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Psychosomatic Medicine 68:207-212 (2006)
© 2006 American Psychosomatic Society

ORIGINAL ARTICLES

Anger Suppression and Adiposity Modulate Association Between ADRB2 Haplotype and Cardiovascular Stress Reactivity

Joseph C. Poole, MS, Harold Snieder, PhD, Harry C. Davis, MS and Frank A. Treiber, PhD

From the Department of Pediatrics (J.C.P., H.S., F.A.T.), Georgia Prevention Institute, Augusta, Georgia; and the Department of Psychiatry (F.A.T.), Medical College of Georgia, Augusta, Georgia.

Address correspondence and reprint requests to Frank A. Treiber, PhD, Medical College of Georgia, Georgia Prevention Institute, Building HS-1640, Augusta, GA 30912. E-mail: ftreiber{at}mcg.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objectives: The purpose of this study was to examine how variation in the beta-2 adrenergic receptor gene (ADRB2), in combination with the moderating influences of race, body mass index (BMI), and anger expression style (anger-in, anger-out), affects blood pressure (BP) at rest and in response to acute laboratory stress.

Methods: Four hundred fifty adolescents (mean age = 18.5 ± 2.7 years; 228 [124 males] whites and 222 [110 males] blacks completed two stressors (video game challenge, forehead cold pressor). Hemodynamic measures were taken before, during, and after each stressor. Stressors were separated by a 20-minute rest period.

Results: Frequency of detrimental haplotype (Gly16/Glu27) carrier status was greater among whites than blacks (p < .05). A significant three-way interaction among haplotype, BMI, and race for resting systolic blood pressure (SBP) found the highest BP level to be among high BMI carriers, but only for whites. A separate three-way interaction was found to be significant for haplotype, anger-in and race such that high anger-in carriers showed the highest level of resting SBP (p < .05) and total peripheral resistance (TPR) (p < .05) and the greatest TPR reactivity to the cold pressor task (p < .01). Post hoc analyses revealed these interactions with anger-in were only present among blacks. No significant interactions with anger-out for either ethnic group were observed.

Conclusions: This study demonstrates modulating influences of BMI and anger expression styles on ADRB2 gene associations with hemodynamic function at rest and in response to laboratory stress. These findings support the hypothesis that consideration of gene–environment interactions may better characterize the role of ADRB2 variation in the development of stress-induced essential hypertension.

Key Words: ADRB2 • stress • anger • cardiovascular reactivity • race • BMI

Abbreviations: EH = essential hypertension; BP = blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure; TPR = total peripheral resistance; CO = cardiac output; ADRB2 = beta-adrenergic receptor; SNP = single nucleotide polymorphism; BMI = body mass index; ET-1 = endothelin 1; AI = anger-in; AO = anger-out; AC = anger control.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Alterationsin peripheral vasodilation capacity have been implicated in the etiology of essential hypertension (EH) (1). Catecholamine-mediated action at beta-2 adrenergic receptors on endothelium and vascular smooth muscle represent an important vasodilatory mechanism. Decreased beta-2 adrenergic receptor density results in increased blood pressure (BP) in response to epinephrine (2), and pharmacologic blockade of these receptors significantly lowers maximum dilation response to exogenous catecholamine (3). BP may be further affected by the function of beta-2 adrenergic receptors expressed outside the vasculature, particularly in the heart (cardiac structure and function), kidney (salt and water excretion), and adipose tissue (mobilization of lipids). The beta-2 adrenergic receptor gene (ADRB2) has been well characterized and several single nucleotide polymorphisms (SNPs) have been identified (4). Two SNPs within the ADRB2 coding region (Arg16Gly and Gln27Glu) affect receptor function in response to adrenergic stimulation (5–10). These polymorphisms have been commonly associated with elevated resting blood pressure (8,11–17), although the identity of the detrimental allele (Arg/Gly at the 16 position, Gln/Glu at the 27 position) has differed across studies, and some studies did not find an association (18–21). This inconsistency between studies may be partly explained by the lack of consideration of potential blood pressure-related modulating influence of subject characteristics (e.g., race, sex, body mass index [BMI]) and psychosocial factors such as anger coping style (22). The efficacy of considering these potential effects within a gene–environment stress-induced model of EH has recently been suggested (22).

