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Institute of Medicine (US) Committee on Assessing Interactions Among Social, Behavioral, and Genetic Factors in Health; Hernandez LM, Blazer DG, editors. Genes, Behavior, and the Social Environment: Moving Beyond the Nature/Nurture Debate. Washington (DC): National Academies Press (US); 2006.

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Genes, Behavior, and the Social Environment: Moving Beyond the Nature/Nurture Debate.

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4Genetic, Environmental, and Personality Determinants of Health Risk Behaviors

INTRODUCTION AND OVERVIEW

Tobacco use, obesity, and physical inactivity are the greatest preventable causes of morbidity and mortality in the United States (Mokdad et al., 2004). These behaviors involve motivational and reward systems within the individual that develop through gene interactions with the social environment. Therefore, a better understanding of the genetic, social environmental, and individual determinants of risk behaviors, such as tobacco use, unhealthy eating behaviors, and physical inactivity could contribute to improved strategies for primary, secondary, and tertiary disease prevention.

Models of gene, environment, and behavior interactions in disease have been proposed, one of which has been adapted here to illustrate the central role of health risk behaviors (Rebbeck, 2002). Risk behaviors such as tobacco use, unhealthy eating behaviors, and physical inactivity play an important role in models of genetic and environmental interactions in health outcomes. As illustrated in Figure 4-1, gene-environment interactions contribute to the initiation and maintenance of these risk behaviors, which in turn increase risk for poor health outcomes (pathway a). In addition, gene-environment interactions can modify the effects of these risk behaviors on disease states and health outcomes (pathway b) and also can have direct effects on health outcomes (pathway c) (see also models of gene-environment interactions in Chapter 8 and Appendix E).

FIGURE 4-1. Role of genes, environment, and risk behaviors in health (adapted from Rebbeck, 2002).

FIGURE 4-1

Role of genes, environment, and risk behaviors in health (adapted from Rebbeck, 2002).

The goal of this chapter is three-fold: (1) to provide a brief overview of the epidemiology of tobacco use, unhealthy diet/obesity, and physical inactivity in relation to health outcomes; (2) to describe the genetic and environ mental determinants of these risk behaviors and their underlying motivational systems; and (3) to discuss how the measurement of intermediate phenotypes (recently termed endophenotypes), such as personality and temperament, can advance our knowledge of the role of gene-environment interactions in risk behaviors and health.

DEFINITIONS OF HEALTH RISK BEHAVIORS

Although definitions of health risk behaviors vary across studies, there are some generally accepted definitions that will be presented for the purposes of this chapter. With regard to tobacco use, the behavioral definition of smoking used in most prevalence studies includes having smoked more than 100 cigarettes in one’s lifetime and smoking every day or most days (CDC, 2005). Increasingly, studies of the determinants of tobacco use, including genetic studies, are using more refined behavioral definitions to characterize trajectories of smoking initiation and progression, as well as phenotypes related to nicotine addiction and smoking persistence (Audrain-McGovern et al., 2004b).

The definition of obesity is more straightforward. The World Health Organization (WHO) defines overweight as having a body mass index (BMI) from 25 to 30, and obesity as a BMI greater than 30 (WHO, 1998). Broadly speaking, physical activity includes any bodily muscular movements that produce energy expenditure (Caspersen et al., 1985; Pate et al., 1995). To reduce health risks, it is recommended that healthy adults engage in at least 150 minutes of moderate intensity physical activity per week (Pate et al., 1995), which can include brisk walking and some forms of aerobic exercise such as running and bicycle riding.

The importance of phenotype definition for investigations of genetic risk factors and gene-environment interaction cannot be overestimated. Increasingly, studies are focusing on intermediate phenotypes, the intermediate measures of these health behaviors that are considered more proximal to the biological determinants. For example, in studies of tobacco use, laboratory-based intermediate phenotypes have included individual differences in the rewarding value of nicotine, the psychophysiological and cognitive effects of nicotine, as well as the effects of nicotine tolerance and deprivation (Munafo et al., 2005b). In obesity studies, psychological intermediate markers have included the reinforcing value of food, food preferences, food intake, and satiety (see Appendix C for additional discussion). As discussed in more detail below, these intermediate phenotypes also may include the dimensions of personality and temperament that are partly biologically based and that may increase the likelihood that an individual will engage in health risk behaviors.

