Open Access

The insertion/deletion variation in the α2B-adrenoceptor does not seem to modify the risk for acute myocardial infarction, but may modify the risk for hypertension in sib-pairs from families with type 2 diabetes

  • Amir Snapir1Email author,
  • Mika Scheinin1,
  • Leif C Groop2 and
  • Marju Orho-Melander2
Cardiovascular Diabetology20032:15

DOI: 10.1186/1475-2840-2-15

Received: 20 August 2003

Accepted: 24 November 2003

Published: 24 November 2003

Abstract

Background

An insertion/deletion polymorphism in the α2B-adrenoceptor (AR) has been associated with the risk for acute myocardial infarction (AMI) and sudden cardiac death. In this study we tested whether this polymorphism is associated with the risk for AMI among members of families with type 2 diabetes.

Methods

154 subjects with a history of AMI were matched for age and sex with one of their siblings who did not have a history of AMI. The prevalence of the genotypes of the α2B-AR insertion/deletion polymorphism was compared between the siblings using McNemar's test. We also explored the data to see whether this genetic variation affects the risk for hypertension by using logistic regression models in the two subpopulations of subjects, with and without a history of AMI.

Results

Among all study subjects, 73 (24%) carried the α2B-AR deletion/deletion genotype, 103 (33%) carried the insertion/insertion genotype, and 132 (43%) were heterozygous. The distribution of genotypes of the α2B-AR insertion/deletion variation in the group of subjects with a history of AMI and their phenotype-discordant siblings did not statistically significantly differ from that expected by random distribution (p = 0.52): the deletion/deletion genotype was carried by 34 subjects with AMI (22%), and by 39 subjects without AMI (25%). Neither did we observe any significant difference in deletion allele frequencies of the α2B-AR insertion/deletion polymorphism between patients with a history of AMI (0.44) and their sib-pair controls (0.46, p = 0.65). In an exploratory analysis, the α2B-AR deletion/deletion genotype was associated with increased odds for hypertension compared with subjects carrying any of the other genotypes.

Conclusions

The deletion/deletion genotype of the α2B-AR does not emerge in this study as a risk factor for AMI among members of families with type 2 diabetes; however, it might be involved in the development of hypertension.

Keywords

Receptors adrenergic alpha 2 polymorphism genetics myocardial infarction hypertension.

Background

Vascular disease is the major cause of morbidity and mortality in patients with diabetes mellitus [1]. In vivo studies in humans have shown that α2-adrenoceptors (ARs) mediate constriction of large and small coronary arteries [2], an effect augmented by atherosclerosis [3], and mediate peripheral vasoconstriction [4]. However, lack of α2-AR subtype-selective drugs has precluded the clarification of the precise roles of each subtype in these responses to α2-AR activation. Based on studies on genetically engineered mice lacking the α2-AR A or B or C subtype, it has been demonstrated that the α2B-AR subtype mediates peripheral vasoconstriction [5].

A variant form of the human α2B-AR gene encodes a receptor protein with deletion of three glutamate residues [6]. Studies on transfected cells have revealed that this deletion variant manifests significantly impaired agonist-promoted receptor desensitization [7]. In vivo studies in humans have associated the deletion/deletion (DD) genotype with reduced flow-mediated dilatation of the brachial artery [8], and reduced coronary blood flow and increased peripheral resistance upon adrenaline infusion [9]. In a population-based, prospective study on 912 middle-aged men, the DD genotype was associated with an increased incidence of acute myocardial infarction (AMI) in comparison to the other two genotypes [10]. In another population of men who died suddenly outside of a hospital, the DD genotype was associated with increased relative risks for AMI and sudden cardiac death [11]. The relative risks for AMI and sudden cardiac death were especially high in men who died before the age of 55 [11].

To explore the possible effect of the insertion/deletion variation in the α2B-AR gene on the risk for AMI in a population at high risk for type 2 diabetes and cardiovascular disease, we conducted a study on 154 sibling-pairs from Finland, discordant for AMI. We hypothesized that the DD genotype will be more prevalent among patients with a history of AMI than among their phenotype-discordant sib-pairs. We also explored the possibility that the DD genotype is associated with hypertension in this study population.