Exaggerated hemodynamic reactivity to behavioral stress has been shown to be predictive of hypertension (23). Stress exposure protocols may be particularly relevant for studying beta-adrenergic-mediated changes. Two studies have examined the relationship between ADRB2 gene polymorphisms and hemodynamic reactivity to acute behavioral stress (24,25). McCaffery et al. (24) found an association between the Arg16Gly polymorphism and resting BP, but not in BP reactivity to mental arithmetic or the Stroop Color Interference test. Li et al. (25) reported a positive association between the Arg16Gly polymorphism with BP both at rest and in response to mental arithmetic and cold pressor task. Possible explanations for this inconsistency include the differential influence of specific modulating factors and/or inherent differences between the white (24) and European populations (25). These findings further emphasize the need for in-depth consideration of potential gene–environment interactions in the link between ADRB2 and altered risk for EH.

Associations between anger expression constructs (i.e., anger-out, anger-in, and anger control) and increased risk for EH have been reported (26–31). High anger suppression (represented by "anger-in") has been shown to be associated with increased blood pressure at rest (27,28,30,31) and greater blood pressure reactivity to behavioral stress (32). By contrast, some studies have reported "anger-out" (rather than anger-in) to be the toxic component of anger expression, being associated with higher resting BP (29) and increased carotid atherosclerosis (26). Recently, an association between low anger management skills and exaggerated vasoconstrictive reactivity to stress was observed in young adults, but only among subjects who were carriers of a detrimental endothelin-1 (ET-1) allele (32a). In light of this finding, the link between anger expression and cardiovascular reactivity may be explained by changes in specific BP control systems, including alterations in beta-2 receptor-mediated vasodilation.

Because beta-2 adrenergic receptors act on adipocytes to mediate fat breakdown and energy balance, it has been suggested that ADRB2 variants may be relevant to the etiology of obesity-related hypertension (15). BMI may, therefore, be an important factor that interacts with a detrimental ADRB2 variant to predict EH risk. Further, an accumulating body of evidence indicates that adiposity is often associated with increased blood pressure reactivity (33–36), supporting the use of cardiovascular stress reactivity for studying potential interactions between ADRB2 variation and adiposity.

A complicating feature of ADRB2 gene association studies is the fact that the Arg16Gly and Gln27Glu polymorphisms occur in specific allele combinations more frequently than would be expected by chance. This linkage disequilibrium has been reported between the Arg16Gly and Gln27Glu loci, as well as with additional ADRB2 SNPs (10). Indeed, Drysdale et al. (10) found that all known ADRB2 SNPs comprise four common haplotypes in blacks and three common haplotypes in whites, suggesting that combinations of ADRB2 SNPs may be more pertinent to BP control than single SNPs. Based on a review of the relevant literature (8,17,37,38), including our own work (39), we contend that the haplotype 16Gly/27Glu (containing both minor alleles) may be particularly detrimental for BP control.

We hypothesized that the coupling of a detrimental ADRB2 haplotype with high BMI or poor anger coping skills would result in exaggerated hemodynamic function at rest and in response to acute laboratory stress. We focused on the outcome variables that best captured ADRB2’s role as a peripheral mediator of resistance (i.e., systolic blood pressure [SBP], diastolic blood pressure [DBP], and total peripheral resistance [TPR]). We tested this hypothesis in a multiethnic cohort of young adults who participated in a competitive video game challenge and a forehead cold stressor.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Study Population
The cohort consisted of 450 subjects (222 black and 228 whites; 220 males and 230 females; mean age 18.5 ± 2.7 years) who are participants in a longitudinal study investigating the development of stress-related cardiovascular disease risk factors (40). Data analyzed for this study were collected at laboratory visits occurring between January 1999 and June 2001. The criteria used for the classification of subjects as "black" or "white" was based on parental self-report and is presented elsewhere (40). Subjects had a physician-verified family history of cardiovascular disease (essential hypertension and/or premature myocardial infarction) (41).

Protocol
The Institutional Review Board from the Medical College of Georgia approved the study. Informed consent was obtained from each subject, and in the case of subjects <18 years old, parents provided consent. Subjects underwent a battery of anthropometric assessments including height (in centimeters) and weight (in kilograms) according to established protocols. BMI was calculated as kilograms per meters squared and standardized for age and sex (i.e., BMI Z-score). Blood pressure measures were obtained with a Dinamap/Pediatric Vital Signs Monitor (model 1846SX; Critikon). Heart rate and cardiac output (CO) were measured with the thoracic bioimpedance monitor (NCCOM-3, version 6; BoMed Medical Manufacturing Ltd.), and total peripheral resistance was calculated as mean arterial pressure (MAP)/CO (mm Hg/L per minute). MAP was estimated by (SBP + 2 DBP)/3.

