Risk factors and myocardial infarction in patients with obstructive sleep apnea: impact of β2-adrenergic receptor polymorphisms
- Nina K Bartels†1,
- Jan Börgel†2Email author,
- Stefan Wieczorek1,
- Nikolaus Büchner3,
- Christoph Hanefeld2,
- Daniel Bulut2,
- Andreas Mügge2,
- Lars C Rump3,
- Bernd M Sanner4 and
- Jörg T Epplen1
© Bartels et al; licensee BioMed Central Ltd. 2007
Received: 24 July 2006
Accepted: 01 January 2007
Published: 01 January 2007
The increased sympathetic nervous activity in patients with obstructive sleep apnea (OSA) is largely responsible for the high prevalence of arterial hypertension, and it is suggested to adversely affect triglyceride and high-density lipoprotein (HDL) cholesterol levels in these patients. The functionally relevant polymorphisms of the β2-adrenergic receptor (Arg-47Cys/Arg16Gly and Gln27Glu) have been shown to exert modifying effects on these risk factors in previous studies, but results are inconsistent.
We investigated a group of 429 patients (55 ± 10.7 years; 361 men, 68 women) with moderate to severe obstructive sleep apnea (apnea/hypopnea index (AHI) 29.1 ± 23.1/h) and, on average, a high cardiovascular risk profile (body mass index 31.1 ± 5.6, with hypertension in 60.1%, dyslipidemia in 49.2%, and diabetes in 17.2% of patients). We typed the β2-adrenergic receptor polymorphisms and investigated the five most frequent haplotypes for their modifying effects on OSA-induced changes in blood pressure, heart rate, and lipid levels. The prevalence of cardiovascular risk factors and coronary heart disease (n = 55, 12.8%) and survived myocardial infarction (n = 27, 6.3%) were compared between the genotypes and haplotypes.
Multivariate linear/logistic regressions revealed a significant and independent (from BMI, age, sex, presence of diabetes, use of antidiabetic, lipid-lowering, and antihypertensive medication) influence of AHI on daytime systolic and diastolic blood pressure, heart rate, prevalence of hypertension, and triglyceride and HDL levels. The β2-adrenergic receptor genotypes and haplotypes showed no modifying effects on these relationships or on the prevalence of dyslipidemia, diabetes, and coronary heart disease, yet, for all three polymorphisms, heterozygous carriers had a significantly lower relative risk for myocardial infarction (Arg-47Cys: n = 195, odds ratio (OR) = 0.32, P = 0.012; Arg16Gly: n = 197, OR = 0.39, P = 0.031; Gln27Glu: OR = 0.37, P = 0.023). Carriers of the most frequent haplotype (n = 113) (haplotype 1; heterozygous for all three polymorphisms) showed a five-fold lower prevalence of survived myocardial infarction (OR = 0.21, P = 0.023).
Our study showed no significant modifying effect of the functionally relevant β2-adrenergic receptor polymorphisms on OSA-induced blood pressure, heart rate, or lipid changes. Nevertheless, heterozygosity of these polymorphisms is associated with a lower prevalence of survived myocardial infarction in this group with, on average, a high cardiovascular risk profile.
At position -47 in the untranslated region of the β2-adrenergic receptor gene, a cytosine (C)/thymine (T) polymorphism results in either arginine (Arg) or cystine (Cys) in the 5' leader sequence. This sequence encodes a peptide that modifies β2-adrenergic receptor gene translation. In human airway smooth muscles, the Cys variant showed a consistently greater expression of the β2-adrenergic receptor [12, 13].
At position 46 of the coding region, adenine (A) or guanine (G) can be found, resulting in arginine (Arg) or glycine (Gly) at amino acid position 16.
At nucleotide position 79, a C/G polymorphism results in glutamate (Glu) or glutamine (Gln) at amino acid position 27.