TOBACCO USE

Epidemiology and Health Consequences of Tobacco Use

Although the prevalence of tobacco use in adults has declined significantly since the Surgeon General’s report in 1965, 23 percent of the American population continues to smoke (NCHS, 2003; CDC, 2004a). Smoking rates remain higher in persons who have less than a high school education, compared to college graduates. Furthermore, 18 percent of 13-year-olds and 58 percent of high school students report having smoked a whole cigarette (CDC, 2004b).

Tobacco use is the leading cause of preventable mortality in the United States, accounting for one in five cancer deaths (CDC, 2002; Mokdad et al., 2004). Furthermore, continued smoking following a diagnosis of cancer increases the risk of recurrence and reduces the likelihood of survival (Browman et al., 1993; Kawahara et al., 1998; Khuri et al., 2001; McBride and Ostroff, 2003). The nicotine in cigarettes is known to have significant adverse effects on cardiovascular function (Benowitz and Gourlay, 1997), and smoking cessation following an acute myocardial infarction can reduce mortality rates (Kinjo et al., 2005). Nicotine, thiocyanate, and other toxins in cigarette smoke also can impair thyroid, pituitary, and renal function and contribute to insulin resistance (Kapoor and Jones, 2005). Evidence from rodent models suggests that nicotine also may alter antibody formation and T-cell function (Friedman and Eisenstein, 2004).

Genetic and Environmental Determinants of Tobacco Use

Motivation to begin smoking is strongly influenced by the social environment, although genetic factors also play a role (Audrain-McGovern et al., 2004a). Risk factors for smoking initiation in youth include peer and family smoking, family conflict, and exposure to tobacco industry promotional campaigns (Pierce et al., 1998; Choi et al., 2002). In contrast, physical activity has protective effects on youth smoking (Audrain-McGovern et al., 2003a). The importance of the social environment also is supported by evidence for the efficacy of some anti-tobacco media campaigns, smoke-free environment policies, and cigarette taxes (Holm, 1979; Chaloupka et al., 2002).

Once tobacco use has been initiated, smoking cessation can be difficult because of the development of an addiction to nicotine. There is abundant evidence from animal and human studies for an inherited susceptibility to the rewarding effects of nicotine and to nicotine addiction. In fact, data from twin studies indicate that as much as 70 percent of the variance in nicotine addiction is attributable to genetic factors (Sullivan and Kendler, 1999). Investigations of the specific genetic mechanisms that underlie nicotine addiction have focused on candidate genes in neurobiological pathways that play a role in nicotine’s reinforcing and addictive effects, including the dopamine, serotonin, and opioid pathways, as well as genetic variation in nicotine metabolic pathways and neuronal nicotinic receptors (Lerman and Berrettini, 2003). While several genetic associations have been reported in the literature, heterogeneity in ascertainment, population stratification, and limitations in phenotype definition have contributed to nonreplication (Lerman and Swan, 2002; Munafo and Flint, 2004; Redden et al., 2005). Given the importance of smoking persistence to health outcomes, efforts are increasing to elucidate the role of inherited genetic variation in response to pharmacotherapies for nicotine dependence (Lerman et al., 2005).

Clearly, tobacco use and nicotine addiction are complex traits arising from the interactions among social-environmental, psychological, and genetic factors (Swan et al., 2003). For example, evidence from twin studies suggests that the importance of genetic factors in cigarette smoking depends, in part, on family functioning (Kendler et al., 2004). Specifically, the heritability estimates for cigarette smoking were lower in families with reports of higher levels of family dysfunction. This finding highlights both the importance of gene-environment interactions in risk behaviors, as well as the potential for identifying and quantifying such interactions through careful research. Furthermore, the genetic effects on the progression to regular smoking among adolescents are greatest among those with higher levels of depressive symptoms (Audrain-McGovern et al., 2004a). Despite awareness of the importance of gene-environment interactions in tobacco use, few molecular genetic studies have incorporated social environmental effects, and few studies of social environment have considered whether such influences are moderated by genetic factors.

