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Genetics and trauma: Coded for injury

Trauma is rarely thought to have a genetic link, but scientists are starting to look at how genes make some people more likely to take risks and impact reactions to physical stress and recovery.

By Victoria Stagg Elliott, amednews staff. March 4, 2002.

In the movie "Unbreakable," Samuel L. Jackson plays a man who is exactly the opposite of the title -- with a long history of broken bones related to osteogenesis imperfecta. He can't even walk down a flight of stairs without shattering his leg. But Bruce Willis, his counterpart, is invulnerable. He walks away from a devastating train wreck that kills everyone else on board.

It's only a movie. But the story line brings up a perplexing question: Why is it that some people always seem to bounce, while others break?

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The notion that genetics may play even a small role in how people respond to trauma is not without controversy.

Francis S. Collins, MD, PhD, director of the National Human Genome Research Institute, actually maintains that trauma is the only medical condition not affected by genetics.

"If you're walking down the street and somebody seven floors up drops a brick on your head, it was probably not your genes that played a role in that outcome," said Dr. Collins during an interview last year.

"Maybe the person on the roof was the risk-taker or maybe your bone fragility made it a really bad fracture, but at a certain level having a brick dropped on your head from seven stories up is going to cause trauma in anybody."

The same genes that predispose one person to reckless driving may spur another to become a downhill skier.

But more and more, scientists are starting to explore the issue -- and search for factors beyond fate and good or bad luck to explain different outcomes by different patients. Those researchers talk about genes for risk-taking, depression and harm avoidance that put people in situations where they are more likely to get injured. They also talk about genes for bone density and skin fragility; genes for repair and infection-fighting capacity; and genes for multisystemic organ failure.

"You would think the genetics of trauma would be restricted to the stupid gene, but, in fact, that's probably not a good way to think about it," said Timothy Buchman, MD, PhD, professor of surgery, anesthesiology and medicine at Washington University in St. Louis.

But thinking about it in any way poses serious challenges -- mostly related to studying the genetic aspects of conditions that might not affect more than one person in a family. Specifically, numerous relatives may be affected by Huntington's disease at the same time, but family members rarely experience trauma in the same way or at the same time. Thus, researchers talk about a genome-wide approach to trauma, different from the approach used to understand single-gene disorders.

"We've been used to looking on a gene-by-gene basis," said Barbara Zehnbauer, PhD, associate professor of pediatrics and pathology at Washington University. "That's going to be inadequate for most of what we do from now on. We need to be looking at the full complement of their genes."

Risky behavior

It's the behavioral genes that are perhaps the most murky.

For every study implicating the D2 and D4 dopamine receptor genes in pleasure-seeking, risky behavior and addiction, there is another one that fails to find a connection. Similarly, serotonin transporter promoter genes have been linked to such behavior only to be exonerated in follow-up studies.

"Each gene counts for a small percentage of the picture, and they have additive effects," said David Comings, MD, director of the Dept. of Medical Genetics at City of Hope Medical Center in Duarte, Calif. "For different people, different genes may be involved. So that makes it rather more difficult."

Moreover, these groups of genes aren't necessarily bad. The same genes that may predispose one person to reckless driving may, in another person in a different environment, create a champion downhill skier.

"We are what our genes make of us, but it's not all genes," Dr. Comings said. "You have this basic predisposition for risk-taking behaviors, but your environment probably determines which one you chose. There certainly aren't genes for snowboarding as opposed to bungee-jumping, but there are definitely genes for that kind of behavior versus sitting and watching television."

And many believe that the future direction of research will have some utility, providing fuel to tailor prevention strategies.

"Behavior has potential to be modified," said Jon Adler, MD, an emergency physician at Massachusetts General Hospital in Boston. "It's possible that if you knew someone had a genetic marker that put them at risk that you could educate people about that."

Resilience

Other researchers are looking at how the body responds to physical stress, but again, this is difficult to study in humans. In a vehicle collision, for example, even victims in the same car are not subject to the same force because of differences in location, safety device use and numerous other factors.

"We see people in car accidents, and one person is fine and one person is not," said Dr. Adler, who is also president and chief medical officer of eMedicine.com. "They both lived through basically the same thing. Why? It probably has more to do with the biomechanics of the forces they experienced than genetic predisposition."

But there are genetic diseases -- such as osteoporosis, hemophilia and the one portrayed in "Unbreakable" -- that make people more fragile. But many suspect that the human body may have a wide range of resilience that, although not pathological, may make some more delicate than others.