Methods

Study population

This study had a phenotype-discordant sib-pair design with AMI as the selection phenotype. 154 subjects (88 men, 66 women) from eastern [12] and western [13] Finland who reported having had an AMI were selected from families with type 2 diabetes participating in the Botnia study [13]. Each case-subject was matched for sex and age with one of his or her siblings who had not had an AMI. Characteristics of the study population are presented in Table 1. Before participating in the study, voluntary informed written consent was obtained from each subject. The study protocol was approved by the ethics committee of Lund University.
Table 1

Characterization of the study population by AMI phenotype and the α2B-adrenoceptor insertion/deletion genotype.

 

Phenotype

Genotype

 

AMI (n = 154)

No AMI (n = 154)

P

DD (n = 73)

ID (n = 132)

II (n = 103)

P

ID + II (n = 235)

P (vs. DD)

Age (years)

67.1 ± 0.8

66.9 ± 0.8

0.59

66.7 ± 1.0

67.0 ± 0.8

67.2 ± 1.0

0.35

67.1 ± 0.6

0.45

BMI (kg/m2)

28.0 ± 0.3

27.2 ± 0.3

0.038

28.1 ± 0.5

27.2 ± 0.4

27.9 ± 0.5

0.62

27.5 ± 0.3

0.43

Systolic BP (mmHg)

143 ± 1

145 ± 2

0.38

145 ± 2

144 ± 2

143 ± 2

0.81

144 ± 1

0.56

Diastolic BP (mmHg)

80.0 ± 0.9

82.1 ± 1.0

0.063

80.8 ± 1.1

81.7 ± 1.0

80.2 ± 1.2

0.62

81.1 ± 0.8

0.94

LDL cholesterol (mmol/l)

3.71 ± 0.09

3.76 ± 0.08

0.44

3.82 ± 0.11

3.70 ± 0.10

3.71 ± 0.10

0.84

3.71 ± 0.07

0.55

HDL cholesterol (mmol/l)

1.13 ± 0.02

1.27 ± 0.03

<0.001

1.19 ± 0.02

1.18 ± 0.03

1.19 ± 0.04

0.57

1.20 ± 0.03

0.32

Hypertension

127 (89%)

101 (70%)

<0.001

60 (53)

96 (97)

72 (78)

0.049

168 (175)

0.023

Smoking

76 (56%)

50 (38%)

<0.001

25 (29)

57 (55)

44 (42)

0.75

101 (97)

0.47

Diabetes

115 (75%)

90 (58%)

0.002

47 (49)

87 (88)

71 (69)

0.80

158 (156)

0.53

Data for continuous variables are presented as mean ± SEM. Discrete variables are presented as number of subjects, and in parenthesis, either percentage of the group for which data are available (AMI phenotype) or the expected number by random distribution (α2B-adrenoceptor insertion/deletion genotype). Paired t test and McNemar's test were used to calculate the p value comparing the siblings discordant for history of AMI. Linear mixed models were used to calculate the p values in the comparison of the genotype groups.

Using a multiple-risk-factor assessment equation [14], with complete data available for 79% of the study population, global risk-assessment scoring was calculated, and the age-stratified relative risk for coronary heart disease was estimated. The majority of the subjects (60%) had above average relative risk for coronary heart disease (26% moderately above average relative risk, 34% high relative risk), 27% had below average relative risk, and 13% had an average relative risk. Taking into account the relatively old age of the subjects in this population (44% over 70 years, 63% over 65 years), the absolute risk for coronary heart disease in this population may thus be considered high.

Phenotypic characterization of the study subjects

A standardized health questionnaire was filled by a trained nurse together with the subject, covering medical history, including current medication (use of any drug prescribed by a physician at the time of examination), and smoking and alcohol consumption habits. A subject was defined as a smoker if he or she had smoked for a period of at least one year.

