological mechanisms underlying the disease.

“The criteria for diagnosing lupus are not driven by biology or disease understanding,” she said. “They're based on clinical and laboratory features.”

Still, these disease features have been useful. For example, patients with lupus who produce antibodies to double-stranded DNA are more likely to have severe disease, such as kidney involvement.

“Also, smokers are more likely to have severe rheumatoid arthritis characterized by anti-CCP [cyclic citrullinated peptide] autoantibodies,” said Criswell.

Lupus epigenetics

Epigenetic factors, which affect gene function but do not change the underlying genetic code, play a significant role in the development of autoimmune diseases. One way scientists have explored epigenetics is through the study of identical twins, who begin life with the same genetic blueprint, altered differentially over time by environmental exposures.

Research on identical twin pairs where one twin has lupus and the other does not have revealed an association between disease status and DNA methylation, which is the addition of methyl tags to DNA that influences the level of expression of genes.

“While DNA methylation controls gene expression to a great extent, methylation itself may be mediating some of the genetic contribution to the disease,” Criswell said.

DNA methylation can be influenced by a variety of environmental factors, such as exposure to metals, pesticides, or oxidative stress brought on by smoke or air pollution (see sidebar). In some cases, specific DNA methylation changes have been linked with specific environmental exposures, suggesting that DNA methylation may serve as a useful biomarker.

Compared to genetic factors, Criswell said, the potential number of environmental influences on the disease is vast. Still, the quality of the environmental risk factor evidence is limited, and in some cases anecdotal.

“It’s been difficult to study the environmental contributions in a rigorous, comprehensive, and systematic way,” she said.

Nature vs. nurture

During the Q&A, several NIEHS leaders wanted to know more about how gene-environment interactions could explain the development of lupus and point to potential treatments for the disease. Woychik asked to what extent do genetics and epigenetics “crosstalk,” or interact, in the suppression of gene activity.

“What I can say is that genetic variants don't fully explain disease risk,” Criswell said. “DNA methylation controls gene expression to a great extent, and some genetic variants influence disease risk through differences in methylation. Is the methylation under genetic control, or is it mediating genetic association with disease? DNA methylation is telling us something above and beyond what we can glean from the underlying genetics.”

NIEHS Scientific Director Darryl Zeldin, M.D., wondered about how lupus treatment may change over the next 10 years. He asked: “Will we be able to take a personalized medicine approach and decide which treatments are best in a particular patient?”

“One reason most clinical trials on lupus have failed is we don't fully understand the underlying biology,” Criswell said. “But new therapies will eventually be suggested by ongoing research in this area. We have tools to get there. Drug repurposing, for example, holds tremendous promise.”

Fred Miller, M.D., Ph.D., scientist emeritus at the NIEHS Environmental Autoimmunity Group (now headed by Rider), asked: “In what ways are you putting environmental exposures together into a gene-environment interaction approach?”

To that end, Criswell is collaborating with the NIEHS Metabolomics Core facility to compare levels of chemicals in samples collected from patients during periods of high versus low lupus activity. Genetic and epigenetic data is also available for these individuals, allowing her team to study the combination of these factors on disease risk and severity. In addition, Criswell recently received support through the Intramural Targeted Climate Change & Health program to study the effects of wildfire smoke exposure on the epigenome and health in a multiethnic cohort.

“Since I was a kid, I've been fascinated by nature versus nurture, genes and environment,” Criswell said. “The environmental piece has been much more complicated, but I can imagine a future where we understand the major environmental contributions to lupus.”