UNHEALTHY EATING BEHAVIORS AND OBESITY

Epidemiology and the Health Consequences of Obesity

The WHO defines overweight as having a BMI from 25 to 30, and obesity as a BMI greater than 30 (WHO, 1998). Based on this definition, approximately 57 percent of adult Americans are classified as being overweight or obese (Flegal et al., 2005), and rates of obesity have increased in recent decades (Allison et al., 1999; CDC, 2000; Flegal et al., 2005). The rising prevalence of obesity in the United States has been linked to increased health risks (Harris, 1998).

Like tobacco use, obesity is a major cause of mortality in the United States, with approximately 325,000 deaths attributable to obesity among nonsmokers (Allison et al., 1999). Obesity is a major risk factor for the development of diabetes, cardiovascular disease (CVD), osteoarthritis, and many forms of cancer (Allison et al., 1999; Bianchini et al., 2002). Poor diet and obesity can also increase treatment complications and reduce the likelihood of survival following a cancer diagnosis (Pinto et al., 2000; Rock and Demark-Wahnefried, 2002). Although the mechanisms linking obesity to these disease outcomes remains the subject of intense investigation, the adverse health outcomes result in part from alterations in the metabolism of steroid hormones, metabolic alterations including lipid and glucose levels, and increases in the turnover of free fatty acids that lead to insulin resistance syndrome (Seidell et al., 1994; Turcato et al., 2000; Rose et al., 2002; Eckel et al., 2002). In addition, excess adiposity has been linked to impaired immune function and increased cortisol secretion (Stallone, 1994), possibly influencing the adverse pathophysiological effects of environmental and psychological stress.

Genetic and Environmental Determinants of Unhealthy Eating Behaviors and Obesity

The development and maintenance of obesity, like tobacco use and nicotine addiction, result from a complex interplay of social, motivational, emotional, and genetic factors (Kopelman, 2000). Increases in obesity prevalence may be largely attributable to changes in the social environment that support a sedentary lifestyle (e.g., television and video games), the promotion of high-calorie fast foods and “supersize” portions, and increased access to vending machines with high-calorie foods in schools and community settings (Hill and Peters, 1998). Although these environmental factors clearly increase the likelihood of feeding behaviors that lead to obesity in the population as a whole, genetic factors are thought to influence an individual’s susceptibility to unhealthy feeding behaviors given a particular social environment, and to his/her likelihood of becoming obese given a particular level of energy intake and expenditure (Costanzo and Schiffman, 1989; Hill and Peters, 1998).

There is abundant evidence from animal and human models for genetic contributions to obesity, with 40 to 70 percent of the variability in susceptibility to human obesity attributable to heritable factors (Comuzzie and Allison, 1998). There are single gene disorders that include obesity as part of the syndrome, such as Prader-Willi and Bardet-Biedel; however, such major genetic effects are rare. Mutations studied in rodent models of obesity that are associated with leptin abnormalities also are rare in humans (Kopelman, 2000). For example, a single gene mutation in the melanocortin 4 receptor (MC4R) is thought to account for less than 5 percent of morbid obesity (Vaisse et al., 1998). Molecular genetic studies have identified a very large number of susceptibility genes for multiple obesity phenotypes, including BMI, feeding behavior, and satiety (Comuzzie and Allison, 1998); however, the attributable risks associated with these variants remain unclear. Candidate genes identified in these studies include those coding for agouti signaling proteins, leptin and leptin receptors, and cholecystokinin A receptor (reviewed in Comuzzie and Allison, 1998). Genetic variation in the dopamine transporter and dopamine 2 receptor also has been associated with obesity in some studies (Noble et al., 1994; Epstein et al., 2002). Despite the known complex etiology of obesity, studies of genetic modulation of social environmental exposures are rare. However, there is evidence that fetal nutrition may affect gene expression, possibly altering susceptibility to diet and environmental stressors that promote obesity in later life (Barker et al., 1989; Barker, 1995).

