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Published online before print July 11, 2007, 10.1183/09031936.00152006
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Eur Respir J 2007; 30:743-747
Copyright ©ERS Journals Ltd 2007

ß3-Adrenergic receptor Trp64Arg polymorphism and increased body mass index in sleep apnoea

J. Piérola1, A. Barceló1, M. de la Peña1, F. Barbé2,3, J. B. Soriano4,5, A. Sánchez Armengol6, C. Martínez7 and A. Agustí1,4

1 Serveis de Anàlisis Cliniques i Pneumologia, Son Dureta University Hospital, Palma de Mallorca, 2 Arnau de Vilanova University Hospital , and 3 Institut de Recerca Biomedica de Lleida, Lleida, 4 Fundació Caubert-CIMERA, Illes Balears, Buñola, 6 Hospital Virgen del Rocio, Seville, 7 Txagorritxu Hospital, Vitoria-Gasteiz, and 5 CIBER Enfermedades Respiratorias, Spain.

CORRESPONDENCE: A. Barceló, Serveis de Anàlisis Cliniques i Pneumologia, Hospital Universitari Son Dureta, C/ Andrea Doria 55, 07014 Palma de Mallorca, Spain. Fax: 34 971175228. E-mail: abarcelo{at}hsd.es

Keywords: ß3-Adrenergic receptor polymorphism, body mass index, sleep apnoea

Received: November 23, 2006
Accepted July 5, 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Obesity is an important risk factor for obstructive sleep apnoea syndrome (OSAS), insulin resistance and cardiovascular disease. The substitution of tryptophan 64 with arginine (Trp64Arg) polymorphism (Arg variant) of the ß3-adrenergic receptor (ADRB3) has been associated with obesity. In this study, the prevalence of the Trp64Arg ADRB3 polymorphism in a large group of patients with OSAS and its association with body mass index (BMI), insulin resistance and hypertension were evaluated.

ADRB3 genotype was determined in 387 patients with OSAS and 137 healthy subjects recruited from three Spanish tertiary hospitals.

The distributions of the ADRB3 genotypes were similar in OSAS and controls, and, in a multivariate model, the risk of OSAS was not associated with the presence of the Arg variant of the ADRB3 gene. However, BMI was higher in those patients with OSAS who carried this genetic variant than in those with the Trp variant. Furthermore, a linear trend for higher BMI was found in those with the Arg variant (56, 75 and 100% for Trp/Trp, Trp/Arg and Arg/Arg, respectively). Insulin resistance, blood pressures and serum levels of lipids and glucose were not associated with the presence of the Arg variant of the ADRB3 gene.

The presence of the arginine 64 allele of the ß3-adrenergic receptor gene does not increase the risk of obstructive sleep apnoea syndrome, but is associated with the development of obesity in those patients who suffer obstructive sleep apnoea syndrome.

Obstructive sleep apnoea syndrome (OSAS) is a common disorder characterised by excessive daytime sleepiness, repeated episodes of upper airway obstruction during sleep and nocturnal hypoxaemia 1. Obesity is a risk factor for OSAS 2, 3, and it has been hypothesised that genetic variants that predispose to obesity might facilitate the development of OSAS 4, 5.

The ß3-adrenergic receptor (ADRB3) is mainly expressed in adipose tissue, and contributes to variations in energy expenditure and body fat distribution 6–8. Polymorphisms of the ADRB3 have been suggested to participate in the pathogenesis of obesity 7, 9. In particular, a single nucleotide polymorphism in the ADRB3 gene (substitution of tryptophan 64 with arginine (Trp64Arg)) has been associated with obesity, insulin resistance, abnormal lipid profile and arterial hypertension 10–15. However, since the prevalence of the Trp64Arg mutation differs among ethnic groups 7, other studies have failed to show any relationship between this polymorphism and obesity 16, 17. Furthermore, it has been suggested that the association of this ADRB3 polymorphism with body weight and obesity-related phenotypes may be dependent upon the presence of other susceptibility genes and/or exposure to other environmental factors 7.