The latter two polymorphisms and their haplotypes modify the down-regulation of the β2-adrenergic receptor upon agonist stimulation. In a previous study , the Gly16/Gln27 haplotype underwent enhanced down-regulation compared with the Arg16/Gln27 haplotype, while the Arg16/Glu27 haplotype showed almost no down-regulation. Many population-based studies have been performed to investigate the modifying potency of these polymorphisms on cardiovascular risk factors in vivo, but the results have been inconsistent or contradictory.
Previously, a significant negative influence of the severity of OSA on BP, prevalence of arterial hypertension, heart rate, and serum levels of high-density lipoprotein cholesterol (HDL-C) was shown in the parent study cohort of the patients [4, 7] included in this report. In the present study, we scrutinised the modifying effects of β2-adrenergic receptor polymorphisms on these risk factors, which are mediated by elevated sympathetic activity. We further investigated whether the three polymorphisms have an effect on the comparatively high prevalence of coronary heart disease (CHD) and survived myocardial infarction (MI) in our patients with OSA.
Patients and parent study data
The study protocol was approved by the local ethics committee (Ruhr-University Bochum, Germany). Patients were consecutively enrolled during the years 1999 to 2001 in the sleep laboratory of the Marienhospital, Herne, Ruhr-University Bochum, Germany. The patients were admitted to the hospital because of a history of apnea, snoring, or hypersomnic symptoms such as daytime tiredness or impairment of cognitive functions.
Detailed information on the determination of cardiac risk factors and polysomnography have been described extensively in previous publications [4, 7]. In brief, after informed consent, the severity of OSA was assessed using the apnea/hypopnea index (AHI). Dyslipidemia was diagnosed by the presence of anamnesis and use of lipid-lowering drugs or presence of dyslipidemic serum levels. For blood analysis, the following cut-off values were defined as abnormal: total cholesterol ≥ 200 mg/dL, triglycerides ≥ 180 mg/dL, HDL-C ≤ 40 mg/dL, and low-density lipoprotein cholesterol (LDL-C) ≥ 150 mg/dL. Diabetes was defined by presence of anamnesis and use of antidiabetic medication or insulin treatment. The diagnosis of hypertension was established by use of antihypertensive medication or if the mean of three measured BP readings exceeded 140 mmHg (systolic) or 90 mmHg (diastolic).
Peripheral blood samples from the patients were taken after they had given informed consent.
The following primers were synthesised to amplify a 283-bp fragment containing the Cys-47Arg polymorphism: 5'-AATGAGGCTTCCAGGCGTC-3' (sense) and 5'-ACTTGGCAATGGCTGTGATG-3' (antisense). PCR was carried out in a final volume of 10 μL with 50 ng DNA, 2 mM dNTPs and 1 U Taq polymerase. PCR cycling started with initial denaturation for 5 minutes at 94°C. The annealing temperature of the first cycle was 69°C, second cycle 66°C and the remaining 28 cycles 63°C, each cycle being 1 minute. Extension was performed at 72°C for 1 minute (final extension 5 minutes). Allele-specific restriction digests were performed with MspAII, which fails to digest the Cys-47 allele because of the C→G transition. Digested DNA was separated by electrophoresis on 1.5% agarose gels.
For the Gly16Arg polymorphism, the following primers were synthesised to obtain a 96-bp fragment: 5'-GCCAGTGCGCTTACCTGC-3' (sense) and 5'-TGGTCCGGCGCATGGCTT-3' (antisense). Final volume of the PCR was 10 μL, containing 50 ng DNA, 2 mM dNTPs, 1 U Taq polymerase and 1% radioactively labelled dATP. The PCR cycles after denaturation (94°C for 5 minutes) were 70°C (1 cycle), 67°C (1 cycle) and 64°C (28 cycles), with each cycle lasting 1 minute. Extension at 72°C was performed for 1 minute, and 5 minutes at the end. The PCR products were digested with the restriction endonuclease NcoI in order to optimize the demonstration of the polymorphism by single-strand conformational polymorphism analysis. Restriction products were separated in an 8% polyacrylamide (19:1 acrylamide:bisacrylamide) gel containing 10% glycerol.
