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

被引:234
作者
Zabetian, CP
Anderson, GM
Buxbaum, SG
Elston, RC
Ichinose, H
Nagatsu, T
Kim, KS
Kim, CH
Malison, RT
Gelernter, J
Cubells, JF
机构
[1] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA
[2] Yale Univ, Ctr Child Study, New Haven, CT 06520 USA
[3] Connecticut Mental Hlth Ctr, New Haven, CT USA
[4] Yale Univ, Sch Med, VACHS, Dept Psychiat, W Haven, CT 06516 USA
[5] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA
[6] Fujita Hlth Univ, Inst Comprehens Med Sci, Toyoake, Aichi, Japan
[7] Harvard Univ, McLean Hosp, Sch Med, Mol Neurobiol Lab, Belmont, MA 02178 USA
关键词
D O I
10.1086/318198
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
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收藏
页码:515 / 522
页数:8
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