Myocardial infarction was defined as an acute coronary event requiring hospitalization; the information was verified against the subject's hospital records.

A subject was classified as having hypertension if he or she had systolic blood pressure (BP) ≥ 160 mmHg, or diastolic BP ≥ 90 mmHg, or was treated with antihypertensive medication [15]. Diagnosis of type 2 diabetes mellitus was based upon the WHO criteria of 1998 [15].

Measurements and assays

BP was measured three times from the right arm at 5 min intervals with the subject in seated position after a 30 min rest, and the mean of the three values was used. This procedure followed well established routines of how to measure BP [16].

Serum total cholesterol, HDL cholesterol, and triglyceride concentrations were measured on a Cobas Mira analyzer (Hoffman LaRoche, Basel, Switzerland). The LDL cholesterol concentrations were calculated using the Friedewald formula.

Genotyping

Genomic DNA was extracted from whole blood using standard methods. The method used to genotype the α2B-AR insertion/deletion polymorphism was based on PCR amplification and DNA electrophoresis, and has been described elsewhere [10].

Statistical analyses

Paired t tests (for continuous variables) and McNemar's test (for discrete variables) were used in the characterization of the population. Since the study population was sampled as sibling pairs, analysis of the entire population according to the three genotypes must take into account the possibility that error terms are not independent but are correlated between siblings. We therefore used linear mixed models with the genotype group information as a fixed factor, and the sib-pair information as a random factor to characterize the genotype groups. The effect of the α2B-AR insertion/deletion polymorphism on the risk for AMI was estimated by the difference in the frequency of the DD genotype between the phenotype-discordant sibling pairs, and was tested using McNemar's test. Odds ratios for hypertension and their 95% confidence intervals (95% CI) were calculated using logistic regression models. Using a univariate logistic regression model, the effect of the different genotypes of the α2B-AR insertion/deletion variation on the odds for hypertension was explored. In multivariate logistic regression models, age, sex, smoking, diabetes, body mass index, serum LDL cholesterol, and the α2B-AR genotype were added as covariates in a conditional stepwise fashion with p = 0.05 for entry and 0.1 for removal. Statistical computations were performed with SPSS/Win version 11.0.1 software (SPSS Inc., Chicago, IL, USA).

Results

Genotype information was obtained for all 308 subjects. Of these, 73 (24%) carried the DD genotype, 103 (33%) the insertion/insertion (II) genotype, and 132 (43%) the insertion/deletion (ID) genotype. Except for hypertension, no differences (p > 0.1) in major risk factors for coronary heart disease were found between the α2B-AR insertion/deletion genotype groups (Table 1).

The prevalence of the DD genotype did not statistically significantly differ between subjects with a history of AMI and their sib-pair controls (p = 0.5): the DD genotype was carried by 34 subjects with AMI (22%), and by 39 subjects without AMI (25%). Neither did we observe any significant difference in D allele frequencies of the α2B-AR insertion/deletion polymorphism between patients with a history of AMI (0.44) and their sib-pair controls (0.46, p = 0.65).

To explore the possible association of the α2B-AR insertion/deletion variation and hypertension, we compared the prevalence of hypertension in the genotype groups. In subjects with no history of AMI, the DD genotype was associated with increased odds for hypertension when compared with the II genotype group (odds ratio (OR) 3.7, 95% CI 1.2–11.1, p = 0.021), or when compared with the II + ID genotype groups combined (OR 3.2, 95% CI 1.2–8.9, p = 0.026) (Table 2). Among subjects with AMI, there were only 16 individuals who were not classified as hypertensive according to the employed criteria, and no statistically significant associations were found between the α2B-AR genotypes and hypertension.
Table 2

Odds ratios for hypertension in relation to the α2B-adrenoceptor genotype and other cardiovascular risk factors.