After being instrumented with a blood pressure cuff and bioimpedance electrodes, subjects were placed in the supine position for an initial 20-minute rest period. Hemodynamic measurements were collected at minutes 11, 13, and 15. Baseline hemodynamics were calculated as the average of minutes 13 and 15. Reactivity was defined as change scores (peak – resting level). Following the first rest period, subjects engaged in a competitive video game challenge (Atari "Breakout") for 10 minutes according to a standardized protocol (41). Hemodynamics were recorded every 2 minutes during the video game challenge as well as during each 20-minute recovery period. After the video game challenge and the postvideo game recovery period, subjects completed a 1-minute forehead cold stressor, "Chilly Willy," according to a previously established procedure (41,42). A large, zip-locking bag filled with six cups of crushed ice and 1.5 cups of water (3°–5°C) was placed across the subject’s forehead for 1 minute. CV responses were recorded during the final 30 seconds of the stressor. Subjects concluded the reactivity protocol with a final recovery period.

Genotyping
Extraction of genomic DNA from plasma buffy coats or buccal swabs was performed with the QiaAmp DNA Blood Mini Kit (Qiagen). For haplotype analysis, two common SNPs (allele frequency >0.05) were selected for genotyping: G46A (Gly16Arg) and C79G (Gln27Glu). Genotyping was completed by polymerase chain reaction/restriction-enzyme digestion, as described elsewhere (39). Carriers of the detrimental haplotype were identified as those individuals having Gly at AA position 16 and Glu at AA position 27. Haplotype frequencies for ADRB2 SNPs were estimated by PHASE 2.0 (43).

Anger Expression
The Spielberger Anger Expression Scale was used to measure the multidimensional construct of anger expression. This 24-item Likert scale captures three distinct components of anger expression: anger-in (AI) (i.e., suppression or inhibition of anger), anger-out (AO) (i.e., outward expression of anger), and anger control (AC) (i.e., effective anger restraint). Based on general feelings or actions to anger-provoking situations, subjects assigned each item a value ranging from 1 ("almost never") to 4 ("almost always"). Because the literature review indicated that AI and AO were strongly associated with BP control, only those subscales were used in the data analysis. The Spielberger AI and AO subscales have been found to have adequate internal consistency (0.73 < alpha < 0.84) and 1-year test–retest reliabilities of 0.52 and 0.75, respectively (44,45).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Descriptive characteristics of the cohort and resting hemodynamics by race and haplotype carrier status are presented in Table 1. Blacks were older, higher in BMI, and had greater SBP, DBP, and TPR at rest than whites (p < .05). Hemodynamic differences remained significant after controlling for differences in age. Detrimental haplotype (16Gly/27Glu) frequency was greater among whites (71.2%) than blacks (28.8%) (p < .001). Anger-in (AI) and Anger-out (AO) did not differ significantly by race (p > .05). Descriptive characteristics for reactivity change scores by race and haplotype carrier status are presented in Table 2. Significant differences by ethnic group were present for video game SBP and DBP and cold pressor SBP and TPR such that blacks showed greater reactivity compared with whites. The codon 16 and 27 polymorphisms were in strong linkage disequilibrium for both black (D' = 0.97, r2 = 0.42, p < .001) and white subjects (D'= 1.0, r2 = 0.22, p < .001).


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  		TABLE 1. Descriptive Characteristics by Race and ADRB2 Gly16/Glu27 Carrier Status (Means ± Standard Deviation)

 

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  		TABLE 2. Stress Reactivity Change Scores by Race and ADRB2 Gly16/Glu27 Carrier Status (Means ± Standard Deviation)

 

To avoid inflation of the type 1 error rate owing to the consideration of multiple dependent measures, a multivariate analysis was done using the following terms: SBP, DBP, and TPR at rest; change scores in SBP, DBP, and TPR to the video game stressor; and change scores in SBP, DBP, and TPR to the forehead cold stressor. Haplotype status (carrier or noncarrier of Gly16/Glu27), race, BMI, anger-in, anger-out, and all two- and three-way interactions involving haplotype were entered as independent variables. Gender, age, and baseline hemodynamic values were entered into the model as control variables. This model was reduced by eliminating nonsignificant interactions and main effects not included in significant higher-order interactions. The final multivariate model had main effects for gender, race, BMI, haplotype, AI, two-way interaction terms for haplotype by race, haplotype by BMI, haplotype by AI, race by AI, and three-way interaction terms for haplotype by race by BMI and haplotype by race by AI.