PHYSICAL INACTIVITY

Epidemiology and the Health Consequences of Physical Inactivity

It is recommended that, to reduce health risks, healthy adults engage in at least 150 minutes of moderate intensity physical activity per week (Pate et al., 1995). Despite the positive effects of regular physical activity on breast and colon cancer (McTiernan et al., 1998) and on CVD risk factors (U.S. DHHS, 1996), approximately one-half of adult Americans do not engage in moderate physical activity for at least 30 minutes at least 3 times a week (Sullivan et al., 2005). Engaging in regular physical activity also has important benefits following a cancer diagnosis. A meta-analysis of randomized controlled trials of physical activity interventions concluded that such interventions have significant benefits for cardiovascular respiratory fitness and can reduce cancer treatment side effects (Schmitz et al., 2005b). Physical activity interventions for cancer patients also have been shown to reduce body fat and plasma levels of insulin-like growth factor (Schmitz et al., 2005a).

Genetic and Environmental Determinants of Physical Activity

Levels of physical activity are determined by a complex set of factors. Yet, these determinants are less well studied than those for tobacco use and obesity. Investigations of locomotor activity in inbred mouse strains provide evidence for significant genetic influences on activity when confined to a running wheel (Mhyre et al., 2005). However, it is yet to be determined which behavioral systems underlie this effect (e.g., reward, exploration, or motor drive) or how activity levels would be affected when the animal’s environment provided the opportunity for a variety of behaviors requiring different levels of activity for different types of rewards (McClintock, 1981; Hermes et al., 2005). Environmental factors, such as food shortage, can enhance or attenuate mouse strain differences in locomotor activity in response to stimulants, underscoring the importance of gene-environment interactions (Cabib et al., 2000). In humans, approximately 30 to 60 percent of the variance in physical activity and sports participation is due to heritable factors (Perusse et al., 1989; Beunen and Thomis, 1999). A polymorphism in the MC4R gene has been implicated in physical activity levels in nonobese humans and in the general population. This association has been attributed to the role of this receptor in metabolic rate and energy expenditure, however, the precise mechanism is not yet clear (Loos et al., 2005). Features of the social environment that reinforce a sedentary lifestyle (e.g., television, video games, computers) as well as the built environment (large shopping malls located outside of the city, zoning laws prohibiting building businesses within walking distance of homes) contribute to physical inactivity and may modify the effects of genetic predisposition to inactivity.

Specific genetic factors should be examined in conjunction with known social environmental determinants (e.g., media exposure, family and peer influences). For initiation studies, there is a need to focus on critical development periods; for example, early to late adolescence for tobacco use and early childhood through adolescence for obesity and physical inactivity. For studies of persistence and behavior change, there is a need to include investigations of critical periods in adulthood when environmental transitions occur, such as young adulthood (ages 18 to 25).

USING INTERMEDIATE PHENOTYPES TO INVESTIGATE THE EFFECTS OF GENE-ENVIRONMENT INTERACTIONS

Intermediate phenotypes are traits or outcome measures that mediate the effects of gene-environment influences on risk behaviors (see Figure 4-2). Such measures tend to be more proximal to the biological determinants than are the risk behaviors themselves, and therefore, they can be assessed with greater experimental control in human models. For example, in studies of tobacco use, laboratory-based intermediate phenotypes have included individual differences in the rewarding value and tolerance of nicotine, its cognitive and autonomic effects, and the effects of nicotine deprivation (Munafo et al., 2005b). Intermediate phenotypes in obesity studies have included the reinforcing value of food, food preferences, food intake, and satiety (see also the commissioned paper on obesity in Appendix C). As discussed in more detail below, these measures also may include dimensions of personality or temperament that are partly biologically based and that may increase the likelihood that an individual will engage in health risk behaviors. In fact, some of the most convincing evidence for gene-environment interactions has been provided by research in these areas. However, while intermediate phenotypes are likely to provide useful research tools, they are quite complex and, therefore, caution should be used when extrapolating the clinical application of such research.

