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 the 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.