Researchers are studying mice bred across the spectrum of bone strength. Others have been studying the link between the development of cerebral edema after head trauma and polymorphisms of the APOE gene, implicated in Alzheimer's and other neurological conditions.

Healing genes

Perhaps the area with the most likely application to clinical practice is the research examining how a body heals.

"There are large variations in how people pull out once they've had something horrible happen to them," Dr. Adler said. "Genetics may be quite significant in that."

Several biotech companies are investigating genetically based compounds to improve wound-healing, and genetics was a hot topic at the January Society of Critical Care Medicine Annual Congress. In addition, the National Institutes of Health will host an April conference on the functional genomics of critical illness and injury. It also recently issued several grants to investigate the genetic differences among intensive care patients to discern who is more likely to fall to sepsis or succumb to multisystemic organ failure.

Meanwhile, researchers have been hunting for years, with mixed results, for single genes that might play a large role in the systems that help a body heal. These latest studies will look for collections of genes and how they work together.

Scientists will search for genes that dictate response to treatment, susceptibility to infection and likelihood of death if infected.

"We need to expand studies to include many of these markers and how they interact," said Dr. Zehnbauer, a researcher who, along with her husband, Dr. Buchman, received an NIH grant to investigate the genetics of sepsis. "Not just a single marker at a time -- genetics isn't that simple any more. We all have multigenic diseases, and this is a very complicated clinical condition."

Those involved in the studies feel that the information gained will lead to drug trials designed with genetics in mind. They also hope that it will allow them to better risk-stratify patients and target treatment. "It would be awfully nice to know which patients are at greatest risk for having bad outcome," Dr. Buchman said. "Those are the ones [where] we really want to focus our efforts."

Treatment options for sepsis long have been limited to supportive care and treatment for the infection, but experts hope that greater genetic understanding of the phenomenon will lead to new treatment and better use of the therapies already in the armamentarium.

In November 2001, for example, a new treatment for severe sepsis was approved by the Food and Drug Administration. The first new drug of its kind in years, activated drotrecogin alfa -- Xigris, made by Eli Lilly -- reduces the infection mortality rate from 31% to 25%.

"It's designed to help improve the survival of patients with sepsis," Dr. Zehnbauer said. "It's had very modest results. If we could understand who's more likely to do poorly when they become septic, we may be able to target other therapeutics to them. Or target the dosing of available agents so they respond better."

But there are many, particularly those in the public health arena, who doubt that the genetic approach to injury and injury prevention will be useful.

"What's the magnitude of importance of these things?" Dr. Adler asked. "The mechanics of what an individual experiences -- the physical forces -- are much more important than any genetic factor."

And there are many who worry that genetics will be overemphasized.

"You don't want to get focused on genetic determinism where everything is genes, genes, genes," said Gregory Pastores, MD, assistant professor of neurology and pediatrics at New York University. "What influences accidents is external and doesn't have much to do with genetics."

But some experts hope that a greater understanding of the genetics in play will lead to a shift in how injury is viewed.

"One of the challenges as clinicians is to try to convince people that injury is a disease," said Scott D. Berns, MD, MPH, national director of chapter program support for the March of Dimes. He also worked as a pediatric emergency physician for 10 years.

"If more conclusive evidence comes out regarding certain genes being associated with certain outcomes in trauma," Dr. Berns said, "then hopefully it'll help the argument that trauma and injury is a disease that can be prevented at some level."

ADDITIONAL INFORMATION:

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Symposium, "Functional Genomics of Critical Illness and Injury," National Institutes of Health Clinical Center, April 4-6, 2002 (http://www.cc.nih.gov/ccmd/Symposium2002/)

Abstract, "A multivariate analysis of 59 candidate genes in personality traits: the temperament and character inventory," Clinical Genetics, November 2000

AMA Genetics and Molecular Medicine page (http://www.ama-assn.org/go/genetics)

Society of Critical Care Medicine (http://www.sccm.org/)

Research, "Mouse Models for Genetic and Endocrine Regulation of Bone Density and Body Composition," Jackson Laboratory (http://www.jax.org/research/documents/research_areas/word_docs/donahue.html)

Home page for the Touchstone Pictures movie "Unbreakable" (http://www.areyouunbreakable.com/)

National Human Genome Research Institute (http://www.nhgri.nih.gov/)