Genetic and Physiological Influences

Based on the extensive evidence relating central nervous system (CNS) serotonin function to the expression of psychosocial factors like hostility and the potentially pathogenic biobe-havioral characteristics that are found in persons with high hostility, Williams (1994) proposed that reduced CNS serotonin function is one brain mechanism that could account for the clustering of hostility and biobehavioral factors that increase disease risk. Using the prolactin response to fenfluramine/citalopram challenge as an index of CNS serotonin function, Manuck's research group has provided extensive evidence supporting this hypothesis, showing that lower CNS serotonin function is associated with increased aggressiveness (Manuck et al, 1998, 2002), increased expression of the metabolic syndrome (Muldoon et al, 2006), and even increased carotid arteriosclerosis (Muldoon et al, 2007). They have also used cerebrospinal fluid (CSF) levels of the major serotonin metabolite 5HIAA to index CNS serotonin function in cynomolgus macaques and found that males with lower CSF 5HIAA levels exhibit increased dominance behaviors (Kaplan et al, 2002).

It is not surprising, given these findings linking CNS serotonin function with hostility and associated biobehavioral characteristics that could mediate the effects of hostility on pathogenesis, that considerable research attention has been devoted to evaluating the effects of genes that influence serotonin function on these psychosocial and biobehavioral characteristics. In a seminal early study, Lesch and colleagues (1996) found that persons carrying the less active short (S) allele of a functional polymorphism of the serotonin transporter promoter (5HTTLPR) have higher levels of neuroticism (including the angry hostility facet) and lower levels of agree-ableness - a profile that is characteristic of high hostility - than those homozygous for the more active long (L) allele. Manuck and colleagues (2000) found that the less active alleles of a functional polymorphism in another gene that influences CNS serotonin function, monoamine oxidase A (MAOA-uVNTR), are associated with increased aggressiveness in men.

While these studies finding main effects of serotonin gene variants on hostility and related psychosocial characteristics are informative, it has become clear that any attempts to identify gene variants that influence the expression of psychological and biobehavioral phenotypes involved in disease etiology and/or course must include consideration of environmental exposures that can modify the influence of the genes on these characteristics (Moffitt et al, 2005). In a study employing this strategy that provides one example of a gene x environment interaction influencing the development of hostility, Caspi et al (2002) showed that in men who had been abused during childhood those with the less active alleles of the MAOA-uVNTR polymorphism were more likely than those with the more active alleles to engage in violent behaviors during adulthood.

Further evidence linking CNS serotonin function with hostility and other negative and positive psychological characteristics comes from a study by Siegler and colleagues (2008) in which high brain serotonin levels - indexed by high CSF 5HIAA in men with less active MAOA-uVNTR alleles - were found to be associated with lower levels of hostility and depression and higher levels of conscientiousness, altruism, and perceived social support. In addition to providing evidence that low CNS serotonin function is associated with high hostility, this study also provides evidence that CNS serotonin function could account for the clustering of hostility with other negative and positive psychosocial characteristics.

While the examples cited thus far may appear fairly straightforward, it is important to understand that this work has only recently begun, that the mechanisms being studied are far from simple, and that much additional research will be required before the final story has been told. This complexity can be illustrated with a few additional examples. Williams et al (2003) found that CSF 5HIAA levels are associated with 5HTTLPR genotypes, but in ways that vary as a function of both race and sex. In men and whites, the SS genotype is associated with lower CSF 5HIAA levels, but in women and blacks those with the SS genotype have higher 5HIAA levels than carriers of the L allele of both races and sexes. This finding suggests that both race and sex need to be tested in any attempts to relate 5HTTLPR genotypes to phe-notypes whose expression may be influenced by CNS serotonin function. The importance of this approach is illustrated by recent findings in a study by Brummett and colleagues (2008a) in which the 5HTTLPR S allele was associated with increased depressive symptom levels in women exposed to chronic stress during both childhood and adulthood, while in men it was the L allele that was associated with increased depressive symptoms. Brummett et al (2008b) documented this sex moderation of 5HTTLPR genotype effects on negative affects in an experimental study in which the increase in negative affects induced by intravenous infusion of the amino acid precursor of serotonin, tryptophan, was larger in men with the 5HTTLPR LL genotype, but larger in women with the SS genotype. In contrast to these moderations of 5HTTLPR effects on CSF 5HIAA and negative affects by race and sex, the 5HTTLPR L allele has been found associated with larger cardiovascular responses to acute mental stress in the lab in both men and women, blacks and whites (Williams et al, 2008). Support for the pathogenic effects of the 5HTTLPR L allele comes from three independent case-control studies, one in Japan (Arinami et al, 1999) and two from Europe (Coto et al, 2003; Fumeron et al, 2002) in which the 5HTTLPR LL genotype was found associated with increased risk of myocardial infarction (MI).

The foregoing indicates that the strategy of evaluating CNS serotonin function - and genes that influence it whether as main effects or via gene x environment interactions - has enabled us to make good progress towards understanding the origins of hostility and associated potentially pathogenic biobehavioral factors. But it is also clear that there is much more work to be done, both with respect to serotonin and related genes. This work will also need to focus on a broad range of other biologically plausible candidate genes, including those that influence the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis as well as the metabolic, cardiovascular, hemostatic, and inflammatory functions whose expression is influenced by the SNS and HPA axis.

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