A quantitative-trait analysis of human plasma-dopamine β-hydroxylase activity:: Evidence for a major functional polymorphism at the DBH locus

Dopamine-beta -hydroxylase (D betaH) catalyzes the conversion of dopamine to norepinephrine and is released from sympathetic neurons into the circulation. Plasma-D betaH activity varies widely between individuals, and a subgroup of the population has very low activity levels. Mounting evidence suggests that the DBH structural gene is itself the major quantitative-trait locus (QTL) for plasma-D betaH activity, and a single unidentified polymorphism may account for a majority of the variation in activity levels. Through use of both sequencing-based mutational analysis of extreme phenotypes and genotype/phenotype correlations in samples from African American, European American (EA), and Japanese populations, we have identified a novel polymorphism (-1021C-->T), in the 5' flanking region of the DBH gene, that accounts for 35%-52% of the variation in plasma-DbH activity in these populations. In EAs, homozygosity at the T allele predicted the very low D betaH-activity trait, and activity values in heterozygotes formed an intermediate distribution, indicating codominant inheritance. Our findings demonstrate that -1021C-->T is a major genetic marker for plasma-D betaH activity and provide new tools for investigation of the role of both DbH and the DBH gene in human disease.