For genotyping the Gln27Glu polymorphism, the primers 5'-AAGCCATGCGCCGGACCA-3' (sense) and 5'-ACTTGGCAATGGCTGTGATG-3' (antisense) primers were chosen, which produce a 134-bp long product. PCR was performed with a final volume of 10 μL comprising 50 ng DNA, 2 mM dNTP and 1 U Taq polymerase. The chosen temperatures after denaturation were 70.5°C (1 cycle), 67.5°C (1 cycle), and 64.5°C (28 cycles). Allele-specific restriction was performed with BbvI and bands separated in a 1.5% agarose gel.
Results are presented as means +/-SD. All reported P-values are two-tailed. Statistical analyses were performed with SPSS for Windows software (SPSS, Chicago, IL, USA). Multivariate linear regressions were calculated in order to determine independent associations between the AHI and BP, heart rate and lipid serum levels in the presence of body mass index (BMI), age, and sex. The relationship between the severity of OSA represented by the AHI and the prevalence of arterial hypertension was calculated using multiple logistic regression analysis using BMI, age, and sex as covariates. Demographic characteristics of the patients with OSA were compared between the different genotypes using the χ2 test; P < 0.05 was considered significant. The phenotypic values were compared between the genotypes using analysis of variance (ANOVA). Student's t-test for unpaired samples was used for comparisons between particular genotypes/haplotypes and the rest of the group.
An additional model was established in which the homozygous states of each polymorphism were pooled in one group and compared with the heterozygous genotype. The influence of heterozygosity of each polymorphism on survived MI was then analysed in a multivariate logistic regression model, adjusted for diabetes, dyslipidemia, hypertension, sex, BMI, AHI, and age.
Demographics in the different genotypes of the β2-adrenergic receptor.
(% of all)
mean ± SD
mean ± SD
n (% of n*)
n (% of n*)
n (% of n*)
n (% of n*)
n (% of n*)
55.2 ± 10.7
31.1 ± 5.6
55.9 ± 11.3
30.8 ± 5.2
55.1 ± 10.7
31.1 ± 6.0
54.2 ± 9.7
31.5 ± 5.6
57.0 ± 9.9
31.6 ± 6.0
54.0 ± 11.1
31.1 ± 6.0
54.7 ± 10.5
31.0 ± 5.0
55.9 ± 11.0
31.5 ± 5.4
56.0 ± 10.5
31.0 ± 6.0
52.9 ± 10.5
30-9 ± 5.2
Allele frequencies of the different polymorphisms were: Arg-47Cys = 0.53/0.47, Arg16Gly = 0.37/0.63 and Gln27Glu = 0.49/0.51. The β2-adrenergic receptor polymorphisms Arg-47Cys and Gln27Glu were found to be strongly concordant, generating the haplotypes -47Cys/27Glu (83.5% of -47Cys homozygotes are 27Glu homozygotes). The five most common haplotypes accounted for 73.2% of all observed haplotypes.
Use of antihypertensive or lipid-lowering medication was distributed equally in the genotype subgroups and consisted of angiotensin-converting enzyme inhibitors (n = 128; 29.8%), β-receptor blockers (n = 87; 20.3%), diuretics (n = 70; 16.3%), calcium-channel blockers (n = 86; 20.0%), nitrates (n = 41; 9.6%) and α-receptor blockers (n = 1; 0.2%). Of the 40 patients on lipid-lowering medication, 37 were using statins and 3 fibrates. Total cholesterol and triglycerides measurement was available for 360 patients, and lipoprotein determination for 278 patients.