FIGURE 4-2. Intermediate phenotypes of gene-environment effects on risk behaviors and health.

FIGURE 4-2

Intermediate phenotypes of gene-environment effects on risk behaviors and health.

Measuring biological and genetic modifiers of risk also is essential, particularly for predicting whether engaging in a health risk behavior actually results in disease. For example, some people who consume large quantities of animal fat do not necessarily have proportionately high low-density lipoprotein (LDL) levels, which are associated with increased risk for CVD. The Inuit of Greenland, who eat a traditional diet of orsoq, seal, and whale fat, do not have the expected high LDL cholesterol levels or the resultant high rates of CVD (Bjerregaard et al., 1997). Likewise, polymorphisms in apolipoprotein E, a carrier protein important to liver metabolism of LDL, result in different levels of LDL and cardiovascular risk in people who eat similar diets (Miltiadous et al., 2005). A more detailed discussion of both biological and behavioral traits is provided in the following section.

Beyond Risk Behaviors

The inclusion of measurable intermediate phenotypes will assist investigators in the exploration of the relationship among gene-environment interactions, risk behaviors, and health. This may involve incorporating more extensive assessments of biologically based dimensions of personality and temperament and/or incorporating laboratory-based measures of risk behavior propensity (e.g., the rewarding value of nicotine or high-fat foods). Animal and human laboratory models can be performed in parallel to test the effects of genetic factors and environmental influences on intermediate phenotype measures (Blendy et al., 2005). Using genetic animal models and human genetic association studies to stratify populations, the genetic effects on risk behaviors can be measured in the presence and absence of key social environmental cues and stressors.

However, it is not only through risk behaviors like smoking, poor eating habits and obesity, or low exercise levels that gene-environment interactions influence health. Another key pathway that is just as important involves effects of gene-environment interactions on biological characteristics involving neuroendocrine, autonomic, cardiovascular, metabolic, inflammatory, and hemostatic functions. There are several examples in the recent literature that illustrate these gene-environment interaction effects on biomarkers.

The Lys198Asn polymorphism of the Endothelin-1 gene moderates the impact of both obesity and socioeconomic status on systolic blood pressure reactivity to an acute environmental stressor in African American and Caucasian young adults (Treiber et al., 2003). The G308A polymorphism of the TNFα gene moderates the impact of chronic environmental stress, as measured by vital exhaustion levels, on plasma levels of C-reactive protein, a potent risk factor for CVD (Jeanmonod et al., 2004). The extensively studied promoter polymorphism of the serotonin transporter gene (5HTTLPR) moderates the impact of acute mental stress on blood pressure (Williams et al., 2001), an effect that has been cited as one potential mechanism that could be mediating the reported association between the 5HTTLPR long allele and increased risk of myocardial infarction (Fumeron et al., 2002).

Personality and Temperament as Intermediate Phenotypes in Investigations of Risk Behaviors and Health

After many years of distrust and disuse, the concept of a personality trait is once more proving useful in many types of studies. New tools of analysis have made it possible to define and refine the idea of what personality traits actually are, and to demonstrate the universality of certain kinds of individual differences. The term personality captures the collective and dynamic organization of all the psychophysical systems that determine the adjustment of the person to his/her environment (Svrakic and Cloninger, 2005). Temperament is defined more restrictively as the body’s biases as it modulates behavioral responses to and styles of coping with prescriptive physical stimuli, such as danger, stressors, or various types of reward. Personality and temperament are of importance to health professionals because they can underlie certain psychiatric illness (Hirschfeld, 1999). In addition, certain aspects of personality have been associated with increased risk for coronary artery disease and the contraction of human immunodeficiency virus (HIV), psoriasis, ulcerative colitis, and many other diseases that have been described as psychosomatic (McCown, 1993; Tyrer, 1995). Dimensions of temperament may also predispose people to health risk behaviors such as tobacco use.

