This project centers around investigation of genetic variations influencing the disposition of catecholamines. The general hypothesis that forms the basis of this project is that deficiencies or polymorphisms of genes affecting the expression or function of enzymes, transporters or receptors central to the functioning of catecholamine systems should produce distinct clinical phenotypes that can be predicted and/or interpreted from our current understanding of these catecholamine systems. Previous studies examining the neurochemical and clinical consequences of specific genetic deficiencies of monoamine oxidase (MAO) isoenzymes A and B have been followed by studies of a common polymorphism affecting the activity of catechol-O- methyltransferase (COMT), an important enzyme in the extraneuronal metabolism of catecholamines. Forty nine normal volunteers were genotyped for the presence of heterozygous and homozygous low activity and high activity forms of the enzyme. The association of these polymorphisms with differences in neurochemical metabolic profile, red blood cell COMT activity, and variations in behavior and psychological profile were examined. Highly significant reductions in activities of both soluble and membrane bound forms of COMT were found in subjects with the polymorphism for the low activity COMT gene, with a clear cut gene dose affect existing between heterozygotes and homozygotes. There were also weak relationships between COMT activity and plasma levels of metanephrines, the O-methylated metabolites of catecholamines. However, differences in plasma levels of catecholamines and metabolites showed no relationship to the COMT gene polymorphism suggesting that other factors (e.g., variations in MAO activity, extraneuronal catecholamine transport) may have an over-riding effect on any influence of variations in COMT activity on catecholamine metabolism. The established relationship of the COMT polymorphism with anxiety and behavioral indices of obsessive-compulsive behavior remain to be connected to any distinct neurochemical profile; it is possible that such a profile, while not expressed in the periphery, may be present in brain.