The three-way interaction, haplotype by race by AI, was significant for resting SBP and TPR and for TPR reactivity to forehead cold (all p’s < .05). To better interpret the importance of these three-way interactions, we further analyzed the haplotype by AI interaction separately by ethnic group. These post hoc analyses revealed the haplotype by AI interactions in whites to be nonsignificant (all p > .05). In blacks, the haplotype by AI interaction was significant such that carriers of the detrimental haplotype who were also high in AI showed the greatest resting SBP (Fig. 1) and the greatest TPR reactivity to the forehead cold stressor (all p’s < .05) (Fig. 2). The haplotype by AI interaction for resting TPR in blacks was not significant (p > .05). The haplotype by BMI by race interaction was significant for resting SBP and DBP (p’s < .03). In post hoc analyses, the haplotype by BMI interaction for resting SBP remained significant for whites only and revealed that high BMI carriers showed significantly higher resting SBP compared with low BMI individuals and high BMI noncarriers (p < .001) (Fig. 3). To distinguish between "high" and "low" BMI, we used the values 1 standard deviation above and below the mean, respectively.


Figure 15
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  		Figure 1. Interaction of ADRB2 Gly16/Glu27 haplotype carrier status and anger-in for resting systolic blood pressure in blacks (means).

 

Figure 25
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  		Figure 2. Interaction of ADRB2 Gly16/Glu27 haplotype carrier status and anger-in for total peripheral resistance reactivity (change score) in response to the cold pressor task in blacks (means).

 

Figure 35
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  		Figure 3. Interaction of ADRB2 Gly16/Glu27 haplotype carrier status and body mass index for resting systolic blood pressure in whites (means).

 

Significant main effects and two-way interactions were generally subsumed within significant three-way interactions. The only significant effects not subsumed within these three-ways included: a significant main effect of BMI for resting TPR and video DBP indicating that high BMI individuals had lower TPR at rest and higher DBP reactivity to the video game stressor compared with their low BMI counterparts; a significant haplotype by AI interaction for resting DBP indicating that carriers of the Gly16/Glu27 allele who were the lowest in anger suppression showed the lowest DBP at rest compared with all other groups; and a significant race by AI interaction for SBP reactivity to forehead cold (p < .04) indicating that blacks who were high in AI were more reactive to the ice stressor compared with whites and blacks who were low in AI.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
In this study, we tested the hypothesis that carriers of a detrimental ADRB2 haplotype, particularly in combination with additional EH risk factors (e.g., unhealthy anger expression and BMI) would exhibit the highest levels of BP at rest and in response to acute stress. We designated an ADRB2 haplotype (consisting of a glycine residue at amino acid position 16 and a glutamate residue at position 27) as unfavorable based on our previous gene association study and additional reports of altered functionality of Gly16 and Glu27 (8,17,37,38).

A key finding from this study was a significant interaction between haplotype carrier status and anger suppression in blacks for resting SBP. Carriers of the detrimental haplotype who reported high levels of anger suppression had significantly higher SBP than carriers with low anger suppression and noncarriers, irrespective of anger suppression status. Interestingly, low anger-suppressing carriers displayed the lowest SBP at rest. That is, this group had lower resting SBP than noncarriers and high anger-suppressing carriers. In subsequent analyses, this same group (low anger-suppressing carriers) displayed lower DBP and TPR at rest. These findings suggest a potential protective function of low anger suppression among carriers of an otherwise harmful haplotype.

An important issue stemming from our findings involves the differential impact of race, anger suppression, and ADRB2 haplotype on TPR reactivity between the two stressors. The forehead cold stressor elicits extremely high vasoconstrictive responses compared with the video game, particularly among blacks (46). Regarding the role of anger on stressor response, we speculate that individuals who are prone to suppress feelings of anger may have done so in response to the pain component of the forehead cold stressor. This may have partially contributed to their vasoconstrictive-mediated stress responses. We further hypothesize that the difference in degree of TPR reactivity between the video game (approximately 2 mm Hg/L per minute) and forehead cold stressor (approximately 5–6 mm Hg/L per minute) may partially explain the differential impact of the ADRB2 gene on effect size. That is, the compensatory, vasodilatory function of ADRB2 would become more important under conditions of greater vasoconstriction (i.e., the forehead cold stressor). As a result, differences in effect size owing to an individual’s physical capacity to vasodilate would be more likely to be observed with the forehead cold stressor. Thus, blacks with high anger suppression who were also carriers of a detrimental ADRB2 haplotype would be expected to show the greatest TPR reactivity, particularly to the forehead cold stressor.