The mean ± SD AHI in our study group was 29.1 ± 23.1 events per hour, and the mean minimal nocturnal oxygen saturation was 81.0 ± 10.9%. Linear and independent relationships between the AHI and daytime systolic and diastolic BP, daytime heart rate, the prevalence of hypertension, and HDL-C serum levels have been shown in this study group previously . Because DNA tests could not be performed for all members of the parent study cohort (n = 540), we performed a new, adjusted regression for our subgroup of 429 subjects . Multivariate linear or logistic regressions revealed a significant influence of the severity of OSA on daytime systolic BP (β = 0.129, P = 0.008), diastolic BP (0.129, P = 0.012), heart rate (β = 0.197. P < 0.001) prevalence of hypertension (β = 0.026, P = < 0.001), and HDL-C serum levels (n = 78, β = -0.146, P = 0.003). This influence was independent of diabetes, BMI, age, sex, or antidiabetic, lipid-lowering, or antihypertensive treatments.
Blood pressure, heart rate and lipid levels in different genotypes of the β2-adrenergic receptor polymorphisms.
130.5 ± 15.7
79.6 ± 9.2
76.8 ± 9.5
224.7 ± 39.4
171.5 ± 95.7
46.8 ± 14.3
146.6 ± 35.9
130 ± 1 ± 16.3
79.8 ± 9.4
77.0 ± 9.1
226.0 ± 40.3
168.6 ± 76.5
46.0 ± 14.3
148.9 ± 32.9
130.9 ± 15.6
79.6 ± 9.3
76.6 ± 8.9
222.5 ± 38.5
175.3 ± 102.5
47.3 ± 13.9
144.0 ± 38.6
130.1 ± 15.1
79.4 ± 8.7
76.9 ± 11.0
227.6 ± 40.1
167.9 ± 105.2
46.9 ± 15.5
148.3 ± 35.1
133.6 ± 17.2
80.9 ± 9.3
78.4 ± 9.3
228.2 ± 45.7
178.5 ± 114.2
49.7 ± 15.9
149.5 ± 34.8
130.0 ± 15.9
79.8 ± 9.5
76.6 ± 9.4
221.4 ± 38.6
164.7 ± 92.5
47.0 ± 14.4
143 ± 37.2
129.9 ± 14.9
79.0 ± 8.9
76.5 ± 9.7
227.2 ± 37.8
176.0 ± 91.8
45.7 ± 13.8
149.4 ± 34.9
130.7 ± 14.5
80.2 ± 9.0
77.2 ± 9.2
222.7 ± 42.3
175.9 ± 89.4
44.9 ± 14.0
145.6 ± 32.9
130.8 ± 15.2
79.2 ± 9.1
76.6 ± 9.2
225.3 ± 38.3
174.1 ± 100.9
47.2 ± 14.3
146.5 ± 38.2
130.5 ± 15.7
79.9 ± 9.5
76.8 ± 10.2
224.8 ± 39.4
163.3 ± 93.0
48.0 ± 14.8
147.8 ± 35.2
Of the 429 patients with OSA, 27 (6.3%) had survived a MI. Patients heterozygous for the Arg-47Cys and Gln27Glu polymorphisms showed a lower rate of survived MI than those with the homozygous forms. There was a trend towards a lower rate of survived MI in patients heterozygous for the Arg16Gly polymorphism (Table 1).
Risk factors, coronary heart disease and myocardial infarction in haplotypes of the β2-adrenergic receptor.
Diabetes, n (% of Hap.)
Hypertension,, n (% of pt)
Dyslipidemia n (% of Hap.)
CHD, n (% of Hap.)
MI, n (% of Hap.)
P = 0.021
Relative risk for myocardial infarction in OSA patients heterozygous for β2-adrenergic receptor polymorphisms.
Relative risk for myocardial infarction: odds ratio (95% confidence interval)
We analysed β2-adrenergic receptor polymorphisms in a study group of untreated patients with OSA in whom a linear and independent relationship between the frequency of nocturnal apnea/hypopnea and daytime systolic and diastolic BP, daytime heart rate, prevalence of arterial hypertension, and HDL serum levels were shown previously [4, 7]. The elevated sympathetic nerve activity in patients with OSA [1–3] is suggested to mediate these effects, especially in relation to the cardiovascular system.
