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Dopamine--hydroxylase in postural tachycardia syndrome

¹Autonomic Dysfunction Center and ²Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee

Submitted 20 December 2006 ; accepted in final form 3 April 2007

	ABSTRACT

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Norepinephrine is frequently elevated in postural tachycardia syndrome (POTS), a syndrome of heterogeneous etiology characterized by a >30 beats/min increase in heart rate with standing. Norepinephrine is synthesized from dopamine by dopamine--hydroxylase (DBH). The results of a preliminary study suggested that the T allele frequency of the DBH –1021CT polymorphism is elevated in POTS. This allele correlates with low DBH activity and might predict reduced serum DBH activity in patients with POTS. To test the hypothesis that low DBH activity and the underlying –1021CT polymorphism are associated with increased susceptibility to POTS, we measured serum DBH activity in POTS and determined its relationship to the DBH genotype and plasma norepinephrine. Serum DBH was similar for 83 normal volunteers and 42 patients with POTS: median (range) = 22.5 (0.5–94.2) and 19.6 (0.1–68.8) nmol·min^–1·ml^–1, respectively (P = 0.282). The genotype frequencies for 254 control and 157 POTS patients were not different between groups (63% CC genotype and 5% TT genotype, P = 0.319). The T allele associated with lower serum DBH in both groups [control serum DBH = 15.7 (SD 12.3) and 35.1 nmol·min^–1·ml^–1 (SD 18.6) for T carriers and noncarriers, respectively; POTS serum DBH = 8.2 (SD 5.6) and 28.5 nmol·min^–1·ml^–1 (SD 14.7) for T carriers and noncarriers, respectively]. High DBH in POTS was linked to elevated plasma levels of norepinephrine. Although DBH activity and genotype are unlikely to be primary determinants of susceptibility to POTS, differences in DBH activity in POTS may reflect differences in the level of sympathetic activation.

–1021CT; catecholamines

In the catecholamine synthetic pathway, dopamine--hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE). During sympathetic stimulation, DBH is released with NE from vesicles in sympathetic nerve terminals and enters the circulation. It was initially proposed that circulating DBH could be measured as a marker of sympathetic nerve activity (25, 33, 42, 46). Although elevations in plasma DBH activity have not been found following various sympathetic stimuli (31), plasma DBH may still reflect long-term trends in sympathetic nerve activity or the potential to increase activity (51).

Remarkably, baseline plasma DBH activity in healthy individuals varies more than 100-fold. Individual variation in DBH activity is primarily genetically determined. Among the polymorphisms found in the DBH gene that affect either enzyme levels or function (3, 4), the –1021CT polymorphism in the promoter region accounts for up to 52% of variation in plasma DBH activity (5).

Because of individual variability in DBH, associations between DBH activity and various diseases have been elusive (25). Nevertheless, plasma and cerebrospinal fluid DBH activity in a variety of diseases have deviated significantly from healthy control values (14, 28, 30, 36, 47, 52), and genetic studies have provided evidence for an association of the DBH gene with migraine (26) and Parkinson's disease (13). Patients with POTS are frequently characterized by a hypernoradrenergic state and have elevated plasma NE levels when standing (E. M. Garland, unpublished data) (8, 11, 16–18, 34) The role of DBH in NE synthesis makes the DBH gene an attractive candidate for a genetic contribution to POTS.

In 2003, the results of genotyping in 38 of our patients with POTS indicated a somewhat increased frequency of the T allele of the –1021CT polymorphism in POTS, although it was not significantly greater than in the control population (2). We have now conducted a much larger study to test the hypothesis that low DBH activity and the underlying –1021CT polymorphism are associated with increased susceptibility to POTS. To test this hypothesis, we compared the distribution of DBH genotypes and serum DBH activity in 260 healthy individuals and 159 patients with POTS.

