Gene Variants of a “Stress” Gene Have Profound Impacts on Health

Scientists can study stress by observing people who suffer from it. What are the physiological changes these people undergo, if any? Is their appetite normal? And what about the heart rate? Lots of observations are possible, meaning there a lot of ways to approach scientific research on stress. But now, researcher Liesbeth van Rossum of the Erasmus Medical Center (Netherlands) has found another way to study stress: by looking on the gene-scale level. She discovered that one gene in particular is important for the way we deal with stress. Interestingly, alternative forms of this gene are associated with differences in body composition and metabolic factors.

What is stress?

When the brain encounters a stressor, whether it be an environmental condition, stimulus, or threat, a coordinated physiological response is activated. This response includes the stress reaction, which you’ve might have felt, for example, when you’re heart is racing as you stand for your professor during an oral examination. It sure can save your life, in many different ways. Any normal stress response makes you feel alert, focused, and energetic. Stress can arise from a variety of situations: when working towards important deadlines, talking to superiors, or giving a presentation for a demanding audience.

Our response to stress is mediated through two classes of hormones: catecholamines and glucocorticoids [1]. A hormone is a chemical substance, produced by one or more cells in your body, which signals to other cells in your body. Catecholamines work through the nervous system and within seconds. The reaction enabled is called flight-or-fight (the acute stress response). For example, all actions that your scared cat performs when seeing a dog are part of this flight-or-fight reaction. Examples of catecholamines include adrenaline and noradrenaline. Glucocorticoids such as cortisol, on the other hand act more slowly. The synthesis and secretion of glucocorticoid hormones is regulated by the hypothalamic nuclei, a part of the brain that receives stimuli from the central nervous system. Over the course of minutes and hours, the glucocorticoid hormones support the activity of the catecholamines.

The rest of this article will focus on the glucocorticoids, which are important for normal brain maturation and function [2]. Glucocorticoids function by activating glucocorticoid receptors (GR), which are found on almost every cell in the body. The gene that codes for GR has been shown to vary among individuals, and thus, individuals respond differently to stressors.

Polymorphisms and effects

A number of polymorphisms (or different versions) of the GR gene have been identified, two of which are particularly interesting: BclI and ER22/23EK. Both of these genes are associated with metabolism or fats and can consequently have important impacts on health [4]. The BclI variant has been associated with what seemed to be conflicting data regarding body composition. However, very recently it has been shown that the different effects may be age specific.  It is linked with an increased abdominal obesity in middle-aged people, while at an older age, BclI polymorphism carriers exhibit lower lean body mass (= total body weight minus body fat weight). As for ER22/23EK, carriers of this polymorphism have lower total cholesterol, specifically reduced low-density lipoprotein (LDL) cholesterol levels, as well as low levels of C-reactive protein (CRP), which in high concentrations is related to an increased risk of cardiovascular disease.

The storyline of lipoproteins

To understand why the effects of these different polymorphisms are an amazing find, we need to learn a bit more about lipoproteins. Lipoproteins are large biological complexes made up of many molecules that function to transport lipid (fatty compounds) through the watery blood plasma. Lipoproteins can be separated into chylomicrons (CMs), very low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). The density of these different complexes is determined by the relative amounts of proteins and lipids in the complex; the more protein content the higher the density.

Figure 1. This image shows how lipoproteins secreted from the liver are degraded from VLDLs to IDLs and the cholesterol rich LDLs. Image from Lehninger, Principles of Biochemistry (Nelson and Cox; W. H. Freeman 2008).

The liver synthesizes fatty acids and cholesterol, which are packaged for transport in the blood plasma in VLDL particles. In body fat and muscle tissue the fatty acids are released from the VLDLs to be stored and to provide energy, respectively. As the tissue absorbs the fatty acids, the VLDLs gradually shrink to IDLs, which can be further broken down to LDLs – as fatty acids are absorbed by the tissues, the remaining particles become cholesterol rich.

LDLs serve as the main source of cholesterol accumulation in peripheral tissues and have acquired the common title of “bad” cholesterol because of the association between high plasma levels of LDL and the formation of stroke and heart attack-causing atherosclerotic plaques [4]. Saying that LDL levels need to be reduced for good health, however, seems to be a contentious idea. So far, the only drugs (statins) known to reliably reduce the risk of stroke and heart attack may end up having other effects on the body, rather than working directly upon LDL cholesterol levels [5].

HDLs, on the other hand, are colloquially referred to as “good” cholesterol, as their major function is to remove excessive cholesterol from the tissues and transport it to the liver for excretion or reuse (recycling into other lipoproteins) [4,6].

Because carriers of the ER22/23EK polymorphism have lower levels of both total and low-density lipoprotein (LDL) cholesterol, does that mean they probably have better cardiovascular health than carriers of the BclI polymorphism? Interestingly, having the ER22/23EK polymorphism is correlated with healthier metabolic conditions, including a beneficial body composition at young age and a reduced risk of dementia in the elderly.

Contribution of environment and other genes

Van Rossum found that fifty percent of people have the “normal” GR gene, forty percent are carriers of the BclI polymorphism, and the ER22/23EK alternative is present in 10% of people.

Now should all people be tested to identify their variant of the GR gene? It is not that conclusive, van Rossum says. First, although BclI is associated with obesity, also environmental, dietary, and socioeconomic factors are important for the obesity phenotype. It’s been known for a long time now that the environment has effects upon our genotypes. This interplay is scientifically referred to as genotype-by-environment (GxE) interactions. Second, there are more genes, as well as their different polymorphisms, that affect our health. So it may just be that BclI indeed gives a higher risk for obesity at some point in one’s life or cardiovascular disease, but that for some people these risks are reduced by other genetic or environmental variables. The same applies to the ER22/23EK variant; the 10% of people who carry it should not start smoking or visiting greasy spoons instead of doing their daily exercises just because this variant may be beneficial for their health. We do not know enough about how other genes or environmental factors may interact to impact each individual’s health.

The key idea is that we are only beginning to understand how genetics can play a big role in a variety of diseases commonly thought to be more environmentally determined. More research is needed to understand the underlying mechanisms at a molecular level.

(DH, Science in the News — Harvard University)

References

[1] Staufenbiel SM, Penninx BWJH, Spijker AT, Elzinga BM & EFC van Rossum 2012. Hair cortisol, stress exposure, and mental health in humans: A systematic overview. Psychoneuroendocrinology doi:10.1016/j.psyneuen.2012.11.015. <http://dx.doi.org/10.1016/j.psyneuen.2012.11.015>

[2] Lupien SJ, McEwen BS, Gunnar MR & C Heim 2009. Effects of stress throughout the lifespan on the brain, behavior and cognition. Nature Reviews Neuroscience, 10 (6): 434-445.

[3] Van Rossum EFC & SWJ Lamberts 2004. Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition. Recent Progress in Hormone Research 59: 333–357.

[4] Badimon JJ, Fuster V & L Badimon 1992. Role of high density lipoproteins in the regression of atherosclerosis. Circulation 86 (6): III86-III94.

[5] Ledford H 2013. Cholesterol limits lose their lustre. Nature 494: 410-411. < http://www.nature.com/news/cholesterol-limits-lose-their-lustre-1.12509>

[6] Barr DB, Russ EM & HA Eder 1951. Protein-lipid relationship in human plasma: II. In atherosclerosis and related conditions. American Journal of Medicine 11: 480-493.