The underlying mechanisms between the severity of OSA and modulation of lipid serum level have been discussed in detail elsewhere . The fact that we could not find any influence despite the sympathetic pathway supports the notion that the effect of these polymorphisms in vivo is minor, and confirms previous negative results . Kim et al investigated 195 Korean subjects and found no difference between β2-adrenergic receptor genotypes (Arg16Gly and Gln27Glu) in relation to plasma glucose, fasting serum insulin, LDL, HDL, or triglyceride levels. However, in another study of 19 healthy individuals with propanolol-induced dyslipidemia, a significantly decreased HDL serum level was found in subjects homozyous for Gln27 homozygotes, and raised triglyceride levels in subjects homozygous for Glu27 .
The genetic role of the β2-adrenergic receptor gene in the development of hypertension has been the subject of many population-based studies. The distal segment of chromosome 5 (5q31.1-qtr), which harbors the β2-adrenergic receptor gene, has been linked both to systolic and to post-exercise diastolic BP in genome-wide scans performed in large study populations [17, 18]. In a large sample of 638 individuals from 212 Polish pedigrees, maximum linkage to essential hypertension and adjusted systolic and diastolic BP was found for a marker in close proximity to the β2-adrenergic receptor gene. However, no significant association of the Arg16Gly and Gln27Glu polymorphisms was detected with these parameters in the same study .
The published studies that have shown an influence of these polymorphisms on BP and hypertension are confusing. On the one hand, the Gly16 and Glu27 genotypes were significantly associated with the prevalence of hypertension and systolic BP in two large populations of Chinese individuals [20, 21]. On the other hand, a more than twofold increased relative risk for hypertension and higher BP was detected in homozygous Arg16 carriers with diabetes . One could argue that this represents a linkage phenomenon in two different populations, but in view of the functional relevance of these polymorphisms, such contradictory results remain difficult to explain. Finally, in the most extensive and prospective population based study, the Cardiovascular Health Study, with over 5000 participants, no effect of the Arg16Gly and Gln27Glu polymorphisms on BP control, new-onset hypertension, ankle-arm index, carotide intima-media thickness, or brachial flow-mediated dilation was detected . Interestingly, in this study cohort, Glu27 carriers (heterozygous and homozygous) had a significantly lower risk for coronary events, and there was a similar trend for Gly16 carriers . Recently, in the same study population, it was shown that Glu27 carriers also have a significantly lower risk for sudden cardiac death .
In contrast to the aforementioned studies, we investigated a cohort of patients in which an OSA-induced, elevated sympathetic activity exacerbated BP, heart rate, and HDL levels. Thus, the known functional relevance of these polymorphisms in vitro would be likely to be detected in vivo in such patients. The fact that we could not detect any significant result underlines the minor effect of β2-adrenergic receptor polymorphisms in the development of these cardiovascular risk factors, and supports the results of the Cardiovascular Health Study.
Sympathetic activation also influences the risk of MI . Thus, patients with OSA show a higher incidence of fatal and non-fatal cardiovascular events . In our study group, with a mean age of 56 years, we found a high percentage of CHD (12.8%) and survived MI (6.3%). Although no effect was seen on the prevalence of CHD, we found a clear and independent protective effect of the heterozygous β2-adrenergic receptor genotypes on survived MI. This result again supports the hypothesis that was deducted form the Cardiovascular Health Study; namely, that variations of the β2-adrenergic receptor gene influence vulnerability to coronary events.
In the statistical model that was chosen in the Cardiovascular Health Study, carriers of the Gly variation were pooled into one group. It is not apparent whether heterozygosity alone is protective, but a protective effect of heterozygosity in the β2-adrenergic receptor has already been shown in pulmonary research. Joos et al examined 587 smokers from the Lung Health Study. Those subjects who were heterozygous at position 27 of the β2-adrenergic receptor gene had a significantly lower decline in lung function at 1-year follow-up compared with the homozygous genotypes (P < 0.001) . Our results support those findings; by pooling homozygous and heterozygous individuals into two different groups, we could show a protective effect of heterozygosity on MI, independent of other risk factors such as diabetes, arterial hypertension, dyslipidemia and BMI in a logistic regression model. Interestingly, patients heterozygous at position 27 were slightly but significantly older in spite of the lower rate of MI (Table 1). This may be an additional indicator for the protective effect of this polymorphism.
