Tryptophan 64 --> arginine polymorphism of beta-3-adrenergic receptor in Chilean women with polycystic ovary syndrome

OBJECTIVE: To establish the frequency of the Trp64Arg polymorphism of the beta3 adrenergic receptor (ADRB3) in women with polycystic ovary syndrome (PCOS) from a Chilean population, focusing particularly on the interaction with body weight. In addition, we evaluated the relationship of the Trp64Arg variant with other metabolic components of this syndrome. PATIENTS AND DESIGN: In a case-control design study, a total of 106 women with clinical and hormonal evidence of PCOS and 82 healthy women (HW) were evaluated. MEASUREMENTS: An oral glucose tolerance test (OGTT) was performed and serum glucose and insulin were measured before the glucose load and 30, 60, 90 and 120 min after. Lipid profile was determined in the basal sample. Insulin resistance was assessed by the homeostatic model assessment (HOMA(IR)) and insulin sensitivity index (ISI) composite. A polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis was performed to determine the Trp64Arg polymorphism of ADRB3. RESULTS: The frequency of the heterozygous condition was similar between PCOS and HW (39%vs. 35%). Only two subjects were homozygous for arginine, both belonging to the PCOS group and having a body mass index (BMI) > 30 kg/m2. In the crude analysis, hypothesis tests and odds ratios show that there is no evidence of association between the ADRB3 Trp64Arg variant and PCOS (P = 0.47). Moreover, when data were stratified by BMI categories, the statistical test for interaction between Trp64 carrier status and obesity was not significant (P = 0.29). This variant was present in 52% of the obese PCOS patients and 40% of the obese HW. In normal weight and obese PCOS carriers, the presence of the Trp64Arg variant was associated with high triglyceride (TG) levels. A major effect of the Trp64Arg variant on insulin resistance parameters could not be demonstrated. CONCLUSIONS: The frequency of the Trp64Arg polymorphism was similar in healthy women and PCOS women, and a possible interaction between the effect of this variant and obesity in PCOS could not be demonstrated. However, our results showed an association between triglyceride levels and the presence of this genetic variant in PCOS women.     

Lack of relationship between beta3-adrenergic receptor gene polymorphism and gestational diabetes mellitus in a Taiwanese population

The Trp64Arg polymorphism of beta(3)-adrenergic receptor (ADRB3) has been reported to be associated with insulin resistance and gestational diabetes mellitus (GDM). The objective of this study is to investigate whether the ADRB3 Arg variant confers susceptibility to GDM in a Taiwanese population. A total of 299 pregnant women (mean +/- SD, 31.1 +/- 4.2 years) was recruited. Two-hour, 75-g oral glucose tolerance tests (OGTT) were conducted at 24 to 31 weeks gestation (28.3 +/- 1.6 weeks). Forty-one GDM subjects and 258 controls with normal glucose tolerance (NGT) level were genotyped for the ADRB3 Trp64Arg polymorphism. The genotype distribution and allele frequency of ADRB3 did not significantly differ between GDM and NGT subjects (9.8% v 14.5%). Body weight gain during pregnancy was not different between ADRB3 genotypes. However, the GDM subjects with the Arg64 variant had higher fasting (P =.04) and postload 120 minutes (P =.03) insulin levels as compared with the GDM subjects with the Trp64Trp allele. In all subjects, the women with the Arg64 allele (n = 76) had significantly higher level of insulin secretion (the ratio of Deltainsulin(60)/Deltaglucose(60)) during OGTT than those without (n = 223) (P =.03) despite similar plasma levels of glucose and insulin in both genotypes. Our results indicated that the ADRB3 Trp64Arg variant is not related to the development of GDM and has no effect on obesity during pregnancy in a Taiwanese population. However, ADRB3 polymorphism might be a possible determinant of insulin resistance.     

