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

Abstract

Dopamine-beta-hydroxylase (D beta H) catalyzes the conversion of dopamine to norepinephrine and is released from sympathetic neurons into the circulation. Plasma-D beta H 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 beta H 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-D beta H activity in these populations. In EAs, homozygosity at the T allele predicted the very low D beta H-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 beta H activity and provide new tools for investigation of the role of both D beta H and the DBH gene in human disease.

Figure 1

Distribution of plasma-DβH activity in AA (A), EA (B), and Jp (C). Subjects are grouped in successive 2.5-nmol/min/ml increments. The hatched bar indicates the results for the very low DβH-activity group. The EA and Jp mean activity values differed significantly (P<.01, one-way ANOVA; followed by Dunnett C post-hoc test).

Figure 2

Distribution of square-root plasma-DβH activity, by genotype, at DBH polymorphism −1021C→T in AA (A), EA (B), and Jp (C). Green bars denote T/T homozygotes, red bars denote C/T heterozygotes, and blue bars denote C/C homozygotes. A single C/C homozygote with an extreme activity value of 11.2 square-root nmol/min/ml was omitted from the EA distribution plot, for the purpose of graphical clarity.