The interaction between ADRB2 haplotype carrier status and BMI on resting SBP in whites is an interesting finding given the mixed literature on the link between ADRB2 alteration and adiposity measures (47–49). Notably, we found no statistically significant associations between haplotype carrier status and BMI or additional adiposity-related measures (i.e., waist circumference, waist-to-hip ratio, skinfold thickness). These findings lend support to the viewpoint that ADRB2 is more directly related to BP control than adiposity (50). In whites, the significant interaction between haplotype and BMI indicated that the coincident occurrence of both factors is particularly harmful, although this finding was not replicated in the black subjects.

It is important to note that in both ethnic groups haplotype-specific analyses generated statistically significant findings, although no associations involving the ADRB2 gene at the SNP level reached statistical significance. The two SNPs (Gly16Arg and Gln27Glu) are in fairly high linkage disequilibrium; however, they are not mutually exclusive. Therefore, individuals that are carriers of both "detrimental" alleles of the two SNPs represent a unique subgroup with distinct characteristics (both genetic and environmental) that may result in altered BP control.

These results carry important implications for the primary and secondary prevention of EH. Early behavioral interventions aimed at reducing ineffective anger expression (especially anger suppression) may hold particular value as a preventive measure in blacks with a family history of EH. Similarly in whites, and particularly carriers of the detrimental ADRB2 haplotype, the preemptive use of exercise and dietary interventions in individuals at risk for obesity may decrease the likelihood of future blood pressure dysregulation and EH. In addition to these primary prevention approaches, the prudent use of antihypertensive medications (e.g., the use of beta-1 specific beta blockers or drugs other than beta blockers) in individuals with known genetic and environmental features may increase the efficacy of treatment and reduce the incidence of EH-related sequelae, including stroke, ischemic heart disease, and renal failure.

Although we are excited by the potential implications of this study, the findings must be interpreted cautiously as a result of limitations of the study design. All subjects participating in this study had medically documented family history of cardiovascular disease. Whether these results translate to the general population is unknown. The ADRB2 allele frequencies in our subjects were in line with studies that used random sampling from the population at large, but important differences in BP risk profiles between our subjects and the general population are possible. However, the prevalence of cardiovascular disease, particularly EH, is quite high in the geographical region from which the cohort was recruited (i.e., "stroke belt") (51). Thus, our findings involving these subjects are likely to generalize to other individuals in this region. A second limitation of this study is the cross-sectional design that provides a one-time "snapshot" of each subject. The advantages of using a longitudinal design for determining EH risk profiles have been well established. Longitudinal assessment would help in determining when significant differences between subgroups first appear, allowing for the development of time-sensitive interventions.

Findings from this study indicate that adiposity and anger suppression may play important race-specific roles as modulators of EH risk among carriers of a detrimental ADBR2 haplotype. The physiological pathways by which these interactive effects may occur are largely unknown. Mills and Dimsdale have suggested a potential beta-adrenergic receptor-mediated mechanism linking anger suppression and increased likelihood for cardiovascular disease (32). They found high beta-adrenergic receptor sensitivity and increased SBP reactivity to a math stressor among subjects who routinely suppressed their anger. Altered beta-2 adrenergic sensitivity has been linked to carriers of the Gly16 and Glu27 alleles (5,6,8). Both in vitro and in vivo work (in animal models and humans) is necessary to determine the extent to which inherited ADRB2 dysfunction affects overall risk for hypertension and how the additional factors of BMI, anger, and race affect this relationship. Additional evaluation of these relationships within a longitudinal cohort framework would go far in elucidating the importance of these factors in the etiology of EH.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 

This work was supported in part by grant HL 69999 from the National Heart, Lung, and Blood Institute.