The beta 3-adrenergic receptor gene and obesity in a population sample of African Americans

OBJECTIVE: To examine the role of the Trp64Arg polymorphism in the beta 3-adrenergic receptor gene and the beta 3-adrenergic receptor gene locus in obesity-related traits in African Americans. SUBJECTS: A total of 687 individuals representing 193 African American families who were residents of metropolitan Chicago. MEASUREMENTS: Genotyping of the Trp64Arg polymorphism in the beta 3-adrenergic receptor gene and three microsatellite markers flanking the beta 3-adrenergic receptor gene (ADRB3) locus and measuring various obesity-related traits, including body mass index (BMI), fat-free mass, fat mass, percentage fat mass, waist circumference and serum lipid levels. RESULTS: The prevalence of obesity (defined as body mass index > or = 30 kg/m(2)) in the population was 27.3% and 51.2% in men and women, respectively. The frequency of the Arg64 allele was 10.0%. Multivariate regression analyses confirmed the existence of a significant contribution of familial variance to each of the five obesity-related traits noted above. Likelihood ratio statistics computed in a multivariate regression analysis failed to demonstrate a significant association between the Arg64 allele and any of the five obesity-related traits. Single and multipoint analyses using extended Haseman--Elston regression analyses failed to demonstrate suggestive evidence of linkage of three microsatellite markers that flank the beta 3-adrenergic receptor gene to BMI, percentage body fat, waist circumference or serum leptin levels. CONCLUSION: Given the contribution of familial variance to obesity-related traits in this population, neither the null finding for the Arg64 allele nor the lack of evidence of linkage of the ADRB3 locus to obesity-related traits could be attributed to lack of transmissibility of the traits suggesting that neither the Arg64 variant of the beta 3-adrenergic receptor gene nor another genetic variant in or near the ADRB3 locus contribute significantly to familial aggregation of obesity-related traits in African Americans. International Journal of Obesity (2001) 25, 54-60     

The Trp64Arg polymorphism of the beta3-adrenergic receptor gene is associated with hypertension in men with type 2 diabetes mellitus

A missense mutation of the beta3-adrenergic receptor gene (ADRB3) resulting in a tryptophan/arginine exchange at position 64 (Trp64Arg polymorphism) has recently been associated with greater capacity to gain weight, a low resting metabolic rate, higher blood pressure, and an early onset of type 2 diabetes. These findings prompted us to examine the relationship between this mutation, blood pressure, and vascular complications in German patients with type 2 diabetes. White patients with type 2 diabetes mellitus (n = 417) were enrolled in the study. The Trp64Arg polymorphism of the ADRB3 gene was detected by polymerase chain amplification and subsequent restriction digest with BstN I. Stepwise logistic regression analysis of the entire study population revealed a significant interaction between gender and genotype (P = .019). We therefore performed separate analyses for men and women. There was a significant relationship between hypertension and the ADRB3 Trp64Arg variant in men (P = .015), but not in women. Furthermore, blood pressure levels in male patients with the minor allele had higher blood pressure levels (P < .05), despite a significantly greater number of antihypertensive medications (P = .01). There was no association between ADRB3 genotype and vascular complications in these patients. In conclusion, our data are compatible with a contribution of this genetic variant of ADRB3 to hypertension in male patients with type 2 diabetes. Further studies will be needed to determine the role of this polymorphism as a predictor of hypertension or vascular complications in patients with type 2 diabetes.     

Gender specific associations of the Trp64Arg mutation in the beta3-adrenergic receptor gene with obesity-related phenotypes in a Mediterranean population: interaction with a common lipoprotein lipase gene variation

OBJECTIVE: To investigate the association between the Trp64Arg beta3-adrenergic receptor (ADRB3) mutation and obesity-related phenotypes in a Mediterranean Spanish population considering the effect of other genetic and environmental factors. DESIGN AND SUBJECT: Cross-sectional study in 1063 (476 men and 587 women) randomly selected from this population (aged: 18-68 years). MEASUREMENTS: Anthropometric (weight, height and waist-to-hip ratio), blood pressure, biochemical (lipids, fasting glucose, and uric acid), life-style variables, and the Trp64Arg, HindIII-Lipoprotein lipase (LPL) and apolipoprotein E polymorphism. RESULTS: Frequency of the Arg64 allele was low (0.051; 95% CI: 0.042-0.060). We found gender-specific associations between the Trp64Arg mutation and obesity related phenotypes. In men, carriers of the Arg64 variant had higher body mass index (BMI) (27.63 +/- 3.81 vs. 26.34 +/- 3.57 kg m-2, P=0.049) and total cholesterol (5.85 +/- 1.45 vs. 5.28 +/- 1.06 mmol L-1; P=0.011) compared with wild-type individuals. Logistic regression analysis, revealed that the risk of overweight was two times higher in male carriers of the Arg64 allele. In women, the Arg64 variant was only associated with higher fasting glucose (P=0.031). These genotype effects persisted after adjustment for age, genetic and life-style variables. For the LPL polymorphism, the H-/H- genotype was associated with lower BMI and with lower risk of overweight (OR: 0.49; 95% CI: 0.30-0.81) in both men and women. However, after adjustment for covariates, these associations only remained statistically significant (P < 0.02) in women. Moreover, in women, a statistically significant interaction (P=0.026) between the LPL and the ADRB3 gene loci in determining BMI was found. Thus, the Arg64 allele was associated with a higher BMI only in H+/H+ women. CONCLUSIONS: The Trp64Arg mutation was associated with BMI and lipids in men. In women, an additional gene-gene interaction with the LPL-HindIII polymorphism may explain the results.     