The potential role of this polymorphism of the ADRB3 gene in OSAS had not been explored until recently, when it has been shown to be associated with obesity in male Chinese patients 18. However, as the prevalence of the Trp64Arg mutation differs among ethnic groups 7, the present study was designed to: 1) estimate the prevalence of the Trp64Arg ADRB3 polymorphism in Spanish patients with OSAS; and 2) examine whether or not this gene variant was associated with other clinical phenotypes frequently present in patients with OSAS, such as obesity, insulin resistance and arterial hypertension.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects and ethics
The present case–control study was designed to determine the presence of the Trp64Arg mutation of the ADRB3 gene and its association with body mass index (BMI), lipid profile, glucose metabolism and the presence of arterial hypertension in a group of Spanish individuals with (n = 387) and without OSAS (n = 137). Participants were recruited and studied at the sleep units of three tertiary university hospitals in Spain (Son Dureta University Hospital, Palma de Mallorca; Hospital Virgen del Rocio, Seville; and Txagorritxu Hospital, Vitoria-Gasteiz). The diagnosis of OSAS was established by full polysomnography (E-Series; Compumedics, Abbotsford, Australia), and included recording of oronasal flow and thoracoabdominal movements, ECG, submental and pre-tibial electromyography, electro-oculography, electroencephalography and transcutaneous measurement of arterial oxygen saturation. The apnoea/hypopnoea index (AHI) was defined as the number of apnoeas plus hypopnoeas per hour of sleep. OSAS was diagnosed when the AHI was ≥10 events·h–1. In controls, the diagnosis of OSAS was excluded by conventional polysomnography (in subjects whose BMI was >30 kg·m–2) or a cardiorespiratory sleep study that recorded nasal flow, thoracic movements, cardiac frequency, snoring, body position and transcutaneous oxyhaemoglobin saturation (Edentec, Eden Prairie, MN, USA). Exclusion criteria (for both cases and controls) were presence of chronic obstructive pulmonary disease, liver cirrhosis, thyroid dysfunction, rheumatoid arthritis, chronic renal failure and/or psychiatric disorders.

Arterial hypertension was diagnosed if systolic blood pressure was >140 mmHg or diastolic blood pressure >90 mmHg. Similarly, the threshold for diabetes was a glucose level of >126 mg·dL–1, for insulin resistance a homeostasis model assessment (HOMA) index of >4, for hyperlipidaemia a total cholesterol level of >200 mg·dL–1 and for obesity a BMI of >30 kg·m–2.

The present study was approved by the ethics committees of the participating institutions, and all participants signed their consent after being fully informed of its goal and characteristics.

Measurements
Blood samples (10 mL) were obtained between 08:00 and 10:00 h after an overnight fast, and collected in tubes containing ethylenediamine tetra-acetic acid (EDTA) but no anticoagulant for biochemical determinations. After centrifugation, serum and plasma were immediately separated into aliquots and stored at -80°C. Blood in EDTA tubes and aliquots of serum and plasma were transported in dry ice from Txagorritxu Hospital and Virgen del Rocio Hospital to Son Dureta Hospital and stored at -80°C until centralised analysis at the latter hospital.

Biochemical analysis
Glucose, triglyceride, cholesterol and high-density lipoprotein–cholesterol complex concentrations were determined by standard enzymatic methods using a Hitachi 917 biochemical analyser (Roche Diagnostics, Indianapolis, IN, USA). The plasma concentration of insulin was measured using a commercial chemiluminescent assay and an Immulite 2000 analyser (DPC, Los Angeles, CA, USA). Insulin resistance was calculated using HOMA 19.