	MATERIALS AND METHODS

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Subjects. The study was approved by the Vanderbilt University Institutional Review Board, and subjects gave written informed consent. A diagnosis of POTS was based on the following stringent criteria: 1) a history of daily orthostatic symptoms for at least 6 mo; 2) an increase in heart rate (HR) of at least 30 beats/min with standing or a standing HR 120 beats/min; 3) an absence of orthostatic hypotension (defined as a fall in BP > 20/10 mmHg); and 4) an absence of conditions, such as dehydration, substantial weight loss, or systemic illnesses, that could provoke orthostatic intolerance. All patients underwent an evaluation that included a physical examination, an electrocardiogram, and routine laboratory studies. Renal function, liver function, and hematologic screening were normal. Patients were admitted to the Vanderbilt Autonomic Dysfunction Center between July 1995 and August 2006, and healthy controls were recruited mainly from the Vanderbilt community during the same time period. Serum DBH activity was assessed only in those evaluated after January 2003. Participants were primarily Caucasian (controls: 82% Caucasian, 9% African-American, and 9% other; and patients: 95% Caucasian, 2% African-American, and 3% other) and ranged in age from 18 to 70 yr. Patients and control subjects were free of medications that could affect autonomic tone for at least five half-lives, and smoking was not permitted during the study. Studies were conducted at the General Clinical Research Center at Vanderbilt University. Before being tested, all participants consumed a caffeine-free, low monoamine diet that contained 150 meq sodium/day and 70 meq potassium/day and was free of substances that could interfere with catecholamine analyses.

Genotyping. Genomic DNA was prepared from blood using the Puregene DNA Purification Kit of Gentra Systems (Minneapolis MN). DNA samples were genotyped for the –1021CT polymorphism of DBH (rs1611115) via the 5' nuclease assay for allelic discrimination (TaqMan, Applied Biosystems) according to manufacturer's instructions. The primers and probes are shown in Table 1. Probes were labeled at their 5' end with either VIC or 6-carboxyfluorescein (FAM) reporter dyes. PCR amplification was performed using 5–10 ng of genomic DNA in a thermal cycler (GeneAmp PCR System 9700, Applied Biosystems) with an initial step of 95°C for 10 min followed by 50 cycles of 92°C for 15 s and 60°C for 1 min. After amplification, the fluorescence of each sample was read on the ABI 7900HT Sequence Detection System (Applied Biosystems) and analyzed with the Sequence Detection Software (Applied Biosystems). Each sample was run in duplicate, and the appropriate negative controls were used.

View this table: [in this window] [in a new window]   Table 1. Primers and probes for –1021CT polymorphism of DBH

Orthostatic testing. Posture studies were performed after an overnight fast and 30 min of supine rest. Subjects were asked to stand by the bedside for 30 min or until symptoms necessitated resuming the supine position. HR and BP were recorded at intervals using single measurements from an automated oscillometric blood pressure device (Dinamap, Critikon) (21). Measurements obtained while supine and after being positioned upright for 3–5 min were used for this report. Blood samples were collected from an indwelling catheter in a peripheral arm vein for measurement of plasma catechols at rest and at the end of the standing phase. For catechols, blood was collected in plastic syringes and transferred to chilled tubes containing EGTA and reduced glutathione. In addition to NE, epinephrine, and DA, we measured dihydroxyphenylglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC), the deaminated metabolites of NE and DA, respectively, as well as the catecholamine precursor L-3,4-dihydroxyphenylalanine (DOPA). For all analyses, plasma catechols were isolated by adsorption onto acid-washed alumina and then separated and quantified by reverse-phase, high-performance liquid chromatography with electrochemical detection, according to a modification of the procedure of Goldstein et al. (10). DHPG, DOPA, and DOPAC were not measured in all subjects; the number of subjects for each statistical determination is included in the tables.

Statistical analysis. Genotype frequencies were compared between patients with POTS and controls by ² analysis. Hardy-Weinberg equilibrium was confirmed using the online calculator http://www.genes.org.uk/software/hardy-weinberg.shtml. The association between genotypes and POTS was analyzed by logistic regression and expressed as odds ratio (OR) with a 95% confidence interval (CI). Interactions with age, sex, race, and body mass index were determined by entering these as covariates in the logistic regression analyses, and adjusted ORs were ascertained.

Controls versus POTS. Since most hormone and hemodynamic variables were not normally distributed, the Mann-Whitney U-test was used to test for significant differences between POTS patients and control subjects for continuous variables. Sex and race distributions were compared by ² analysis.

Influence of genotype or serum DBH on posture study results. Supine BP, HR, and catechols were compared between T allele carriers (TT or CT) and noncarriers (CC) by Mann-Whitney U-test. The patient and control groups were divided into tertiles according to serum DBH activity, and the influence of serum DBH activity on posture study results was assessed by the Kruskal-Wallis test.

