(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)



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