N (hypertensives)

AMI 143 (127)

No AMI 144 (101)

 

OR (95% CI)

P

OR (95% CI)

P

Univariate models

    

   α2B-AR D vs. I

1.6 (0.6–4.7)

0.36

1.8 (0.9–3.7)

0.12

   α2B-AR ID vs. II

1.4 (0.4–4.1)

0.59

1.3 (0.6–2.8)

0.53

   α2B-AR DD vs. II

2.6 (0.5–13.2)

0.26

3.7 (1.2–11.1)

0.021

   α2B-AR DD vs. II + ID

2.2 (0.5–10)

0.36

3.2 (1.2–8.9)

0.026

   Age

1.0 (0.9–1.0)

0.79

1.1 (1.0–1.1)

0.008

   BMI

1.1 (1.0–1.4)

0.037

1.1 (1.0–1.2)

0.038

   LDL cholesterol

1.3 (1.0–1.8)

0.059

1.5 (1.0–2.2)

0.032

   Smoking

0.6 (0.2–2.0)

0.43

0.5 (0.2–1.2)

0.11

   Diabetes

1.9 (0.6–5.8)

0.29

1.3 (0.6–2.7)

0.48

Multivariate model*

    

   α2B-AR DD vs. II + ID

N/A

 

4.0 (1.2–13.3)

0.024

   Age

N/A

 

1.1 (1.0–1.1)

0.020

   BMI

N/A

 

1.2 (1.0–1.4)

0.006

   LDL cholesterol

N/A

 

1.8 (1.1–3.0)

0.032

Results are from univariate and conditional multivariate logistic regression models. *Data are presented for the last step of the stepwise conditional insertion of variables into the models. Adjustment was done for age, sex, smoking, diabetes, BMI, and LDL cholesterol, which were inserted into a multivariate logistic regression model in a stepwise manner (p = 0.05 for entry and 0.1 for removal). N/A denotes not applicable (all the variables were rejected by the models). I, insertion; D, deletion; BMI, body mass index

In subjects that were not treated with an antihypertensive drug, a trend for increased systolic and diastolic BP was observed among those carriers of the α2B-AR DD genotype who had not had AMI (Table 3).
Table 3

Blood pressure (mmHg) of subjects not treated with an antihypertensive drug, according to α2B-AR I/D genotypes

 

AMI

No AMI

 

DD (n = 3)

ID (n = 12)

II (n = 8)

P*

ID + II (n = 20)

P*

DD (n = 14)

ID (n = 26)

II (n = 32)

P*

ID + II (n = 58)

P*

Systolic BP

144 ± 9

144 ± 3

130 ± 6

0.090

139 ± 3

0.54

154 ± 8

136 ± 4

146 ± 4

0.043

141 ± 3

0.055

Diastolic BP

86 ± 5

83 ± 3

77 ± 3

0.28

81 ± 2

0.43

86 ± 4

77 ± 2

82 ± 2

0.067

80 ± 1

0.065

*One-way ANOVA was used in the comparison of BP between the three genotype groups; t test was used in the comparison of BP of carriers of the DD genotype with carriers of the other genotypes combined. I, insertion; D, deletion

Discussion

The main finding of this study is a lack of association between the α2B-AR DD genotype and AMI among members of families with type 2 diabetes. Another finding of this study is a possible association between this genotype and hypertension.

Association with AMI

Earlier, association of the α2B-AR DD genotype with AMI was reported in a population-based prospective study on 912 middle-aged men from eastern Finland [10], and in a series of 700 unselected sudden out-of-hospital deaths of Finnish men subjected to medico-legal autopsy [11]. The populations in these studies were younger than the population of the current study, and their relative risk for coronary heart disease was expected to be similar to the general population. The lack of association between the α2B-AR DD genotype and AMI in high-risk subjects observed in the present study may suggest that the mechanism by which the α2B-AR deletion variant confers its observed increased risk for AMI is not directly dependent on established coronary heart disease risk factors that lead to atherosclerosis, and that in subjects at high risk for coronary heart disease the effect of this genetic variation is diluted. This interpretation was supported by the morphometric autopsy findings of the sudden death study [11]. In that study [11], the DD genotype was associated with increased odds for AMI and sudden cardiac death, but not with the severity of coronary atherosclerosis.

