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

Dopamine-beta -hydroxylase (D betaH) catalyzes the conversion of dopamine t o norepinephrine and is released from sympathetic neurons into the circulat ion. Plasma-D betaH activity varies widely between individuals, and a subgr oup of the population has very low activity levels. Mounting evidence sugge sts that the DBH structural gene is itself the major quantitative-trait loc us (QTL) for plasma-D betaH activity, and a single unidentified polymorphis m may account for a majority of the variation in activity levels. Through u se of both sequencing-based mutational analysis of extreme phenotypes and g enotype/phenotype correlations in samples from African American, European A merican (EA), and Japanese populations, we have identified a novel polymorp hism (-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-activit y trait, and activity values in heterozygotes formed an intermediate distri bution, indicating codominant inheritance. Our findings demonstrate that -1 021C-->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 hum an disease.