Personality

A principal reason for the scientific re-birth of personality traits is the use of factor analysis to define and validate them. The “Big Five” model, the one whose use is most widespread and accepted, is based on factor analyses of self-reported descriptions of social and emotional behavior. The five personality domains are: Neuroticism (N, negative affectivity), Extraversion (E versus Introversion), Openness to experience (O), Agreeableness, and Conscientiousness. This model is based on a robust factor structure that has been validated in a variety of populations and cultures using the NEO-Personality Inventory (NEO-PI), a personality test designed to assess normal adult personality (McCrae and Costa, 2002). The population samples were drawn from the United States, Germany, Portugal, Israel, China, Korea, and Japan, and included people from ages 18 to 105 (McCrae et al., 1999; Labouvie-Vief et al., 2000).

Personality traits are consistent and are associated with behavioral trends, coping strategies, and health behaviors. This makes it possible to use them to predict health and life outcomes (Whitbourne, 1987; Bosworth et al., 1999; Caspi and Roberts, 1999), depending on the strength of certain traits. To some extent, Alzheimer’s disease (Siegler et al., 1994) and CVD (Hemingway and Marmot, 1999; Williams et al., 2000) can be predicted from certain personality traits.

Personality, in turn, is influenced by both genes and gene-environment interactions. There is an important body of literature, beginning with a seminal paper by Lesch et al. (1996), that reports associations between genotypes of the promoter polymorphism of the serotonin transporter gene (5HTTLPR) and the personality domains of neuroticism (including facets of anxiety, angry hostility, depression, and impulsiveness) and agreeableness. Lesch and colleagues reported a positive correlation of the 5HTTLPR short allele not only with Harm Avoidance but also with the NEO domain of Neuroticism. There was a negative correlation with Agreeableness, thus relating candidate genes that regulate function of the key neurotransmitter serotonin to personality or temperament.

There have now been three meta-analyses published evaluating studies on the association between the 5HTTLPR polymorphism and anxiety-related traits. Two of these (Schinka et al., 2004; Sen et al., 2004) found that there are reliable associations between 5HTTLLPR and Neuroticism as measured by the NEO-PI, but not Harm Avoidance. A third meta-analysis (Munafo et al., 2005a) found the opposite pattern. Whatever the ultimate outcome of this issue, the weight of the evidence suggests that the five-factor model as assessed by the NEO-PI is reliably associated with variation in one highly studied candidate gene, the serotonin transporter.

There is extensive research showing that psychological factors like depressed affect (as opposed to the illness of major depressive disorder—see below), hostility and anger, and anxiety are associated with increased risk of CVD and the biological and behavioral factors that likely mediate that increased risk (see, for example, Williams et al., 2003a). The critical importance of psychosocial stressors on disease risk has been strongly confirmed in the INTERHEART Study (Rosengren et al., 2004) that examined over 24,000 heart attack patients and controls in countries around the world. The study found that social-environmental factors (such as stress at home or work) and psychological factors (such as depression) were associated with as large an increase in heart attack risk as that associated with biological risk factors (e.g., high blood pressure or high lipids) and with behavioral risk factors (e.g., smoking).

In fact, the psychological risk factor hostility is associated in both prospective and cross-sectional studies with increases in several health risk behaviors, including smoking, overeating/obesity, higher lipid levels, and increased alcohol consumption (Scherwitz et al., 1992; Siegler et al., 1992). Thus it would appear that it is through negative affect and accompanying biological and behavioral characteristics that the social environment influences disease processes in ways that are moderated by genetic factors. There is, moreover, some evidence that the opposite of negative affect (optimism) is associated with more positive outcomes both subjectively and objectively with respect to feelings of well-being and recovery from ill health (Smith and Spiro, 2002), although the genetic associations have not yet been studied.