DOI:10.1097/01.psy.0000204925.18143.4f


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

  1. Olsen MH, Wachtell K, Aalkjaer C, Dige-Petersen H, Rokkedal J, Ibsen H. Vasodilatory capacity and vascular structure in long-standing hypertension: a LIFE substudy. Losartan Intervention For Endpoint-Reduction in Hypertension. Am J Hypertens 2002;15:398–404.[CrossRef][Medline]
  2. Chruscinski AJ, Rohrer DK, Schauble E, Desai KH, Bernstein D, Kobilka BK. Targeted disruption of the beta2 adrenergic receptor gene. J Biol Chem 1999;274:16694–700.[Abstract/Free Full Text]
  3. Okajima M, Takamura M, Vequaud P, Parent R, Lavallee M. Beta-adrenergic receptor blockade impairs NO-dependent dilation of large coronary arteries during exercise. Am J Physiol Heart Circ Physiol 2003;284:H501–10.[Abstract/Free Full Text]
  4. Leineweber K, Buscher R, Bruck H, Brodde OE. Beta-adrenoceptor polymorphisms. Naunyn Schmiedebergs Arch Pharmacol 2004;369:1–22.[Medline]
  5. Dishy V, Sofowora GG, Xie HG, Kim RB, Byrne DW, Stein CM, Wood AJ. The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization. N Engl J Med 2001;345:1030–5.[Abstract/Free Full Text]
  6. Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994;33:9414–9.[CrossRef][Medline]
  7. Cockcroft JR, Gazis AG, Cross DJ, Wheatley A, Dewar J, Hall IP, Noon JP. Beta(2)-adrenoceptor polymorphism determines vascular reactivity in humans. Hypertension 2000;36:371–5.[Abstract/Free Full Text]
  8. Gratze G, Fortin J, Labugger R, Binder A, Kotanko P, Timmermann B, Luft FC, Hoehe MR, Skrabal F. Beta-2 Adrenergic receptor variants affect resting blood pressure and agonist-induced vasodilation in young adult Caucasians. Hypertension 1999;33:1425–30.[Abstract/Free Full Text]
  9. Hoit BD, Suresh DP, Craft L, Walsh RA, Liggett SB. Beta2-adrenergic receptor polymorphisms at amino acid 16 differentially influence agonist-stimulated blood pressure and peripheral blood flow in normal individuals. Am Heart J 2000;139:537–42.[Medline]
  10. Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K, Arnold K, Ruano G, Liggett SB. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci U S A 2000;97:10483–8.[Abstract/Free Full Text]
  11. Busjahn A, Li GH, Faulhaber HD, Rosenthal M, Becker A, Jeschke E, Schuster H, Timmermann B, Hoehe MR, Luft FC. Beta-2 adrenergic receptor gene variations, blood pressure, and heart size in normal twins. Hypertension 2000;35:555–60.[Abstract/Free Full Text]
  12. Jindra A, Horky K, Peleska J, Jachymova M, Bultas J, Umnerova V, Heller S, Hlubocka Z. Association analysis of Arg16Gly polymorphism of the beta2-adrenergic receptor gene in offspring from hypertensive and normotensive families. Blood Press 2002;11:213–7.[CrossRef][Medline]
  13. Bray MS, Krushkal J, Li L, Ferrell R, Kardia S, Sing CF, Turner ST, Boerwinkle E. Positional genomic analysis identifies the beta(2)-adrenergic receptor gene as a susceptibility locus for human hypertension. Circulation 2000;101:2877–82.[Abstract/Free Full Text]
  14. Tomaszewski M, Brain NJ, Charchar FJ, Wang WY, Lacka B, Padmanabahn S, Clark JS, Anderson NH, Edwards HV, Zukowska-Szczechowska E, Grzeszczak W, Dominiczak AF. Essential hypertension and beta2-adrenergic receptor gene: linkage and association analysis. Hypertension 2002;40:286–91.[Abstract/Free Full Text]
  15. Pereira AC, Floriano MS, Mota GF, Cunha RS, Herkenhoff FL, Mill JG, Krieger JE. Beta2 adrenoceptor functional gene variants, obesity, and blood pressure level interactions in the general population. Hypertension 2003;42:685–92.[Abstract/Free Full Text]
  16. Timmermann B, Mo R, Luft FC, Gerdts E, Busjahn A, Omvik P, Li GH, Schuster H, Wienker TF, Hoehe MR, Lund-Johansen P. Beta-2 adrenoceptor genetic variation is associated with genetic predisposition to essential hypertension: the Bergen Blood Pressure Study. Kidney Int 1998;53:1455–60.[CrossRef][Medline]
  17. Kotanko P, Binder A, Tasker J, DeFreitas P, Kamdar S, Clark AJ, Skrabal F, Caulfield M. Essential hypertension in African Caribbeans associates with a variant of the beta2-adrenoceptor. Hypertension 1997;30:773–6.[Abstract/Free Full Text]
