To explore the association between the dopamine β-hydroxylase (DBH) gene C-1021T polymorphism and the occurrence of orthostatic hypotension (OH) in Chinese patients, the DBH C-1021T polymorphism was genotyped in 317 patients with OH and 664 age- and sex-matched controls with orthostatic normotension. All subjects underwent an upright posture study for the measurement of orthostatic blood pressure. OH was defined as a drop in blood pressure of 20/10 mm Hg or more within 3 min of assuming the upright posture. The allele frequency of the DBH C-1021T polymorphism in the orthostatic hypotensive group was similar to the orthostatic normotensive group (17.4 versus 14.9%, P>0.05). No statistical significant association was found between the distribution of the C-1021T genotypes and the risk of OH in both the orthostatic hypotensive and orthostatic normotensive groups even after adjustment for demographic parameters. Among the three different genotypes, blood pressure levels did not significantly differ in the general population in this study. The changes in orthostatic systolic or diastolic blood pressures among the different genotype groups were not detected (all P>0.05). The C-1021T polymorphism of the DBH was not associated with orthostatic hypotensive risk in a Chinese population.
As people spend much of their active time in the upright position, well-functioning cardiovascular reflexes are essential for neutralizing the hemodynamic effects of gravity and maintaining adequate perfusion of the upper body.1 An abnormal fall in blood pressure (BP) upon standing has been described as either postural hypotension or orthostatic hypotension (OH). According to a widely used consensus guideline,2 OH is defined as a decrease in systolic BP (SBP) of at least 20 mm Hg and/or a diastolic BP (DBP) of at least 10 mm Hg within 3 min of standing. OH is a risk factor for falls, syncope, cardiovascular events and mortality.3, 4, 5 Therefore, it is important to elucidate the underlying pathophysiology and genetic background for the prevention and treatment of OH.
The mechanisms of dysregulation in orthostatic BP are largely unknown. Shifting from a supine to a standing position invokes 500–1000 ml of blood to pool into the lower extremities.6, 7, 8, 9 A complex set of compensatory physiological mechanisms, including reflex responses in the cardiovascular and autonomic nervous systems as well as activation of the skeletal muscle and respiratory pumps, maintain the upright posture. These normal baroreflex responses increase heart rate and vascular resistance to restore normal BP, cardiac output and cerebral perfusion.6, 7, 8, 9 Impairment of cardiovascular reflexes, which can lead to inadequate homeostatic responses, may result in OH. Impaired reflexes may result from a reduction or inadequate baroreflex sensitivity,10, 11 baroreflex-mediated heart rate response12, 13 or sympathetic nervous stimulation,3 all of which can be caused by a disorder of the dopaminergic pathway. Norepinephrine is the principal transmitter in the dopaminergic pathway and maintains the heart rate and BP. Dopamine β-hydroxylase (DBH) has a major role in metabolizing dopamine to norepinephrine.14, 15 Genetic deficiency of DBH can lead to hypotension in both humans and knockout mice.16, 17
The DBH gene, located on chromosome 9q34, is composed of 12 exons.14, 15, 18 Mounting lines of evidence have suggested that the DBH structural gene is the major quantitative-trait locus for plasma DBH activity, and an unidentified single-nucleotide polymorphism (SNP) may contribute to varied activity. It has been reported that a C to T SNP at -1021 bp from the transcriptional start site of the DBH gene (-1021C/T, rs1611115) accounts for 35–52% of the variation in plasma DBH activity in several ethnically different populations, including African-American, European-American and Japanese populations.19 In addition, homozygous DBH gene -1021T allele is associated with very low plasma DBH.19 Accumulating data demonstrated that plasma DBH plays an important role in the regulation of blood pressure.20, 21 Yeh et al. found that the DBH -1021C/T polymorphism is significantly associated with SBP and DBP.22 These results suggest a relationship between the DBH gene-1021C/T polymorphism and BP regulation. Thus, the DBH -1021C/T polymorphism may contribute to OH. In this study, we investigated the possible association between the DBH gene C-1021T polymorphism and OH in a Chinese population.
Materials and methods
This study was approved by the ethical committees of both Fu Wai Hospital and a local collaborative hospital, and adhered to the principles of the Declaration of Helsinki. Written informed consent was obtained from each individual enrolled before entry into the study. All the procedures were in accordance with the institutional guidelines.