Association of beta3-adrenergic receptor gene polymorphism with insulin resistance in Japanese-American men

The Trp64Arg variant of the beta3-adrenergic receptor (beta3-AR) gene is relatively common in Japanese people. We hypothesized that this variant may be associated with obesity and insulin resistance when combined with a westernized lifestyle. To test this hypothesis, we investigated the relationships between the beta3-AR gene variant and obesity and insulin resistance in Japanese-American men, who are known to have a higher prevalence of type 2 diabetes mellitus (DM). The subjects were 152 Japanese-American men living in Hawaii, 83 with normal glucose tolerance (NGT), 40 with impaired glucose tolerance (IGT), and 29 with DM. The frequency of the Trp64Arg allele of the beta3-AR gene was 0.18, almost identical to that of the mainland Japanese. The prevalence of the Trp64Arg allele was 30.1% in NGT, 35.0% in IGT, and 41.4% in DM subjects (nonsignificant). The Trp64Arg variant of the beta3-AR gene showed no significant relationship with obesity or insulin resistance in NGT subjects. However, fasting and 2-hour insulin levels and insulin resistance as determined by homeostasis model assessment (HOMA) were significantly higher in IGT subjects with the Trp64Arg variant. Although indices of obesity were the same in IGT subjects with and without the Trp64Arg variant, differences in the body mass index (BMI) and percent body fat between NGT and IGT subjects were greater for individuals with the Trp64Arg variant. Thus, there is an association between the Trp64Arg variant of the beta3-AR gene and insulin resistance in Japanese-Americans with IGT.     

The polymorphism of the beta3-adrenergic receptor gene is associated with reduced low-density lipoprotein particle size

People with a predominance of small, dense low-density lipoprotein (LDL) particles appear to be at increased risk for coronary disease, independent of LDL cholesterol levels. The Trp64Arg variant of the beta3-adrenergic receptor gene is reported to be associated with abdominal obesity and resistance to insulin, and as a consequence, this variant may be a genetic factor in the development of atherosclerosis. Therefore, we investigated whether the beta3-adrenergic receptor polymorphism contributes to the distribution of LDL particle size in 136 Japanese subjects, aged 33 to 59 years, who visited for a routine annual checkup. None of these subjects were taking any medication. The diameter of LDL particles was determined at their peak size using nondenaturing 2% to 16% polyacrylamide gradient gels using fresh plasma samples. The genotype frequencies were: Trp/Trp, 71.3%; Try/Arg, 22.1%; and Arg/Arg, 6.6%, with allele frequencies of 0.82 for Trp64 and 0.18 for Arg64. The subjects with the Arg/Arg genotype had significantly higher levels of fasting plasma insulin and triglycerides and an insulin resistance index of homeostasis model assessment (HOMA-R), and significantly smaller LDL particle size than did the subjects with the Trp/Trp genotype. After adjusting for fasting insulin, body mass index (BMI), and HOMA-R index, there was no longer an observed difference in LDL particle size. The number of the Arg64 allele in individuals was significantly related with fasting insulin, BMI, triglycerides, glycosylated hemoglobin (HbA1c), and fasting glucose, and it was inversely related with LDL particle size. After adjusting for triglyceride, fasting insulin levels, and HOMA-R index, LDL particle size was no longer inversely correlated with the Arg allele. These findings suggest that the Trp64Arg variant in the beta3-adrenergic receptor gene may be associated with reducing LDL particle size, probably due to insulin resistance.     