  18. Candy G, Samani N, Norton G, Woodiwiss A, Radevski I, Wheatley A, Cockcroft J, Hall IP. Association analysis of beta2 adrenoceptor polymorphisms with hypertension in a Black African population. J Hypertens 2000;18:167–72.[CrossRef][Medline]
  19. Herrmann V, Buscher R, Go MM, Ring KM, Hofer JK, Kailasam MT, O’Connor DT, Parmer RJ, Insel PA. Beta2-adrenergic receptor polymorphisms at codon 16, cardiovascular phenotypes and essential hypertension in whites and African Americans. Am J Hypertens 2000;13:1021–6.[CrossRef][Medline]
  20. Jia H, Sharma P, Hopper R, Dickerson C, Lloyd DD, Brown MJ. beta2-adrenoceptor gene polymorphisms and blood pressure variations in East Anglian Caucasians. J Hypertens 2000;18:687–93.[CrossRef][Medline]
  21. Xie HG, Stein CM, Kim RB, Gainer JV, Sofowora G, Dishy V, Brown NJ, Goree RE, Haines JL, Wood AJ. Human beta2-adrenergic receptor polymorphisms: no association with essential hypertension in black or white Americans. Clin Pharmacol Ther 2000;67:670–5.[CrossRef][Medline]
  22. Snieder H, Harshfield GA, Barbeau P, Pollock DM, Pollock JS, Treiber FA. Dissecting the genetic architecture of the cardiovascular and renal stress response. Biol Psychol 2002;61:73–95.[CrossRef][Medline]
  23. Matthews KA, Katholi CR, McCreath H, Whooley MA, Williams DR, Zhu S, Markovitz JH. Blood pressure reactivity to psychological stress predicts hypertension in the CARDIA study. Circulation 2004;110:74–8.[Abstract/Free Full Text]
  24. McCaffery JM, Pogue-Geile MF, Ferrell RE, Petro N, Manuck SB. Variability within alpha- and beta-adrenoreceptor genes as a predictor of cardiovascular function at rest and in response to mental challenge. J Hypertens 2002;20:1105–14.[CrossRef][Medline]
  25. Li GH, Faulhaber HD, Rosenthal M, Schuster H, Jordan J, Timmermann B, Hoehe MR, Luft FC, Busjahn A. Beta-2 adrenergic receptor gene variations and blood pressure under stress in normal twins. Psychophysiology 2001;38:485–9.[CrossRef][Medline]
  26. Bleil ME, McCaffery JM, Muldoon MF, Sutton-Tyrrell K, Manuck SB. Anger-related personality traits and carotid artery atherosclerosis in untreated hypertensive men. Psychosom Med 2004;66:633–9.[Abstract/Free Full Text]
  27. Dimsdale JE, Pierce C, Schoenfeld D, Brown A, Zusman R, Graham R. Suppressed anger and blood pressure: the effects of race, sex, social class, obesity, and age. Psychosom Med 1986;48:430–6.[Abstract/Free Full Text]
  28. Gentry WD, Chesney AP, Gary HE Jr, Hall RP, Harburg E. Habitual anger–coping styles: I. Effect on mean blood pressure and risk for essential hypertension. Psychosom Med 1982;44:195–202.[Abstract/Free Full Text]
  29. Harburg E, Gleiberman L, Russell M, Cooper ML. Anger-coping styles and blood pressure in black and white males: Buffalo, New York. Psychosom Med 1991;53:153–64.[Abstract/Free Full Text]
  30. Johnson EH, Schork NJ, Spielberger CD. Emotional and familial determinants of elevated blood pressure in black and white adolescent females. J Psychosom Res 1987;31:731–41.[CrossRef][Medline]
  31. Johnson EH, Spielberger CD, Worden TJ, Jacobs GA. Emotional and familial determinants of elevated blood pressure in black and white adolescent males. J Psychosom Res 1987;31:287–300.[CrossRef][Medline]
  32. Mills PJ, Dimsdale JE. Anger suppression: its relationship to beta-adrenergic receptor sensitivity and stress-induced changes in blood pressure. Psychol Med 1993;23:673–8.[Medline]
  33. Rabineau K, Treiber F, Poole J, Ludwig D. Interactive effects of anger expression and ET-1 Lys198Asn polymorphism on vasoconstriction reactivity to behavioral stress. Ann Behav Med 2005;30:85–9.[CrossRef][Medline]
  34. Barnes VA, Treiber FA, Davis H, Kelley TR, Strong WB. Central adiposity and hemodynamic functioning at rest and during stress in adolescents. Int J Obes Relat Metab Disord 1998;22:1079–83.[CrossRef][Medline]
  35. Goldbacher EM, Matthews KA, Salomon K. Central adiposity is associated with cardiovascular reactivity to stress in adolescents. Health Psychol 2005;24:375–84.[CrossRef][Medline]