Statistical analyses were carried out using the statistical software SPSS for Windows, version 14.0 (SPSS, Chicago, IL). Reported P values are two-tailed, and P < 0.05 was considered significant. The results are expressed as means (SD), unless otherwise indicated.

	RESULTS

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Demographic characteristics. Descriptive characteristics of the subjects are presented in Table 2. The POTS patient population was somewhat older than the control population [35.2 (SD 10.6) vs. 32.3 yr (SD 9.6), P = 0.007] and had a slightly smaller body mass index [23.6 (SD 5.1) vs. 24.9 kg/m² (SD 4.4), P = 0.038]. A greater proportion of Caucasian individuals comprised the patient group. Consistent with a prevalence favoring females in POTS, the proportion of females was greater in the patient group. As defined in our inclusion criteria, the orthostatic increase in HR in patients exceeded that in control subjects [39 (SD 18) vs. 20 beats/min (SD 11), P < 0.001], and upright plasma NE was also higher in POTS.

Distribution of –1021CT genotypes.

View this table: [in this window] [in a new window]   Table 3. DBH –1021CT polymorphism genotype frequencies in control subjects and patients with POTS

View larger version (9K): [in this window] [in a new window]   Fig. 1. Scatterplots of serum dopamine--hydroxylase (DBH) activity according to DBH –1021CT genotype in healthy control subjects (left) and patients with postural tachycardia syndrome (POTS; right). Horizontal lines indicate means. TT & TC, T allele carriers; CC, noncarriers.

Interaction between –1021CT genotype or DBH activity and orthostatic responses.

View this table: [in this window] [in a new window]   Table 5. Hemodynamic and neurochemical orthostatic data according to DBH –1021CT genotype

View larger version (42K): [in this window] [in a new window]   Fig. 2. Supine and upright plasma L-3,4-dihydroxyphenylalanine (DOPA; top), norepinephrine (NE; middle), and dihydroxyphenylglycol (DHPG; bottom) in patients with POTS (left) and control subjects (right) having low, medium (mid), or high serum DBH activity. Means ± SE are indicated. P values are for the comparison between low- and high-DBH tertiles at the 2 time points.

	DISCUSSION

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The principal new findings in this report are as follows: 1) an association exists between DBH genotype and serum DBH activity in patients with POTS, analogous to that reported previously for healthy populations and confirmed in our control group; 2) abnormalities in plasma DBH levels or DBH genotype are not primary determinants of susceptibility to POTS, since no significant abnormalities in genotype frequency or serum DBH activity were noted in our group of patients with POTS; and 3) differences in DBH activity within our group of patients with POTS may reflect not only the DBH –1021CT genotype but also the level of sympathetic activation, since high DBH among our patients was linked to high plasma NE concentrations.

Our study investigated whether the DBH –1021CT polymorphism and plasma DBH activity associate with a diagnosis of POTS or with the hemodynamic and neurochemical changes that occur with standing in POTS. The remarkable interindividual variability in serum DBH activity was described by Weinshilboum and colleagues (43, 45) who also noted very low activity in a subgroup of individuals comprising 3–4% of European-Americans. Family studies revealed that genetic factors play a major role in determining serum DBH activity (44), and the –1021CT polymorphism was later found to account for up to 52% of the variation in enzyme activity with the TT homozygotes having the lowest DBH activity (51). Serum DBH is biochemically and immunologically similar to that in sympathetic nerves and the adrenal medulla (42) and might be influenced by peripheral sympathetic neuronal activity in addition to DBH genotype (1).

Susceptibility to POTS has previously been shown to be affected by genes encoding the NE transporter (SLC6A2) (35), the ₁-adrenergic (49) and ₂-adrenergic (19) receptors, endothelin-1 (50), and endothelial nitric oxide synthase (NOS3) (9), but these variations can only explain a minor proportion of cases, and a number of other genes are likely to contribute to this multifactorial syndrome. The results of a preliminary study of the association between the DBH –1021CT polymorphism and POTS suggested a somewhat increased frequency of the T allele from 0.159 in controls to 0.315 in patients with POTS (2). Although our larger study demonstrated that genotype influences serum DBH activity in patients with POTS as well as in controls, the genotype frequencies were similar for the two groups. The DBH –1021CT genotype did not influence susceptibility to POTS.