Temperament

Of the many methods proposed to assess temperament, perhaps the most widely used is the Temperament and Character Inventory (Cloninger et al., 1998). Four major temperament traits have been identified through factor analysis and investigated in many experiments: harm avoidance, novelty seeking, reward dependence, and persistence (Cloninger et al., 1998). The study of temperament underscores the notion that genetic risk factors for a disease may not be mediated directly by gene function related to the diseased system, but rather by genetic risk factors for psychological traits that change neuroendocrine function and regulate gene expression involved in disease.

Harm avoidance is a measure of behavioral inhibition and fearfulness (Cloninger et al., 1998). Some studies suggest that individuals high in harm avoidance may be more susceptible to tobacco use (Etter et al., 2003). Adrenal axis function may mediate this association since corticotropin releasing factor-like proteins also are associated with prolonged nicotine withdrawal and higher rates of relapse (Bruijnzeel and Gold, 2005).

Novelty seeking is a measure of behavioral activation and excitement seeking that includes subscales measuring exploratory excitability, impulsiveness, extravagance, and a tendency to disorder (Cloninger et al., 1998) that may increase susceptibility to tobacco use by increasing the likelihood that an adolescent will be exposed to environments in which tobacco is more available (Tercyak and Audrain-McGovern, 2003). Novelty seekers also have been shown to be more susceptible to effects of tobacco advertising (Audrain-McGovern et al., 2003b). Animal models indicate that both of these associations also may be mediated by individual differences in adrenal axis function (Piazza et al., 1993; Spina et al., 2005).

Two aspects of temperament (reward dependence and persistence) have been linked with craving during abstinence from gambling and alcohol. Reward dependence is a measure of social attachment (Cloninger et al., 1998) and persistence is a measure of perseverance (Svrakic and Cloninger, 2005). Reward dependence is negatively correlated with craving for gambling, while persistence is negatively associated with craving for alcohol (Tavares et al., 2005). Thus, if nicotine addiction shares mechanisms with other addictions, future research may uncover a role for these other aspects of temperament and their underlying neuroendocrine and pharmacological systems (Svrakic and Cloninger, 2005).

Temperament has also been investigated regarding its association with specific disease states, such as Attention Deficit Hyperactivity Disorder (ADHD), which is a risk factor for the initiation and persistence of tobacco use (Lerman et al., 2001; Tercyak et al., 2002). Lynn and colleagues (2005) hypothesized that the dopamine D4 receptor mediated the association between novelty seeking and ADHD. However, they found that the DRD4 gene variant independently predicted ADHD, but not novelty seeking. This finding highlights the complexity of the associations between temperament, genetics, neural intermediate phenotypes, and disease states.

Sex/Gender, Race/Ethnicity, and Personality

Both sex/gender and race/ethnicity have been reported to moderate the effects of genotype on personality dimensions. Gelernter et al. (1998) found that the 5HTTLPR short allele was associated with higher Harm Avoidance scores in males but with lower scores in females; and also that the short allele was associated with higher Neuroticism scores in European Americans but with lower scores in African Americans. Interestingly, these effects parallel moderation of 5HTTLPR effects on a measure of central nervous system serotonin function, cerebrospinal fluid levels of the serotonin major metabolite 5HIAA, by both race/ethnicity (short allele → high 5HIAA in African Americans, low 5HIAA in European Americans) and sex/gender (short allele → high 5HIAA in women, low 5HIAA in men) (Williams et al., 2003b). The mechanisms responsible for these differential effects of 5HTTLPR genotype on personality and brain serotonin levels are not clear at present, but could involve differential patterns of linkage disequilibrium between the 5HTTLPR polymorphism and other sites on the serotonin transporter gene in different population groups, as reported by Gelenter et al. (1999).