Association with hypertension and BP

In subjects that had not had an AMI, the DD genotype was associated in univariate logistic regression analysis with increased odds for hypertension. However, since this analysis was conducted as further exploration of the data rather than based on an a priori hypothesis, adjustment for multiple testing should be employed. A corrected p value corresponding to 0.05 when testing 2 independent hypotheses would be 0.0253 (based on the equation α = 1 - 0.951/N where N is the number of hypotheses tested). The observed p value for the association between the DD genotype and hypertension (about 0.02) has therefore only borderline statistical significance.

Two previous studies explored the possible involvement of the α2B-AR insertion/deletion variation in the development of hypertension, and reported lack of association [10, 18]. However, in the study on 912 middle-aged men [10], the prevalence of cardiovascular risk factors was different from that of the current study, making it difficult to compare the results of the studies. Because of the very low frequency of the DD genotype (n = 3) among the subjects in the study on 155 sib-pairs concordant for hypertension [18], that study can be considered to have insufficient power to detect linkage between the α2B-AR DD genotype and the studied phenotype.

Several earlier studies have suggested a role for the α2B-AR in the development of hypertension. α2-adrenergic vasoconstriction in humans [4] is probably mainly mediated by the α2B-AR subtype [5], and the observed decreased agonist-promoted desensitization property of the deletion variant [7] may suggest that the DD genotype confers increased vasoconstriction that leads to increased peripheral resistance – a common finding in hypertension [19]. Furthermore, rodent studies suggest a significant role for the α2B-AR in acquired and hereditary hypertension [2022]. Additionally, loci on human chromosome 2 have been linked with increased BP and hypertension in several recent genome-wide studies [23, 24]. So far, the location of the human α2B-AR gene (ADRA2B, GeneBank accession number M34041) on chromosome 2 has been tentatively placed at 2p13-q13, but more precise mapping will be needed to confirm or exclude the α2B-AR gene as the hypertension risk gene involved in these genome-wide linkage study results.

Methodological considerations

Using a health questionnaire, a subject was categorized as a smoker if he or she had smoked for a period of at least one year. This information may be considered insufficient to provide a complete estimation of the impact of this risk factor on the total risk for AMI.

Interpretation of results from studies with a case-control design, where the studied risk factor may also affect survival, such as in the present study, is not straightforward. Inherently by the study design, only survivors of an acute coronary event were included as index cases in the present study – possibly creating selection bias. Such an effect was demonstrated by Hamajima et al. [17], who showed that the effects of genotypes increasing disease risk and fatality rate are underestimated, while those increasing the risk and improving prognosis are overestimated.

It should also be acknowledged that the apparently unaffected sibs were themselves at higher risk for AMI on the basis of family history, both by belonging to high-risk type 2 diabetes families and by having a sib with AMI. Thus, the unaffected sib may also become affected in a short time.

Conclusions

To conclude, the results of this study suggest that the α2B-AR insertion/deletion variation either does not play a significant role in AMI morbidity in members of families with type 2 diabetes that are at high risk for cardiovascular diseases, or that by affecting mortality, the DD genotype could be underrepresented among the surviving AMI cases. We also propose a role for this genetic variation in the development of hypertension; however, further studies are required to replicate this finding.

