Genes play a key role in stress response

Both nature and nurture - genetic makeup and the environment experienced through life - combine to influence health and well-being, Duke University Medical Center researchers and their colleagues have determined in four new studies.

The researchers showed that people's genes play a key role in how they respond both biologically and psychologically to stress in their environment.

The researchers presented four studies that examine genetics and the environment on Thursday, March 2, 2006, as part of a symposium organized by Duke researchers at the American Psychosomatic Society annual meeting in Denver. The studies were conducted at Vrije Universiteit in Holland, the Medical College of Georgia and Duke. The studies were funded by the National Institute on Aging and the National Heart Lung and Blood Institute.

Two studies from Duke evaluated effects of a particular mutation in the gene that makes monoamine oxidase-A (MAOA-uVNTR), an enzyme responsible for breaking down serotonin as well as other neurotransmitters in the brain. One form of this mutation causes the gene to make more of the enzyme, while the other form results in less production of enzyme. Neurotransmitters are chemical signals by which one neuron triggers a nerve impulse in a neighbor. Thus, neurotransmitters are fundamentally responsible for all brain function, and subtle changes in their level or activity can profoundly affect not only brain function but physiological function influenced by the brain.

"There has been considerable speculation that serotonergic nerves in the brain play an important role in glucose metabolism and obesity," said Richard Surwit, Ph.D., a medical psychologist at Duke who led one of the studies. "Drugs that block serotonergic receptors, such as olanzapine, can produce significant weight gain and diabetes, while drugs that stimulate serotonergic neurons, such as fenfluramine, can induce weight loss and improve metabolism."

The researchers' studies of the effects of mutations in MAOA-uVNTR in 84 people showed that having the active or inactive form of the MAOA-uVNTR mutation appeared to determine how serotonin affected blood levels of glucose and insulin, as well as body mass index.

"It appears that people who carry a particular form of this gene may be more susceptible to developing obesity and diabetes and may be more responsive to therapies that impact on this enzyme," Surwit said.

In a separate study, a Duke research team examined effects of MAOA gene mutations in more than 300 study participants - half of whom were primary caregivers for relatives or spouses with Alzheimer's disease and half who were similar to the caregivers but had no caregiving responsibilities. Their data show a significant effect of the MAOA gene on the levels of stress hormones, particularly in men.

"It appears that men with the less active form of the MAOA gene who were subjected to the stress of caregiving, exhausted their ability to mount a stress hormone response during the day and evening hours," said Redford Williams, MD, director of the Behavioral Medicine Research Center at Duke and lead researcher on the study. "Their ability to maintain cortisol and adrenaline at normal levels during the day and evening was significantly lower than that of men with the more active form of the gene, and all the women with both forms of the gene.

"Ultimately, their body's biological ability to cope with stress became impaired. This exhaustion of their ability to mount a hormonal stress response could place men with the less active form of the gene at higher risk of developing a broad range of health problems as their caregiving duties continue."

The symposium also included a study at the Medical College of Georgia evaluating several families of genes known to affect the stress response and whether the genes affect the risk of developing hypertension, or high blood pressure.

"It has been difficult to show effects of stress on the development of hypertension because it may be that only a subset of people who show a genetic susceptibility will develop high blood pressure after chronic exposure to stress," said Harold Snieder, Ph.D., lead investigator on the work being done at MCG. "Our research shows that effects of different candidate genes on the development of high blood pressure during adolescence depend on the environmental stressors that are present, the gender and the ethnicity, in a group of European American and African American youth that have been followed for 15 years."

In another study reported in the symposium, Eco De Geus, Ph.D., of the Vrije Univeriteit tested blood pressure and heart rate reactivity to acute mental tasks in a sample of 372 adolescent and middle-aged twins. De Geus found that genetic factors had a bigger effect on reactivity to stress than on resting blood pressure.

"Some genes may lie dormant when life is sweet and calm, but swing into action when we are stressed," he said.

The researchers at the symposium said they believe that using genetic markers to determine who is at greater risk of health problems due to both acute and chronic stress and other environmental factors - such as a high calorie diet - could help identify who might benefit from interventions, such as training in more effective coping strategies, or from closer monitoring for obesity and diabetes onset, the researchers said.