As discussed previously by Loos et al,  a reason for the protective effect of heterozygosity may be a phenomenon called heterozygous advantage. For example, a study on the role of the secretor blood group in psoriasis showed that heterozygosity had a strong protective effect (odds ratio = 0.17), even though the allele frequencies did not differ between patients and controls . A possible mechanism for heterozygote advantage is interaction between the wild-type and mutant protein isoforms in heterozygous cells. This is a plausible mechanism for receptor molecules, especially in cases where they form dimers. Heterodimeric receptors consisting of a wild-type and a mutant protein isoform may have different agonist-binding, signal-transduction or agonist-promoted desensitation properties than wild-type or mutant homodimers. Several lines of evidence indicate that β2-adrenergic receptors form dimers like other G-protein-coupled receptors. The formation of β2-adrenergic receptor dimers was shown to have functional effects on receptor-stimulated adenylate cyclase activity . Furthermore, the results of a study of a mutant β2-adrenergic receptor (Cys341Gly) suggested that the dimer is the active form of the receptor .
Limitations of the study
Lipid and lipoprotein serum levels were not available for all patients. Therefore, the diagnosis of dyslipidemia had to be determined by anamnesis alone in some cases, which may have led to inaccuracies in the multivariate regression. The diagnosis of CHD was determined by anamnesis and was not controlled by coronary arteriography. Thus, our proportion of 12.8% may not reflect the real incidence of CHD.
Because our hypothesis included several risk factors for CHD and MI, Bonferroni correction after the statistical analysis should be discussed. After this correction, the results for MI would become insignificant. Because of the explorative character of our study, we refrained from performing Bonferroni corrections here.
We conclude that the investigated β2-adrenergic receptor polymorphisms do not modulate cardiovascular risk factors in patients with OSA-induced elevated sympathetic activity. However, heterozygosity of these polymorphisms may be protective in reducing the vulnerability to survived MI, especially if heterozygosity is present for all polymorphisms. Because the statistical haplotype with heterozygosity in all three polymorphisms was not included in previous studies, we believe that this potentially protective genetic combination should be focussed on in future.
This study was supported by FoRUM (Forschungsförderung der Ruhr-Universität Bochum, Medizinische Fakultät). We thank Michael Haske, Dr. med. Christina Giese and Dr. med. Marion Burmann-Urbaneck for support in patient recruitment and Mrs Anika Huesing for assistance in statistical analysis.
- Somers VK, Dyken ME, Clary MP, Abboud FM: Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest. 1995, 96: 1897-904.View ArticlePubMedPubMed CentralGoogle Scholar
- Lesske J, Fletcher EC, Bao G, Unger T: Hypertension caused by chronic intermittent hypoxia – influence of chemoreceptors and sympathetic nervous system. J Hypertens. 1997, 15: 1593-603. 10.1097/00004872-199715120-00060.View ArticlePubMedGoogle Scholar
- Narkiewicz K, Somers VK: Sympathetic nerve activity in obstructive sleep apnoea. Acta Physiol Scand. 2003, 177: 385-90. 10.1046/j.1365-201X.2003.01091.x.View ArticlePubMedGoogle Scholar