Arg64 variant of the beta3-adrenergic receptor is associated with gallstone formation

OBJECTIVES: The beta3-adrenergic receptor (ADRB3) is a transmembrane receptor highly expressed in adipose tissue and thought to be involved in the regulation of lipolysis. ADRB3 is also highly expressed in gallbladder tissue where it may be involved in gallbladder contraction. Because polymorphisms of ADRB3 are present in populations with a high prevalence of gallstones (e.g., Pima-Indians, obese subjects), we hypothesized that known polymorphisms for ADRB3 (Trp64Arg) may represent an independent risk factor for gallstone disease. METHODS: The EMIL cross-sectional study investigated the health behavior and prevalence of chronic diseases in a small Southwestern German town of 12,475 inhabitants. From 3,893 randomly selected citizens 2,147 subjects were enrolled and screened for gallstones employing ultrasonography. Blood samples were drawn for biochemical analysis and isolation of genomic DNA. ADBR3 genotypes were determined by TaqMan SNP Assay. RESULTS: We identified 171 (8%) gallstone carriers of whom 143 participated (46 male, 97 female), with a mean age of 51.4, and mean BMI of 29.3 kg/m2. For these subjects an age, gender and BMI matched partner without gallstones was recruited from the study population. Genotyping for ADRB3 revealed an Arg64 allele frequency of 5.9 versus 0.7% (HR = 11.9, P < 0.05) compared with controls. CONCLUSIONS: Our results indicate that the ADRB3 Trp64Arg polymorphism is associated with gallstone disease thereby representing a genetic marker that identifies subjects at higher risk for gallstone formation.     

多囊卵巢综合征妇女的β-3-肾上腺素能受体基因与胰岛素抵抗的关系

目的探讨β     

Contribution of a missense mutation (Trp64Arg) in beta3-adrenergic receptor gene to multiple risk factors in Japanese men with hyperuricemia.

Epidemiological data reveal that hyperuricemia is a risk factor of atherosclerosis. The risk is possibly caused by a link between hyperuricemia and insulin resistance-related metabolic syndrome. Recently it has been proposed that a missense mutation (Trp64Arg) in the beta3-adrenergic receptor (beta3-AR) gene may contribute to the accumulation of multiple risk factors related to insulin resistance. The present study was undertaken to further clarify an association between the Trp64Arg mutation and the metabolic syndrome in 47 Japanese men with hyperuricemia, who are substantially at high risk of atherosclerosis. One patient (2%) had the homozygous mutation, 12 (26%) were heterozygous for the mutation, and 31 (72%) had no mutation found by the PCR-RFLP analysis. The Trp64Arg mutation was not related to past maximal body mass index (BMI), BMI and waist/hip ratio. The subjects with the heterozygous mutation showed a slightly higher incidence of impaired glucose tolerance and diabetes mellitus in the 75 g oral glucose challenge (67%), as compared with those without the mutation (39%). Serum insulin response at 60 min and the sum of serum insulin in the glucose challenge were greater in the former subjects than those in the latter subjects (P=0.041 and 0.076, respectively). An increase in serum lipoprotein(a) was also observed in the subjects with the heterozygous mutation, but the Trp64Arg mutation was not associated with other dyslipidemia, blood pressure or ischemic changes on the electrocardiogram. These results indicate that the heterozygous mutation of Trp64Arg in the beta3-AR gene partly contributes to the accumulation of multiple risk factors in male subjects with hyperuricemia. A larger prospective study is necessary to elucidate a possible role of the Trp64Arg mutation in atherosclerotic diseases in future.     

Energy expenditure, body composition and insulin response to glucose in male twins discordant for the Trp64Arg polymorphism of the beta3-adrenergic receptor gene