DNA extraction and genotyping
DNA extraction of each blood sample was performed using a DNA extraction Kit (Wizard Genomic; Promega Corporation, Madison, WI, USA). The ADRB3 Trp64Arg polymorphism was genotyped using PCR. The PCR primers were 5’-CAATACCGCCAACACCAGTGGG-3’ and 5’-GGTCATGGTCTGGAGTCTCG-3’. PCR was carried out in a volume of 30 µL, containing 30 ng genomic DNA, 2.0 mM MgCl2, 200 µM deoxyribonucleoside triphosphates, 300 nM each primer, 0.025 U EuroTaq DNA polymerase (Euroclone, Pero, Italy) and 1x reaction buffer. Amplified products were digested with 3 U Bacillus stearothermophilus NI (New England Biolabs, Beverly, MA, USA), and the resulting fragments separated on 3% agarose gels and visualised with ethidium bromide staining under ultraviolet illumination (Syngene Gen Genius; Synoptics Group, Cambridge, UK)

Statistical analysis
Results are presented as mean±SD. Comparisons between groups were performed with independent ANOVA tests for quantitative variables and Fisher’s exact Chi-squared test for proportions. Correlations between variables were explored using the Spearman test. The Hardy–Weinberg equilibrium for allelic distribution was tested using the formula, 1 = p2+2pq+q2, where p and q are the allelic frequencies of the Trp and Arg variants, respectively 20. The risk of being a carrier of the Arg variant of the ADRB3 polymorphism was quantified with an odds ratio in patients with OSAS versus controls, and the 95% confidence interval calculated. Finally, multivariate logistic regression analysis was conducted, including carrier status and number of comorbid conditions. A p-value of <0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Patients with OSAS (n = 387) and healthy controls (n = 137) were studied. Table 1Go shows the main demographic and clinical characteristics and biochemical profile of all subjects studied. Patients with OSAS were older and had significantly higher BMIs and systolic and diastolic blood pressures, glucose levels, triglyceride levels and HOMA indices than controls (p<0.05 for all). Differences in insulin level were of borderline significance (p = 0.056), and there were no differences in cholesterol level.


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  		Table 1— Characteristics of patients with obstructive sleep apnoea syndrome(OSAS) and controls

 
Table 2Go presents the distribution of genotypes and allelic frequencies of the observed ADRB3 variants in all participants. The genotypic frequency distributions were in Hardy–Weinberg equilibrium in both patients with OSAS and control subjects, and there were no differences between them (X2 = 0.414). Furthermore, being a carrier of the Arg variant of the ADRB3 polymorphism did not significantly increase the risk of suffering OSAS (odds ratio 1.24; 95% confidence interval 0.73–2.11; p = 0.514; tables 2Go and 3Go). However, it was found that patients with OSAS carrying the Arg variant of the ADRB3 gene exhibited higher BMIs than those with the Trp variant alone (p<0.01; table 4Go). By contrast, in control subjects, BMI did not differ according to the presence or absence of the Arg variant (28.5±4.6 versus 28.6±5.1 kg·m–2; p = 0.731).


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  		Table 2— Genotypic and allelic frequencies of theß3-adrenergic receptor gene in patients with obstructive sleep apnoea syndrome (OSAS) and controls

 

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  		Table 3— Gene-by-obesity interaction of arginine (Arg) 64 variant of ß3-adrenergic receptor gene in patients with obstructive sleep apnoea syndrome (OSAS) and controls

 

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  		Table 4— Clinical and biochemical characteristics of obstructive sleep apnoea syndrome patients according to presence of arginine 64 variant ofß3-adrenergic receptor gene

 
In patients with OSAS, the prevalence of obesity (BMI >30 kg·m–2) increased linearly in carriers of the Arg variant of the ADRB3 gene (56, 75 and 100% for Trp/Trp, Trp/Arg and Arg/Arg, respectively; p = 0.001 (trend) and 0.005 (Chi-squared test)). The corresponding BMIs were 31.5±5.7, 33.5±6.9 and 33.9±3.1 for Trp/Trp, Trp/Arg and Arg/Arg, respectively (p = 0.038 (trend)). Finally, a multivariate model was used to investigate whether carrier status influenced the clinical phenotype of OSAS, but no independent effect of the Arg variant of the ADRB3 gene upon the prevalence of obesity, insulin resistance or hypertension could be demonstrated.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
The present study provides two findings of interest. First, the genotypic and allelic frequencies of the ADRB3 gene variants observed in Spanish patients with OSAS did not differ from those in healthy controls of the same ethnic origin. Secondly, BMI was significantly greater in those patients with OSAS who carried the Arg variant of the ADRB3 gene (Trp/Arg and Arg/Arg genotypes) than in those with the Trp/Trp genotype. These two observations suggest that the Trp64Arg polymorphism is not associated with the development of OSAS in this Spanish population, but may favour the development of obesity in patients who already suffer OSAS. Consistent with this hypothesis, a previous study has recently shown an independent effect of this polymorphism on BMI in Chinese patients with OSAS 18.

