More on Genes: How DNA Turns Stress Into Illness

Misery isn't just depressing, it's bad for your health. People going through stressful events, like divorce, are more likely to get sick. People who are HIV-positive see their condition worsen more quickly if they don't have good social support. But nobody knows exactly how mental stress causes illness and death.

--"Misery in the Genes: How DNA Turns Stress Into Illness," by Helen Fields, Chronicle of Higher Education (5.2.10)

We all know that, of course. Simple correlation studies and multivariate analysis have long made the association clear. But because we did not know how stress caused physical illness, we could not be certain that there was not another concomitant or associated factor that was the actual, hidden cause. We just couldn't know for sure.

But that has all changed now--or at least it is changing. Now the causative relationship between stress and physical illness is becoming clear, the pathways are becoming known. From the Chronicle article:

Now a study by researchers at the University of California at Los Angeles and several other institutions has come up with an actual biological pathway: a chain of molecules that connects stress to disease through genes. The scientists also learned that some people can get through tough times without ruining their health, thanks to a particular genetic variation that breaks the chain.


The study, published this spring in the Proceedings of the National Academy of Sciences, is wildly multidisciplinary, spanning psychology, molecular biology, immunology, and epidemiology. That posed challenges in lining up grants, says Steven W. Cole, an associate professor of medicine at UCLA, who led the research. But the study's success signals the growth and increasing sophistication of Mr. Cole's field, psychoneuroimmunology, the study of connections between mind and health.

As interesting as the finding is the ingenuity, breadth and reliability of Dr. Cole's methodological approach--and the possibility of a remedy:

He took inspiration from scientists who scan the entire human genome looking for genes that can be linked to diseases. He developed a computer program with a specific goal: to find mutations in stretches of DNA that attract transcription factors, molecules in a cell that activate genes. Transcription factors can be pushed into action by environmental factors like stress. A mutation in the DNA regions that attract them, which are called binding sites, could disrupt this "on-off switch" and thus change the stress response.

In the list of genes that were physically near the mutations, one stood out: interleukin 6, which...helps turn on the inflammatory response, which brings infection-fighting cells to the area—but a problem if you make it all the time. [I]t can lead to constant inflammation, which is bad for the body. Mr. Cole says, "Things like coronary heart disease, the most prevalent kinds of cancer, neurodegenerative diseases, probably Type 2 diabetes as well" are all linked to chronic inflammation.

Close to the interleukin 6 gene, the computer had turned up a binding site for GATA-1, a transcription factor. "But there was no guarantee that the whole thing the computer recognized took place in reality," says Mr. Cole. So he did a series of experiments to figure out if GATA-1 was indeed the messenger that brings news of stress...

If Mr. Cole was right about the connection between stress and disease, then a change in the GATA-1 binding site—the mutation noted by his computer program, a DNA difference that occurs in about 20 percent of the population—should keep the transcription factor from triggering so much inflammation. So people with that mutation might be healthier than those without it...

[The result:] People who were depressed at the beginning of the study and had the nonmutated sequence were twice as likely to die in the next 10 years as were others; those who had the mutation seemed to be protected. When Mr. Cole examined the data more closely, he saw that this was true only for deaths caused by diseases, such as cardiovascular disease, that are related to interleukin 6. Because the connection held true for such inflammation-related diseases but not for deaths due to other causes, Mr. Cole became more convinced that he was on the right track.

Other researchers have been impressed by Mr. Cole's results and by the combination of computer modeling, experimentation, and epidemiology he used to get there. "It's a fine study," says Gene E. Robinson, a neuroscientist, genome biologist, and professor of entomology at the University of Illinois at Urbana-Champaign, who studies how the environment affects honeybee behavior. "It's a very creative coupling of different kinds of techniques and different perspectives to provide one of the most complete analyses of, basically, how does the social environment get under the skin."

There are certainly other pathways that link stress to disease. But Mr. Cole's method points to a new way to find links between environment and health...

And out of this research may eventually come a method or medication that deters the transcription factor from triggering illness-generating levels of inflamation in that 80% of us without the mutated GATA-1 binding site. Dr. Cole:

The next question is whether happiness might balance out stress in the cells. "We all secretly hope there's a pill," Mr. Cole says—some way to give everyone the benefit of that mutated GATA-1 binding site. Of course, living a calmer life might have the same effect, but not many people manage that. "If people cannot or will not give up stress, is there something we can do biologically to help?" Mr. Cole asks. It's a big question, one that will probably take research wide enough to span many disciplines to answer.

http://chronicle.com/article/Misery-in-the-Genes-How-DNA/65335/?sid=at&utm_source=at&utm_medium=en