AIM: The tryptophan to arginine change in position 64 (Trp64Arg) polymorphism of the beta3-adrenergic receptor (beta3AR) gene has been associated with an increased prevalence of obesity, insulin resistance and type 2 diabetes. In this, decreased rates of energy expenditure and impaired insulin secretion could play a role. METHODS: In 10 male twin pairs discordant for the Trp64Arg polymorphism, we examined insulin response to glucose by an oral glucose tolerance test (OGTT), a frequently sampled intravenous glucose tolerance test (FSIGT), body composition by the bioimpedance method, dual-energy X-ray absorptiometry scanning and energy expenditure by indirect and direct calorimetry. RESULTS: Twins heterozygous for the Trp64Arg polymorphism showed significantly lower fat mass independent of the method used, and significantly lower fasting insulin and glucose concentrations compared with their homozygous wild-type co-twins. Correspondingly, insulin resistance and insulin secretion determined by homeostasis model assessment were significantly lower in twins carrying the Trp64Arg polymorphism. However, there were no significant differences in adiponectin levels, insulinogenic index assessed by OGTT, or insulin sensitivity, acute insulin response to glucose, glucose effectiveness or insulin disposition index assessed by minimal modelling of the FSIGT. Furthermore, there were no differences in sleeping, resting or post-prandial energy expenditure. CONCLUSIONS: In male twins with a high similarity in genetic and environmental background, the Trp64Arg polymorphism of the beta3AR gene is associated with lower fat mass, fasting insulin levels and an appropriate insulin response to glucose. Thus, heterozygosity for the Trp64Arg variant is unlikely to increase the risk of obesity, insulin resistance or type 2 diabetes.     

Nasal obstruction as a risk factor for sleep apnoea syndrome.

Nasal obstruction has frequently been mentioned as a possible risk factor in obstructive sleep apnoea syndrome (OSAS). Over a 2-yr period, 541 unselected consecutive snorers referred for suspected breathing disorders during sleep were included to undergo posterior rhinomanometry. In addition cephalometric landmarks and body mass index (BMI) were obtained. Polysomnography was used to determine the number of abnormal respiratory events that occurred during sleep. OSAS was defined as 15 episodes, or more, of apnoea or hypopnoea per hour of sleep (AHI). Of the 541 consecutive snorers 528 underwent nasal resistance measurement by posterior rhinomanometry (failure rate: 2.4%). Patients with OSAS (259 patients) had higher nasal resistance than patients without OSAS (2.6+/-1.6 hPa x L x s(-1) versus 2.2+/-1.0 hPa x L x s(-1), respectively, p<0.005). A stepwise multiple regression analysis showed that BMI, male sex, nasal resistance, and cephalometric parameters were contributing factors to the AHI. The r2-value of the multiple regression analysis was 0.183. Nasal resistance contributed 2.3% of the variance (p<0.0001), whereas mandibular plane-hyoid distance, BMI, male sex and age contributed 6.2%, 4.6%, 3% and 1.3% of the variance, respectively. To conclude, daytime nasal obstruction is an independent risk factor for OSAS.     

Impaired glucose-insulin metabolism in males with obstructive sleep apnoea syndrome.

The aim of this cross-sectional study was to evaluate the frequency of type-2 diabetes and impaired glucose tolerance (IGT) in a large clinic-based male population presenting various degrees of obstructive sleep apnoea syndrome (OSAS) and to analyse the relationship between OSAS and glucose-insulin metabolism. Male patients (n=595) with suspected OSAS underwent both nocturnal polysomnography and a 2-h oral glucose-tolerance test with measurements of fasting and postload blood glucose and plasma insulin. Insulin sensitivity was evaluated by the ratio of fasting glucose to fasting insulin. OSAS was diagnosed in 494 patients, while 101 patients were nonapnoeic snorers. Type-2 diabetes was present in 30.1% of OSAS patients and 13.9% of nonapnoeic snorers. IGT was diagnosed in 20.0% of OSAS patients and 13.9% of nonapnoeic snorers. Fasting and postload blood glucose increased with severity of sleep apnoea. Insulin sensitivity decreased with increasing severity of sleep apnoea. In addition to body mass index and age, the apnoea/hypopnoea index independently influenced postload blood glucose and insulin sensitivity. The authors conclude that in a clinic-based sample of patients, obstructive sleep apnoea syndrome is associated with a high frequency of type-2 diabetes and impaired glucose tolerance. The relationship between sleep-disordered breathing and impaired glucose-insulin metabolism is independent of obesity and age.     