- Börgel J, Sanner BM, Keskin F, Bittlinsky A, Bartels NK, Büchner N, Huesing A, Rump LC, Mügge A: Obstructive sleep apnea and blood Pressure. Interaction between the blood pressure-lowering effects of positive airway pressure therapy and antihypertensive drugs. Am J Hypertens. 2004, 17: 1081-1087. 10.1016/j.amjhyper.2004.06.026.View ArticlePubMedGoogle Scholar
- Peppard PE, Young T, Palta M, Skatrud J: Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med. 2000, 342: 1378-84. 10.1056/NEJM200005113421901.View ArticlePubMedGoogle Scholar
- Newman AB, Nieto FJ, Guidry U, Lind BK, Redline S, Pickering TG, Quan SF: Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am J Epidemiol. 2001, 154: 50-9. 10.1093/aje/154.1.50.View ArticlePubMedGoogle Scholar
- Börgel J, Sanner BM, Bittlinsky A, Keskin F, Bartels NK, Büchner N, Huesing A, Rump LC, Mugge A: Obstructive sleep apnoea and its therapy influence high density lipoprotein cholesterol serum levels. Eur Respir J. 2006, 27: 121-127. 10.1183/09031936.06.00131304.View ArticlePubMedGoogle Scholar
- Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Javier Nieto F, O'Connor GT, Boland LL, Schwartz JE, Samet JM: Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med. 2001, 163: 19-25.View ArticlePubMedGoogle Scholar
- Marin J, Carrizo S, Vicente E, Agusti A: Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005, 365: 1046-1053.View ArticlePubMedGoogle Scholar
- Lavie P, Herer P, Peled R, Berger I, Yoffe N, Zomer J, Rubin AH: Mortality in sleep apnea patients: a multivariate analysis of risk factors. Sleep. 1995, 18: 149-57.PubMedGoogle Scholar
- Liggett SB: Beta(2)-adrenergic receptor pharmacogenetics. Am J Respir Crit Care Med. 2000, 161: 197-201.View ArticleGoogle Scholar
- McGraw DW, Forbes SL, Kramer LA, Liggett SB: Polymorphisms of the 5' leader cistron of the human beta2-adrenergic receptor regulate receptor expression. J Clin Invest. 1998, 102: 1927-32.View ArticlePubMedPubMed CentralGoogle Scholar
- Johnatty SE, Abdellatif M, Shimmin L, Clark RB, Boerwinkle E: Beta 2 adrenergic receptor 5' haplotypes influence promoter activity. Br J Pharmacol. 2002, 137: 1213-6. 10.1038/sj.bjp.0704935.View ArticlePubMedPubMed CentralGoogle Scholar
- Green SA, Turki J, Innis M, Liggett SB: Amino-terminal polymorphisms of the human beta2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry. 1994, 33: 9414-9. 10.1021/bi00198a006.View ArticlePubMedGoogle Scholar
- Kim SH, Kim DJ, Seo IA, Min YK, Lee MS, Kim KW, Lee MK: Significance of beta2-adrenergic receptor gene polymorphism in obesity and type 2 diabetes mellitus in Korean subjects. Metabolism. 2002, 51: 833-7. 10.1053/meta.2002.33347.View ArticlePubMedGoogle Scholar
- Isaza C, Henao J, Ramirez E, Cuesta F, Cacabelos R: Polymorphic variants of the beta2-adrenergic receptor (ADRB2) gene and ADRB2-relateted propanolol-induced dyslipidemia in the Colombian population. Methods Find Exp Clin Pharmacol. 2005, 27: 237-244. 10.1358/mf.2005.27.4.893582.View ArticlePubMedGoogle Scholar
- Krushkal J, Ferrell R, Mockrin S, Turner ST, Sing CF, Boerwinkle E: Genome-wide linkage analyses of systolic blood pressure using highly discordant siblings. Circulation. 1999, 99: 1407-1410.View ArticlePubMedGoogle Scholar
- Rankinen T, An P, Rice T, Sun G, Chagnon YC, Gagnon J, Leon AS, Skinner JS, Wilmore JH, Rao DC, et al: Genomic scan for exercise blood pressure in the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study. Hypertension. 2001, 38: 30-37.View ArticlePubMedGoogle Scholar