  36. Steptoe A, Wardle J. Cardiovascular stress responsivity, body mass and abdominal adiposity. Int J Obes (Lond) 2005;29:1329–37.
  37. Treiber FA, Barbeau P, Harshfield G, Kang HS, Pollock DM, Pollock JS, Snieder H. Endothelin-1 gene Lys198Asn polymorphism and blood pressure reactivity. Hypertension 2003;42:494–9.[Abstract/Free Full Text]
  38. Iaccarino G, Lanni F, Cipolletta E, Trimarco V, Izzo R, Iovino GL, De Luca N, Trimarco B. The Glu27 allele of the beta2 adrenergic receptor increases the risk of cardiac hypertrophy in hypertension. J Hypertens 2004;22:2117–22.[CrossRef][Medline]
  39. Masuo K, Katsuya T, Fu Y, Rakugi H, Ogihara T, Tuck ML. {beta}2- and {beta}3-Adrenergic receptor polymorphisms are related to the onset of weight gain and blood pressure elevation over 5 years. Circulation 2005;111:3429–34; Epub 2005 Jun 13.[CrossRef]
  40. Snieder H, Dong Y, Barbeau P, Harshfield GA, Dalageogou C, Zhu H, Carter ND, Treiber FA. Beta2-adrenergic receptor gene and resting hemodynamics in European and African American youth. Am J Hypertens 2002;15:973–9.[CrossRef][Medline]
  41. Dekkers JC, Snieder H, Van Den Oord EJ, Treiber FA. Moderators of blood pressure development from childhood to adulthood: a 10-year longitudinal study. J Pediatr 2002;141:770–9.[CrossRef][Medline]
  42. Treiber FA, Musante L, Kapuku G, Davis C, Litaker M, Davis H. Cardiovascular (CV) responsivity and recovery to acute stress and future CV functioning in youth with family histories of CV disease: a 4-year longitudinal study. Int J Psychophysiol 2001;41:65–74.[CrossRef][Medline]
  43. Treiber FA, Musante L, Braden D, Arensman F, Strong WB, Levy M, Leverett S. Racial differences in hemodynamic responses to the cold face stimulus in children and adults. Psychosom Med 1990;52:286–96.[Abstract/Free Full Text]
  44. Stephens M, Donnelly P. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003;73:1162–9.[CrossRef][Medline]
  45. Spielberger CD JE, Russell SF, Crane RJ, Jacobs GA, Worden TJ. The Experience and Expression of Anger: Construction and Validation of an Anger Expression Scale. Anger and Hostility in Cardiovascular and Behavioral Disorders; 1985:5–30.
  46. Musante L, Treiber FA, Davis HC, Waller JL, Thompson WO. Assessment of self-reported anger expression in youth. Assessment 1999;6:225–34.[Abstract/Free Full Text]
  47. Musante L, Turner JR, Treiber FA, Davis H, Strong WB. Moderators of ethnic differences in vasoconstrictive reactivity in youth. Ethn Dis 1996;6:224–34.[Medline]
  48. Galletti F, Iacone R, Ragone E, Russo O, Della Valle E, Siani A, Barba G, Farinaro E, Strazzullo V, Strazzullo P. Lack of association between polymorphism in the beta2-adrenergic receptor gene, hypertension, and obesity in the Olivetti heart study. Am J Hypertens 2004;17:718–20.[CrossRef][Medline]
  49. Gonzalez Sanchez JL, Proenza AM, Martinez Larrad MT, Ramis JM, Fernandez Perez C, Palou A, Serrano Rios M. The glutamine 27 glutamic acid polymorphism of the beta2-adrenoceptor gene is associated with abdominal obesity and greater risk of impaired glucose tolerance in men but not in women: a population-based study in Spain. Clin Endocrinol (Oxf) 2003;59:476–81.[CrossRef][Medline]
  50. Park HS, Kim Y, Lee C. Single nucleotide variants in the beta2-adrenergic and beta3-adrenergic receptor genes explained 18.3% of adolescent obesity variation. J Hum Genet 2005;50:365–9; Epub 2005 Jun 15.
  51. Wallerstedt SM, Eriksson AL, Ohlsson C, Hedner T. Haplotype association analysis of the polymorphisms Arg16Gly and Gln27Glu of the adrenergic beta(2) receptor in a Swedish hypertensive population. J Hum Hypertens 2005;19:705–8.[CrossRef][Medline]
  52. Yang D, Howard G, Coffey CS, Roseman J. The confounding of race and geography: how much of the excess stroke mortality among African Americans is explained by geography? Neuroepidemiology 2004;23:118–22.[CrossRef][Medline]




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