Abbreviations

α2-AR: 

α2-adrenoceptor

AMI: 

acute myocardial infarction

BMI: 

body mass index

BP: 

blood pressure

CI: 

confidence interval

DD: 

deletion/deletion

HDL: 

high density lipoprotein

ID: 

insertion/deletion

II: 

insertion/insertion

LDL: 

low density lipoprotein

OR: 

odds ratio

PCR: 

polymerase chain reaction

Declarations

Authors’ Affiliations

(1)
Department of Pharmacology and Clinical Pharmacology, University of Turku
(2)
Department of Endocrinology, Malmö University Hospital, Lund University, Wallenberg Laboratory, University Hospital MAS

References

  1. Colwell JA: Vascular thrombosis in type II diabetes mellitus. Diabetes. 1993, 42: 8-11.View ArticlePubMedGoogle Scholar
  2. Indolfi C, Piscione F, Villari B, Russolillo E, Rendina V, Golino P, Condorelli M, Chiariello M: Role of alpha 2-adrenoceptors in normal and atherosclerotic human coronary circulation. Circulation. 1992, 86: 1116-1124.View ArticlePubMedGoogle Scholar
  3. Baumgart D, Haude M, Gorge G, Liu F, Ge J, Grosse-Eggebrecht C, Erbel R, Heusch G: Augmented alpha-adrenergic constriction of atherosclerotic human coronary arteries. Circulation. 1999, 99: 2090-2097.View ArticlePubMedGoogle Scholar
  4. Talke PO, Lobo EP, Brown R, Richardson CA: Clonidine-induced vasoconstriction in awake volunteers. Anesth Analg. 2001, 93: 271-276.PubMedGoogle Scholar
  5. Kable JW, Murrin LC, Bylund DB: In vivo gene modification elucidates subtype-specific functions of alpha 2-adrenergic receptors. J Pharmacol Exp Ther. 2000, 293: 1-7.PubMedGoogle Scholar
  6. Heinonen P, Koulu M, Pesonen U, Karvonen MK, Rissanen A, Laakso M, Valve R, Uusitupa M, Scheinin M: Identification of a three amino acid deletion in the alpha 2B-adrenergic receptor that is associated with reduced basal metabolic rate in obese subjects. J Clin Endocrinol Metab. 1999, 84: 2429-2433. 10.1210/jc.84.7.2429.PubMedGoogle Scholar
  7. Small KM, Brown KM, Forbes SL, Liggett SB: Polymorphic deletion of three intracellular acidic residues of the alpha 2B-adrenergic receptor decreases G protein-coupled receptor kinase-mediated phosphorylation and desensitization. J Biol Chem. 2001, 276: 4917-4922. 10.1074/jbc.M008118200.View ArticlePubMedGoogle Scholar
  8. Heinonen P, Jartti L, Järvisalo MJ, Pesonen U, Kaprio JA, Rönnemaa T, Raitakari OT, Scheinin M: Deletion polymorphism in the alpha2B-adrenergic receptor gene is associated with flow-mediated dilatation of the brachial artery. Clin Sci (Lond). 2002, 103: 517-524.View ArticleGoogle Scholar
  9. Snapir A, Koskenvuo J, Toikka J, Orho-Melander M, Hinkka S, Saraste M, Hartiala J, Scheinin M: Effects of common polymorphisms in the alpha1A-, alpha2B-, beta1- and beta2-adrenoreceptors on haemodynamic responses to adrenaline. Clin Sci (Lond). 2003, 104: 509-520. 10.1042/CS20020299.View ArticleGoogle Scholar
  10. Snapir A, Heinonen P, Tuomainen TP, Alhopuro P, Karvonen MK, Lakka TA, Nyyssönen K, Salonen R, Kauhanen J, Valkonen VP: An insertion/deletion polymorphism in the alpha 2B-adrenergic receptor gene is a novel genetic risk factor for acute coronary events. J Am Coll Cardiol. 2001, 37: 1516-1522. 10.1016/S0735-1097(01)01201-3.View ArticlePubMedGoogle Scholar
  11. Snapir A, Mikkelsson J, Perola M, Penttilä A, Scheinin M, Karhunen PJ: Variation in the alpha2B-adrenoceptor gene as a risk factor for prehospital fatal myocardial infarction and sudden cardiac death. J Am Coll Cardiol. 2003, 41: 190-194. 10.1016/S0735-1097(02)02702-X.View ArticlePubMedGoogle Scholar