A community-based cross-sectional study was conducted in Rizhao County, a region in Shandong Province of China, from 2010 to 2011. We recruited 317 patients with OH as the case group and 664 age- and sex-matched subjects with orthostatic normotension from the same demographic area. OH was defined as a decline in SBP of at least 20 mm Hg and/or a decline in DBP of at least 10 mm Hg after shifting from a supine to an upright posture within 3 min.2 The definition of orthostatic hypertension was a postural increase of at least 20 mm Hg in the orthostatic SBP.23 Participants with neither of these two patterns were classified into the orthostatic normotensive (ONT) group. To exclude the effect of antihypertensive drugs on orthostatic BP, only untreated patients were included in the study. Untreated patients were defined as patients diagnosed with hypertension and/or not receiving any antihypertensive drugs for at least 4 weeks, according to participants’ self-reports on medication history. All of the participants participated in an interview, anthropometric measurement and blood sampling. Subjects were excluded from the study if they had any known diseases, including heart failure, renal failure, valvular heart disease, secondary hypertension, severe debilitating chronic illness (cancer, renal or hepatic diseases) and any history of coronary heart disease (for example, myocardial infarction) and stroke, and/or if they were currently receiving antidepressant medications.
Each eligible participant was interviewed at a local hospital of Rizhao in the Shandong province. Medical history and histories of cigarette smoking and alcohol consumption were obtained with a standardized questionnaire. Anthropometric measurements, including height (m) and weight (kg), were measured by trained researchers. Overnight fasting blood was drawn to determine fasting blood glucose, blood lipids (total cholesterol, triglycerides, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol), and serum uric acid levels. Obesity was defined as a body mass index ⩾30.0 kg m−2 according to the World Health Organization criteria. Hypertension was defined as a mean SBP ⩾140 mm Hg, DBP⩾90 mm Hg or current treatment with prescription antihypertensive medications.24 On the basis of the criteria formulated by the World Health Organization in 1999, diabetes mellitus was characterized as a fasting plasma glucose of ⩾7.0 mmol l−1, or a history of oral hypoglycemic or insulin use, or both.25
Supine BP was measured by a nurse or a physician with a standardized mercury sphygmomanometer and appropriate cuff sizes fitted to the subject’s right arm. All of the nurses and physicians completed a training program on the preparation of study subjects for measuring BP and standard BP measurement techniques according to the American Heart Association.26 After more than 5 min of comfortable rest in the supine position, BP and heart rate were determined as the average of two recordings, taken 1 min apart. Orthostatic BP and heart rate were determined at 1, 2 and 3 min after standing up. The maximum change of SBP or DBP after standing was regarded as the orthostatic BP alteration.
Genetic analysis of DBH -1021C/T polymorphism
Genomic DNA was extracted from peripheral leukocytes. The DBH SNP selected in this study was based on previous evidence of potential functionality, validated allele frequency and sequence-proven allelic variation. The DBH -1021C/T polymorphism was determined by ligase detection reaction (LDR) analysis. All aspects of the DNA source, preparation and genotyping were controlled using the paradigms of blindness and randomization. The reproducibility of the genotyping was confirmed by bidirectional sequencing in 100 randomly selected samples. The forward and reverse primers were 5′-IndexTermGCTGGAGGGATCAAGCAGAATG-3′ and 5′-IndexTermCAGGACCTTTGCCATCATCCAC-3′, respectively. For the multiplex PCR reaction, the annealing temperature was 64.5 °C for 11 cycles and 59 °C for 24 cycles. The reaction was completed by a final extension at 72 °C for 2 min using a thermal cycler Gene PCR System 2720 (Applied Biosystems, ABI, Foster City, CA, USA). The amplified PCR products were digested with Exol/Sap (Promega, Foster City, CA, USA) at 37 °C for 1 h. Further amplification was performed in 10 μl volume of LDR reaction mixture containing the resultant PCR product of 3 μl (30 ng), 1 μl Probe mix, 0.2 μl NEB Taq DNA ligase and 3.8 μl ddH2O. The LDR conditions included denaturing for 38 cycles at 94 °C for 1 min, and annealing for 38 cycles at 56 °C for 4 min. LDR products (0.5 μl) were mixed with 0.5 μl Liz500 SIZE STANDARD and 9 μl Hi-Di after denaturing at 95 °C for 5 min. The products were detected with an ABI 3130XL DNA Sequencer and analyzed with a Genemapper (Applied Biosystems).
Statistical analyses were performed using SPSS statistical software (version 17.0; SPSS, Chicago, IL, USA). Categorical variables, Hardy–Weinberg equilibrium of the polymorphisms and genotype/allele frequencies were tested with χ2. Quantitative variables were expressed as mean±s.d. Quantitative variables were compared using one-way analysis of variance, and t-test was used to compare between groups. Logistic regression models were used to assess the association between the DBH -1021C/T polymorphism and OH. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated to estimate the relative risk of OH conferred by the polymorphism. The adjusted ORs were determined from binary multiple logistic regression analyses using age, sex, body mass index, heart rate, fasting blood glucose and dyslipidemia as potential confounders. To avoid the spurious association resulting from multiple comparisons in a database, significant differences were corrected for the number of tests using Bonferroni correction. As three tests, including additive, dominant and recessive models of each polymorphism, were performed between the OH group and the ONT group, probability values of 0.017 (0.05/3) were considered statistically significant. All P-values were based on two-sided tests of significance. P-values less than 0.05 were considered statistically significant, unless otherwise stated.