- Tomaszewski M, Brain NJ, Charchar FJ, Wang WY, Lacka B, Padmanabahn S, Clark JS, Anderson NH, Edwards HV, Zukowska-Szczechowska E, et al: Essential hypertension and beta2-adrenergic receptor gene: linkage and association analysis. Hypertension. 2002, 40: 286-91. 10.1161/01.HYP.0000029105.21202.FE.View ArticlePubMedGoogle Scholar
- Ranade K, Shue WH, Hung YJ, Hsuing CA, Chiang FT, Pesich R, Hebert J, Olivier M, Chen YD, Pratt R, et al: The glycine allele of a glycine/arginine polymorphism in the beta2-adrenergic receptor gene is associated with essential hypertension in a population of Chinese origin. Am J Hypertens. 2001, 14: 1196-200. 10.1016/S0895-7061(01)02213-0.View ArticlePubMedGoogle Scholar
- Ge D, Huang J, He J, Li B, Duan X, Chen R, Gu D: β2-Adrenergic receptor gene variations associated with stage-2 hypertension in Northern Han Chinese. Ann Hum Genet. 2005, 69: 36-44. 10.1046/j.1529-8817.2003.00093.x.View ArticlePubMedGoogle Scholar
- Bengtsson K, Orho-Melander M, Melander O, Lindblad U, Ranstam J, Rastam L, Groop L: Beta(2)-adrenergic receptor gene variation and hypertension in subjects with type 2 diabetes. Hypertension. 2001, 37: 1303-8.View ArticlePubMedGoogle Scholar
- Hindorff LA, Heckbert SR, Psaty BM, Lumley T, Siscovick DS, Herrington DM, Edwards KL, Tracy RP: β2-adrenergic receptor polymorphisms and determinants of cardiovascular risk: The Cardiovascular Health Study. Am J Hypertens. 2005, 18: 392-397. 10.1016/j.amjhyper.2004.10.014.View ArticlePubMedGoogle Scholar
- Heckbert SR, Hindorff LA, Edwards KL, Psaty BM, Lumley T, Siscovick DS, Tang Z, Durda JP, Kronmal RA, Tracy RP: Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly. Circulation. 2003, 107: 2021-4. 10.1161/01.CIR.0000065231.07729.92.View ArticlePubMedGoogle Scholar
- Sotoodehnia N, Sicovick DS, Vatta M, Psaty BM, Tracy RP, Towbin JA, Lemaitre RN, Rea TD, Durda JP, Chang JM, et al: Beta2-adrenergic receptor genetic variants and risk of sudden cardiac death. Circulation. 2006, 113: 1818-1820. 10.1161/CIRCULATIONAHA.105.582833.View ArticleGoogle Scholar
- Albert CM, Mittleman MD, Chae CU, Lee IM, Hennekens CH, Manson JE: Triggering of sudden death from cardiac causes by vigorous exertion. N Engl J Med. 2000, 343: 1355-1361. 10.1056/NEJM200011093431902.View ArticlePubMedGoogle Scholar
- Joos L, Weir TD, Connett JE, Anthonisen NR, Woods R, Pare PD, Sandford AJ: Polymorphisms in the beta2 adrenergic receptor and bronchodilator response, bronchial hyperresponsiveness, and rate of decline in lung function in smokers. Thorax. 2003, 58: 703-7. 10.1136/thorax.58.8.703.View ArticlePubMedPubMed CentralGoogle Scholar
- Beckmann L, Bronnestam R, Cedergren B, Liden S: HL-A antigens, blood groups, serum groups and red cell enzyme thypes in psoriasis. Hum Hered. 1974, 24: 496-506.View ArticleGoogle Scholar
- Hebert TE, Moffett S, Morello JP, Loisel TP, Bichet DG, Barret C, Bouvier M: A Peptide derived from a β2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation. J Biol Chem. 1996, 271: 16384-16392. 10.1074/jbc.271.24.14280.View ArticlePubMedGoogle Scholar
- Hebert TE, Loisel TP, Adam L, Ethier N, Onge SS, Bouvier M: Functional rescue of a constitutively desensitized beta2AR through receptor dimerization. Biochem J. 1998, 15: 287-293.View ArticleGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/5/1/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.