Considerable variability emerged in serum DBH activity in both our healthy controls and patients with POTS, but group means did not differ. Because some studies have shown a modulation of plasma DBH activity by sodium loading and depletion, as well as posture (40), plasma DBH activity was assessed in our study participants following 3 days on a fixed sodium diet and in the supine position. It is unlikely, therefore, that a difference in serum DBH activity between control subjects and patients with POTS was masked by such environmental influences. We likewise believe that it is unlikely that our results were affected by the bias toward Caucasian females in our population of patients with POTS. Previous studies have discovered no differences in DBH activity related to sex (27, 42), and we also obtained similar values for men and women [control men, 29.3 (SD 19.7) vs. control women, 26.4 nmol·min^–1·ml^–1 (SD 18.0), P = 0.482; and POTS men, 18.9 (SD 14.3) vs. women with POTS, 24.1 nmol·min^–1·ml^–1 (SD 15.6), P = 0.429]. Furthermore, although the groups were small, we found no influence of race on serum DBH activity in the control group.

We next assessed the disease-modifying potential of DBH in POTS by comparing the responses to orthostasis, e.g., supine and standing HR, BP, and plasma catechols, in groups identified by genotype or serum DBH activity. We found that the patients with higher DBH had greater plasma levels of NE and DHPG than patients with lower DBH. This finding could reflect 1) a higher potential to synthesize NE, as a result of an increased expression of the DBH enzyme in sympathetic neurons; and/or 2) a greater sympathetic nerve stimulation with release of more NE and DBH from the vesicles via exocytosis. Either explanation would be consistent with the heightened sympathetic nervous system activity demonstrated in POTS (8, 11, 16). Plasma NE is not a perfect biochemical marker of sympathetic nervous system activity since circulating NE levels are also affected by clearance (e.g., NE transporter), leakage from storage vesicles, and adrenomedullary stimulation (6). Nevertheless, we and others have found them to be useful in elucidating pathophysiologies in studies that were too large for a measurement of NE spillover or sympathetic nerve activity. A relative deficiency in NE uptake by the NE transporter has been proposed to contribute to the excessive NE levels in POTS (35), and decreased clearance contributes to the rise in standing plasma levels of NE (22). We calculated the orthostatic increment in plasma DHPG relative to the increment in plasma NE as an indicator of NE transporter uptake activity, as has been suggested previously (11, 12). Similar values, regardless of serum DBH activity, indicate that the increases in plasma NE and DHPG associated with higher DBH activity were not related to differences in NE uptake. Since DOPAC was not influenced by serum DBH activity, it is unlikely that the stimulation of monoamine oxidase contributed to the elevated DHPG levels.

Differences emerged between our patient and control groups in that higher DBH was linked to greater NE and DHPG levels in POTS, with no effect on plasma DOPA levels, but higher DBH in the control group was coupled to lower DOPA and unaffected plasma NE and DHPG levels. One explanation for this divergence might be that the NE synthetic pathway in sympathetic neurons is hyperactive in POTS, driving the formation of more NE as enhanced tyrosine hydroxylase activity produces more DOPA.

Controlling for the genetic proportion of variance in DBH activity may facilitate discoveries of altered activity related to different disorders or environmental influences. Contrary to what might be expected given the hypernoradrenergic status of many patients with POTS, when we stratified our control and patient populations according to genotype, serum DBH tended to be lower in POTS than controls for TT, CT, and CC individuals, although none of the differences was significant. A controlled genotype study of serum DBH activity in a larger number of patients with POTS is needed to confirm these results.

This study contributes another dimension to the phenotype of the complex disorder of POTS. We have eliminated the DBH –1021CT polymorphism as a genetic contributor to POTS. Group means for serum DBH activity were also similar for our healthy controls and patients with POTS. The relationship between supine serum DBH activity and supine and upright plasma NE and DHPG levels in POTS suggests that higher DBH activity in this disorder may reflect greater sympathetic activation.

	GRANTS

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This research was supported in part by National Institutes of Health Grants M01-RR-00095, R01-HL-071784, and P01-HL-56693.

	ACKNOWLEDGMENTS

 
We thank the professional staff of the Vanderbilt Clinical Research Center and the study participants. The Vanderbilt University Center for Human Genetics Research/Clinical Research Center DNA Resources Core provided technical assistance for this work.

	FOOTNOTES

 

Address for reprint requests and other correspondence: E. M. Garland, Autonomic Dysfunction Center, AA3228 Medical Center North, Vanderbilt Univ., Nashville, TN 37232-2195 (e-mail: emily.garland{at}vanderbilt.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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