The prevalence of hypertension and the level of SBP were associated with OH
The characteristics of OH patients and ONT subjects are summarized in Table 1. Most of the characteristics were not different between the two groups. However, the OH group had a significantly higher prevalence of hypertension, supine systolic levels and supine diastolic levels than ONT group. After adjusting for sex, age and other conventional confounders using a binary multiple logistic regression model, the prevalence of hypertension was still significantly higher (44.5%) in OH subjects than in ONT subjects (35.2%; OR=1.55; 95% CI=1.15–2.10; P=0.004), indicating the contribution of hypertension to OH. Similarly, the association of OH and SBP remained statistically significant (OR=1.03; 95% CI=1.01–1.04; P=0.000) after adjustment for sex, age and other conventional confounders. In contrast, DBP was not associated with OH risk (OR=1.0; 95% CI=0.98–1.02; P=0.901) after adjustment for sex, age and other conventional confounders.
The DBH -1021C/T polymorphism is not associated with the risk of OH
To investigate the potential relationship between OH and the DBH -1021C/T polymorphism, we analyzed genotype-specific information on quantitative traits among the participants. There were no significantly statistical differences among different genotypes of the DBH -1021C/T polymorphism and clinical characteristics (Table 2). The DBH -1021C/T genotypes were consistent with Hardy–Weinberg equilibrium OH patients (χ2=1.8, P=0.18) and in ONT subjects (χ2=0.054, P=0.82). The T allele frequency in the ONT and OH groups was 17.4% and 14.9%, respectively (P=0.17). In addition, the prevalence of the CC, CT and TT genotypes was 72.3%, 25.6% and 2.1% in the OH group and 69.4%, 26.5% and 4.1% in the ONT group, respectively (P=0.16). Further analysis with additive, dominant and recessive models demonstrated no significant differences in the genotype frequencies of the -1021C/T polymorphism between OH and ONT subjects (Table 3). After adjusting for age, sex, body mass index, heart rate and fasting blood glucose, an association between OH risk and the 1021C/T DBH polymorphism was not found.
DBH does not affect orthostatic BP changes
We next analyzed the associations between the DBH -1021C/T polymorphism and orthostatic SBP/DBP changes at 1, 2 and 3 min after standing. We found no significant differences in all of the subjects classified by gene polymorphism (Table 4), indicating that the DBH -1021C/T polymorphism does not influence the variation of BP following postural change (all P>0.05).
In the present study, we assessed the DBH -1021C/T genetic polymorphism on orthostatic BP dysregulation in Chinese population. To our knowledge, the current study represented first case-controlled and population-based study to assess the association of the DBH C-1021T polymorphism with OH risk in Chinese community populations. After excluding the effect of antihypertensive drugs and adjusting for age, sex and body mass index, the present study did not demonstrate an apparent association between DBH polymorphisms and OH.
DBH catalyzes the conversion of dopamine to norepinephrine, a key neurotransmitter in the central nervous system and peripheral autonomic neurons. DBH deficiency leads to cardiovascular disease and predisposes an individual to OH. The -1021C/T polymorphism in the 5′-promoter region of the DBH gene is associated with DBH activity.27 Homozygosity of the T allele is associated with reduced gene expression and, consequently, very low DBH activity.19, 27, 28 Variation in DBH activity both in the serum and cerebral spinal fluid has been reported to be over 80% heritable.29 The DBH -1021C/T SNP has been identified as the main regulator of DBH activity19, 30 and is responsible for up to ∼50% of enzyme activity in several different populations.19, 27, 31, 32, 33, 34 These data suggest that the DBH -1021C/T polymorphism may be associated with OH. However, the present study failed to show a significant association between the DBH -1021C/T polymorphism and OH in a Chinese population. Weinshilboum et al.35 reported that the absence of plasma DBH occurs not only in patients with DBH deficiency syndrome, but also in 4% of the normal population. Deinum et al.36 also proposed that the absence of DBH may be associated with an allelic variant in the 5′ flanking region (-1021) of the DBH gene. This variant probably has few or no functional consequences. These observations may partially explain why we found no association between the DBH -1021C/T polymorphism and OH.
