30 A significant association between the 5-HTTLPR S allele and the incidence of poststroke major depression underlines the importance of the reciprocal relationship on a genetic basis.31 Altogether, these findings might lead to the speculation that the HTTLPR contributes to the risk for CVD with both the S- and L allele, with the L allele working via platelet activation and the S allele contributing via the increased susceptibility for depression. The 5-HTTLPR and response to stress The possible impact of the 5-HTTLPR polymorphism on the effects of central 5-HT on cardiovascular

Inhibitors,research,lifescience,medical reactivity in response to mental stress was investigated in healthy volunteers. Subjects with one or two L alleles had higher cerebrospinal fluid levels of the 5-HT metabolite 5-hydroxyindole-acetic acid (5-HIAA) than those with the S/S genotype, and exhibited increased blood pressure and increased heart rate responses to a mental stress.16 Comparable results were obtained in a further study investigating the cardiovascular response during a Inhibitors,research,lifescience,medical psychological challenge in relation to the 5-HTTLPR genotypes. Young healthy male Inhibitors,research,lifescience,medical L allele carriers showed increased heart rate reactivity in response to stress, an association that could not be shown in female L allele carriers. This finding could thus at least mTOR inhibitor partly explain

the sex differences in heart rate response.32 The link between depression and CVD is strengthened by the recent evidence for a gene-environment interaction. Investigating a large representative cohort in a prospective longitudinal study, Caspi Inhibitors,research,lifescience,medical and colleagues33 were able to show that individuals with one or two copies of the S allele exhibited more depressive symptoms, more diagnosable depression, and more suicidality in relation to stressful life events than individuals homozygous for the L allele. This finding suggests that genetic variants may act to promote resistance to environmental influences. In addition, the study by Grabe et al34 demonstrated this gene-environment interaction in relation to the 5-HTTLPR genotypes in a

cohort with Inhibitors,research,lifescience,medical severe mental (eg, unemployment, disrupted social network) and physical (eg, myocardial infarction, stroke, diabetes, and degenerative diseases) distress. They found significant interactions between the Suplatast tosilate 5-HTTLPR S allele and unemployment or chronic disease, but only in females. This finding not only confirms previous findings for a significant gene-environment interaction of the S allele, but it also indicates a higher mental vulnerability to social stressors and chronic disease. The 5-HTTLPR and risk factors for cardiovascular disease Smoking is one of the unquestioned risk factors for CVD, and dependence on tobacco, like many other drug dependencies, is a complex behavior with both genetic and environmental factors contributing to its variance.