The ADRB3 is mainly expressed in adipose tissue and contributes to population variations in energy expenditure and body fat distribution 6. A missense mutation of the gene (Trp64Arg) has been associated with increased BMI and an enhanced capacity to gain weight 8. However, studies carried out in different ethnic groups have reported conflicting results concerning the effect of the Trp64Arg ADRB3 polymorphism on body weight 14, 21–23. In general, meta-analyses are consistent with a small effect of the Arg64 mutation on BMI 17, 24. Although the relevance of this polymorphism to human obesity remains the subject of debate, an important finding is that the Trp64Arg polymorphism is common in diverse populations. Thus, even if the biological effect is small in absolute terms, it may still account for significant population-based attributable risk of obesity 7.

There are several ways of exploring the influence of a genetic background on the phenotypic expression of a given trait. The study of the allelic frequency and prevalence of a given single nucleotide polymorphism are among the most commonly used. In the present study, the allelic frequency of the Arg64 allele was similar between patients with OSAS and controls (table 2Go). The fact that it was similar in obese and nonobese patients (versus obese and nonobese controls, respectively; table 3Go) suggests that this polymorphism is not a major determinant of OSAS. However, the observation that patients with OSAS carrying the Arg64 variant had higher BMI than those with the Trp64 variant is consistent with this polymorphism facilitating the development of obesity in patients who, for other reasons, have developed OSAS.

The molecular mechanisms underlying the association of the Trp64Arg polymorphism with various physiological phenotypes are still unclear 7. Recent evidence suggests that the Arg64 ADRB3 variant has additive and interactive effects with a number of other candidate gene variants, such as the uncoupling protein 1 and 2 genes and lipoprotein lipase gene 25–27. Furthermore, it has been suggested that the sleep disruption that characterises OSAS may influence the expression of these genes and thus the relative importance of a variant at these loci in determining the obesity risk 5.

Studies that have examined the association between the Trp64Arg polymorphism and different comorbid conditions associated with obesity, such as insulin resistance and hypertension, have produced inconsistent results 13–15. In the present study, it was found that the Trp64Arg polymorphism was not associated with glucose levels, lipid concentrations and insulin resistance in patients with OSAS. Furthermore, AHI and blood pressure did not differ between genotypes. These results are in keeping with previous studies reporting that the Arg64 mutation can be associated with obesity independent of blood lipid or glucose levels 12.

Potential limitations
Studies carried out in different ethnic groups have reported conflicting results regarding the effect of the Arg64 ADRB3 variant on body weight 14, 21–23. Although the present results are in concordance with other studies in Mediterranean Spanish populations 27, the present findings may be confounded by inadequately controlled risk factors, such as nutritional status, physical activity and the interaction between the ADRB3 gene and other gene variants. Thus further studies in different sample populations are required in order to determine the independent or possible synergistic effect of these polymorphisms on obesity in OSAS.

Conclusion
In conclusion, the present results do not support a role of the arginine 64 allele of the ß3-adrenergic receptor gene in the pathogenesis of obstructive sleep apnoea syndrome, but show that its presence in those patients who have already developed obstructive sleep apnoea syndrome is associated with a greater tendency to develop obesity.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
The authors would like to thank both the obstructive sleep apnoea syndrome patients and controls for their willingness to participate in the present research study, and the nursing staff of the sleep units of the various participating hospitals for their help during the course of the study.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

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