The genetic influence on the regulation of orthostatic BP remains understudied. Although it has been proposed that genes on chromosome 18q may be responsible for OH,37, 38 no candidate genes have been identified for the regulation of orthostatic BP in this locus. In parallel, several studies have examined other genetic alterations that predispose individuals to OH.39, 40 A population-based study demonstrated mitochondrial DNA mutations in three families with idiopathic OH.41 In addition, a Gly49 polymorphism of the beta1 receptor gene has been associated with orthostatic intolerance.42 OH is associated with a functional polymorphism of the neural precursor cell expressed, developmentally downregulated 4-like gene (NEDD4L), which is an essential regulator of sodium retention in the distal nephron, located proximal to the OH markers on 18q.43, 44 Furthermore, Tabara et al.45 demonstrated an association between OH and a G protein α-subunit (GNAS1) T131C polymorphism and a G protein β-subunit (GNB3) C825T polymorphism, which are components of the sympathetic nervous system and regulate cardiovascular tone and reactivity. Population-based studies have suggested that insulin promoter factor 1 (PDX1), implicated in beta-cell function,46 on chromosome 13 may be associated with altered postural SBP response. Recently, genome-wide association studies have identified several loci (chromosome regions) that are associated with BP at a genome-wide level of statistical significance.47, 48 Nevertheless, no genetic variant (including the -1021C/T polymorphism) in DBH has been reported to be linked with these loci.
Identifying an association between a gene and a complex genetic disease is difficult. One reason is the involvement of a large number of genes in the etiology of OH. Moreover, these genes may interact with each other in complex combinations to give rise to a similar disease phenotype. The magnitude of this problem makes the frequency of any polymorphism contributing to a disease phenotype marginally higher in the disease group compared with unaffected controls.49 Linkage analysis has limited power to detect such small effects.50 A case–control study with matched controls from the same population has a greater probability of detecting such minute effects.51 The inability to find an association between a DBH gene polymorphism and OH in the present study indicates that the DBH gene does not have a predominant role in the pathophysiology of OH in Chinese patients. As hypotension is a complex genetic disorder, it is quite possible that other unidentified genetic and environmental factors lead to the development of OH.
Consistent with the previous studies,52, 53, 54, 55 our study demonstrated that hypertension was associated with OH. Moreover, our results provide evidence that supine SBP is independently associated with OH in Chinese patients.56 A decrease in vascular compliance and subsequent diminution of baroreceptor stretch and relaxation during BP change results in impaired baroreflex sensitivity.55 As BP increases, baroreflex sensitivity declines, which may be responsible, at least in part, for OH.57 In this study, we found that higher supine BPs correlated with a higher prevalence of OH, which is consistent with a previous study.56 Basal SBP has been shown to be an important determinant of prone hypotension58 but needs to be validated in large-scale studies among different patient populations.
This study had several improvements over other studies. We collected extensive information on environmental exposures and other covariates to control for non-genomic influences in multivariate analyses. Secondly, most studies have focused on OH subjects in hypertensive individuals or hospital-based patients, whereas our study included a community-based population.
However, our study had certain limitations. First, we only examined the effects of genes involved in the dopaminergic pathway. Further analysis of candidate genes in other relevant systems, such as the adrenergic pathway, noradrenergic pathway and serotoninergic pathway, is needed to elucidate the relevant genetic effects on OH. Second, the plasma DBH concentration was not obtained, and therefore we could not further evaluate the association between the DBH C-1021T polymorphism and DBP, as well as the relationship between OH risk and DBH. Third, the sample size of this study was relatively small. We will continue to expand the sample size as well as perform a genome-wide association studies in order to further assess the association between the DBH C-1021T polymorphism and the occurrence of OH in Chinese populations.
We found that the C-1021T polymorphism in the 5′ promoter region of the DBH gene was not associated with a genetic predisposition to OH risk. To further understand the genetic background of orthostatic BP regulation, more studies are required to assess genetic effects of the dopaminergic pathway on the orthostatic BP response.
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The study was supported by the Jilin Provincial Science Technology Department (No. 20070729–19 to Yang Zheng) and International S&T Cooperation Program of China (ISTCP; No. 2009DFB30050 to Hui Rutai).
Na Lu, Rutai Hui, Yang Zheng designed the concept. Na Lu, Ye Yuan collected data. Na Lu, Jingzhou Chen, Ye Yuan, Xiaoqiang Cong, Yang Yang, Lin Meng, Kai Sun, Rutai Hui and Yang Zheng approved the article. Na Lu, Kai Sun and Yang Yang performed the statistical analyses.
The authors declare no conflict of interest.
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Lu, N., Chen, J., Yuan, Y. et al. The C-1021T polymorphism of dopamine β-hydroxylase is not associated with orthostatic hypotension in a Chinese population. J Hum Hypertens 29, 173–178 (2015). https://doi.org/10.1038/jhh.2014.54