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It has been one of the toughest problems in genetics. How do investigators figure out not just what genes are involved in causing a disease but what turns those genes on or off? What makes one person with the genes get the disease and another not?

Now, in a pathbreaking paper, researchers at Johns Hopkins University School of Medicine and the Karolinska Institute in Sweden report a way to evaluate one gene regulation system: chemical tags that tell genes to be active or not. Their test case was of patients with rheumatoid arthritis, a crippling autoimmune disease that affects 1.5 million Americans.

It was an investigation of epigenetics, a popular area of molecular biology that looks for modifications of genes that can help determine disease risk.

"This is one of the first studies that looks for an epigenetic disease association in a really rigorous fashion," said Dr. Bradley Bernstein of Harvard, who was not associated with the study.

Kun Zhang of the University of California, San Diego, made a similar observation.

"I am quite impressed with their level of rigor and sophistication," he said. In previous epigenetic studies, researchers with papers in leading journals "have made major claims, but after a few months or a year they were retracted," he said. Those investigators, Dr. Zhang added, "did not treat their data very carefully."

In the new study, researchers compared 354 newly diagnosed rheumatoid arthritis patients and 337 healthy people who served as controls. The goal was to review both groups' white blood cells, examining their DNA for chemical tags — methyl groups — that could attach themselves to genes and turn them on or off.

It was much more complicated than just studying genes themselves. Researchers know a gene will remain stable, but the chemical tags that turn the genes on and off are not so reliable. Their presence can be affected by the environment or medications or even the activity of other, distant, genes. They can be a consequence of a diseases or trigger a disease.

"That's the problem," Dr. Bernstein said, "the arrow of time problem." What is cause and what is effect?

It is known that genes are not the entire story in rheumatoid arthritis and other common diseases, said Dr. Timothy Spector, a professor of genetic epidemiology at Kings College London, who was not associated with the study. For example, though identical twins have identical DNA, they do not always get the same diseases. With rheumatoid arthritis, he added, if one twin gets the disease, there is only a 12 percent chance that the other will too.

In their paper, published on Sunday in Nature Biotechnology, the researchers reported measurement techniques that enabled them to sort things out. They found hundreds of chemical tags but only four that seemed truly related to the disease. Those four were in a cluster of genes that controls the immune response and that was known to affect the risk of rheumatoid arthritis, said Dr. Andrew Feinberg of Johns Hopkins, a lead author of the study. In particular, the tags were in a gene called C6orf10 whose function is unknown.

The chemical tags may help determine if a person with a gene that increases risk of developing a disease actually gets the disease. There were people in the control group who had gene variations associated with arthritis risk, but they did not have those four chemical tags and did not have the disease.

The work, Dr. Feinberg stressed, does not contradict genetic studies pointing to disease susceptibility.

"Instead, it complements them," he said. "It is another arrow in the quiver."