  12. Orho-Melander M, Almgren P, Kanninen T, Forsblom C, Groop LC: A paired-sibling analysis of the XbaI polymorphism in the muscle glycogen synthase gene. Diabetologia. 1999, 42: 1138-1145. 10.1007/s001250051282.View ArticlePubMedGoogle Scholar
  13. Groop L, Forsblom C, Lehtovirta M, Tuomi T, Karanko S, Nissen M, Ehrnström BO, Forsen B, Isomaa B, Snickars B: Metabolic consequences of a family history of NIDDM (the Botnia study): evidence for sex-specific parental effects. Diabetes. 1996, 45: 1585-1593.View ArticlePubMedGoogle Scholar
  14. Grundy SM, Pasternak R, Greenland P, Smith SJ, Fuster V: Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations: A statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation. 1999, 100: 1481-1492.View ArticlePubMedGoogle Scholar
  15. Alberti KG, Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998, 15: 539-553. 10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S.View ArticlePubMedGoogle Scholar
  16. Chalmers J: 1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. Guidelines Subcommittee. J Hypertens. 1999, 17: 151-183. 10.1097/00004872-199917020-00001.Google Scholar
  17. Hamajima N, Matsuo K, Yuasa H: Adjustment of prognostic effects in prevalent case-control studies on genotype. J Epidemiol. 2001, 11: 204-210.View ArticlePubMedGoogle Scholar
  18. Baldwin CT, Schwartz F, Baima J, Burzstyn M, DeStefano AL, Gavras I, Handy DE, Joost O, Martel T, Manolis A: Identification of a polymorphic glutamic acid stretch in the alpha2B-adrenergic receptor and lack of linkage with essential hypertension. Am J Hypertens. 1999, 12: 853-857. 10.1016/S0895-7061(99)00070-9.View ArticlePubMedGoogle Scholar
  19. Beevers G, Lip GY, O'Brien E: ABC of hypertension: The pathophysiology of hypertension. BMJ. 2001, 322: 912-916. 10.1136/bmj.322.7291.912.PubMed CentralView ArticlePubMedGoogle Scholar
  20. Coatmellec-Taglioni G, Dausse JP, Ribiere C, Giudicelli Y: Hypertension in cafeteria-fed rats: alterations in renal alpha 2-adrenoceptor subtypes. Am J Hypertens. 2000, 13: 529-534. 10.1016/S0895-7061(99)00234-4.View ArticlePubMedGoogle Scholar
  21. Makaritsis KP, Handy DE, Johns C, Kobilka BK, Gavras I, Gavras H: Role of the alpha 2B-adrenergic receptor in the development of salt- induced hypertension. Hypertension. 1999, 33: 14-17.View ArticlePubMedGoogle Scholar
  22. Makaritsis KP, Johns C, Gavras I, Gavras H: Role of alpha 2-adrenergic receptor subtypes in the acute hypertensive response to hypertonic saline infusion in anephric mice. Hypertension. 2000, 35: 609-613.View ArticlePubMedGoogle Scholar
  23. Perola M, Kainulainen K, Pajukanta P, Terwilliger JD, Hiekkalinna T, Ellonen P, Kaprio J, Koskenvuo M, Kontula K, Peltonen L: Genome-wide scan of predisposing loci for increased diastolic blood pressure in Finnish siblings. J Hypertens. 2000, 18: 1579-1585. 10.1097/00004872-200018110-00008.View ArticlePubMedGoogle Scholar
  24. Rice T, Rankinen T, Chagnon YC, Province MA, Perusse L, Leon AS, Skinner JS, Wilmore JH, Bouchard C, Rao DC: Genomewide linkage scan of resting blood pressure: HERITAGE Family Study. Health, Risk Factors, Exercise Training, and Genetics. Hypertension. 2002, 39: 1037-1043. 10.1161/01.HYP.0000018911.46067.6E.View ArticlePubMedGoogle Scholar

Copyright

© Snapir et al; licensee BioMed Central Ltd. 2003

This article is published under license to BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

Advertisement