Depression, Genes, the Environment, and Health

Emotional or motivational states also can be a critical intermediate phenotype between gene-environment interaction and health risk behaviors, depression being, perhaps, the prototype. Diagnosed depressive disorders (Schulz et al., 2002) such as major depression as well as depressive symptoms (Blazer et al., 2001) have been associated with adverse health outcomes. Depression has been demonstrated to be a risk for a variety of disorders, including diabetes and certain types of cancer, but especially for CVD (Schulz et al., 2000). The factors by which depression leads to poorer health outcomes may include some that are indirect, such as a reduced likelihood seeking health care and of complying with the recommendations of health care professionals. They also may include direct links (Schulz et al., 2000). For example Schulz et al. (2000) suggested that motivational depletion may directly contribute to compromised cardiac function and increased risk for myocardial infarction. A listing of potential mediators of the effects of both depression and hostility/anger on CDV risk would include decreased parasympathetic tone, increased hypothalamic-pituitary-adrenal axis and sympathetic nervous system activation, and increased inflammatory cytokines, and increased platelet activation.

In addition, depression is clearly determined by an interaction between genetic and environmental factors. It has been recognized for many years that depression is in part an inherited trait, and the influence of that heritability persists into later life (Gatz et al., 1992; Kendler, 1996). In studies of twins reared apart, both genetic and environmental factors have been shown repeatedly to contribute to depressive symptoms (Kendler, 1996). In addition, population studies have demonstrated the interaction of genetic polymorphisms and environmental stressors (Caspi et al., 2003; Kendler et al., 2005).

For example, in a prospective, longitudinal study of a representative birth cohort, Caspi et al. (2003) tested the observation that stressful experiences lead to depression in some people, but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than did individuals homozygous for the long allele. This epidemiological study thus provides remarkable evidence for a gene-environment interaction in which an individual’s response to environmental stressors is moderated by his/her genetic makeup.

Not only does this study have important implications for the investigation of how gene-environment interactions affect health, the rapid and extensive replication of its gene association results has been unusually significant. The 2003 study by Caspi and colleagues was replicated and extended through findings by Eley et al. (2004), Kaufman et al. (2004), Grabe et al. (2005), and Kendler et al. (2005). The immediate replication of gene association findings has been the exception rather than the rule for such studies. The replication of this gene-environment finding with respect not only to incidence of major depression, but also to depressive symptom levels suggests the likelihood that genetic effects on various endophenotypes are far larger when varying levels of critical environmental exposures are taken into account (Moffitt et al., 2005).

In the Caspi et al. (2003) study, for example, there was no effect of the 5HTTLPR genotype on incidence of major depression in persons with no stressful life events over the preceding five years. In marked contrast, among those with four or more stressful life events, there was no increased incidence of major depression among those with the 5HTTLPRL/L genotype, a 21 percent increase in those with the L/S genotype, and a 33 percent increase among those with the S/S genotype.

It would be hard to overstate the implications of this replicated demonstration of a very large genetic effect on the health of persons only with certain social-environmental exposures. It means that if the appropriate environmental exposures are taken into account, it will be far easier to detect and replicate the effects of genes on disease-relevant endophenotypes than it was when the search for genes was conducted in heterogeneous samples. There is reason to believe that this principle will operate not only with respect to chronic levels of stress over time, but also with respect to single, major life stresses. For example, myocardial infarction is a major life stress in which the presence of the 5HTTLPR short allele predicted increased levels of depression over the ensuing months (Nakatani et al., 2005). The same is suggested by a study on stroke that used a very small sample size (Ramasubbu et al., 2006).

CONCLUSION

A better understanding of risk behaviors is critical to improving the public’s health. To date, most efforts have been directed toward modifying risk behaviors, such as programs to increase physical activity or to decrease smoking. Biological augmentation of behavioral modification has been partially successful, such as the use of the nicotine patch for smoking cessation. Health psychologists are increasingly calling attention to the critical role of sociocultural context, a necessary factor to consider if efforts to modify risk behaviors are to be effective. In other words, a risk-prevention program that is effective in one culture may be much less effective in another. Only recently have the genetic contributions of risk behaviors and the environments that lead to the expression of intermediate phenotypes been brought into focus. The recognition that behaviors that increase risk for disease may be driven by genetic factors and modified by social factors presents a rich yet complex paradigm for designing and testing intervention strategies for the future.

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Copyright © 2006, National Academy of Sciences.
Bookshelf ID: NBK19927

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