The Trp(64)Arg polymorphism of the beta(3)-adrenergic receptor gene is not associated with body weight or body mass index in Japanese: a longitudinal analysis

The beta(3)-adrenergic receptor (ADRB3) is expressed mainly in visceral adipose tissue and is thought to contribute to lipolysis and the delivery of free fatty acids to the portal vein. Although many studies have examined the relationship between the Trp(64)Arg mutation of ADRB3 and obesity, the results have been inconsistent. We examined the cross-sectional relationship of ADRB3 variants with indexes of obesity, and their longitudinal changes over 10 yr, in men and women, aged 40-69 yr, who were randomly selected from the Japanese rural population. The study considered both dietary energy intake and physical activity levels. Among the 746 participants, the genotype frequencies of the Trp(64)Trp, Trp(64)Arg, and Arg(64)Arg variants were 483, 224, and 39, respectively. The cross-sectional analysis showed no significant differences in height, weight, body mass index, blood pressure, serum total and high density lipoprotein cholesterols, and hemoglobin A(1c) among the genotype groups even after adjustments for gender, age, smoking, alcohol drinking, physical activity, and energy intake. No significant differences in the weight changes between the genotype groups were evident in the longitudinal analysis. We conclude that the Trp(64)Arg mutation of ADRB3 has little or no influence on either body weight or body mass index in the general Japanese population.     

Obstructive sleep apnoea syndrome impairs insulin sensitivity independently of anthropometric variables

OBJECTIVES: Obstructive sleep apnoea syndrome (OSAS) is strongly associated with obesity and characterized by endocrine and metabolic changes including impairment of insulin sensitivity. The aim of this study was to further clarify the insulin dynamics and glucose metabolism in this condition. DESIGN, PATIENTS AND MEASUREMENTS: We studied 30 obese patients with OSAS [OSA, 21 males, 9 females; age, mean +/- SEM: 53.1 +/- 1.7 years; body mass index (BMI): 38.6 +/- 1.1 kg/m2; waist-to-hip ratio (WHR): 0.99 +/- 0.07; Apnoea/Hypopnoea Index (AHI): 40.5 +/- 5.8 events/h of sleep] by means of overnight polysomnography and oral glucose tolerance testing. Mathematical models were used to assess: (i) whole-body insulin sensitivity index (ISI composite); (ii) hepatic ISI; (iii) the first phase of insulin secretion (DeltaI30'-0'/DeltaG30'-0'). Results were compared with those in 27 weight-matched patients with simple obesity (OB, 12 males, 15 females; age: 48.1 +/- 2.8 years, BMI: 38.5 +/- 1.4 kg/m2, WHR: 0.94 +/- 0.09; AHI: 2.15 +/- 0.5 events/h of sleep) and with 20 normal subjects (NS, 15 females; 5 males, age: 40.4 +/- 2.9 years; BMI: 22.2 +/- 0.6 kg/m2). RESULTS: ISI composite value was significantly lower in OSAS (1.71 +/- 1.41) than in OB (3.08 +/- 0.27) and in NS (6.1 +/- 0.4) even after age-, BMI- and WHR-adjustment. Similarly, hepatic ISI was significantly different among the three groups (OB = 0.25 +/- 0.02, OSAS = 0.16 +/- 0.014 and NS = 0.55 +/- 0.04). Sex did not affect ISI indices. Insulin secretion estimates were not significantly different among the three groups. DISCUSSION: Obese patients with obstructive sleep apnoea syndrome are more insulin resistant than patients with simple obesity independently of the degree and distribution of adiposity. The worsening in insulin sensitivity in obstructive sleep apnoea syndrome patients could reflect the hypoxic state and would account for the increased vascular risk in this condition.     

Predicting sleep apnoea syndrome from heart period: a time-frequency wavelet analysis.

Heart rate fluctuations are a typical finding during obstructive sleep apnoea, characterised by bradycardia during the apnoeic phase and tachycardia at the restoration of ventilation. In this study, a time-frequency domain analysis of the nocturnal heart rate variability (HRV) was evaluated as the single diagnostic marker for obstructive sleep apnoea syndrome (OSAS). The predictive accuracy of time-frequency HRV variables (wavelet (Wv) decomposition parameters from level 2 (Wv2) to level 256 (Wv256)) obtained from nocturnal electrocardiogram Holter monitoring were analysed in 147 consecutive patients aged 53.8+/-11.2 yrs referred for possible OSAS. OSAS was diagnosed in 66 patients (44.9%) according to an apnoea/hypopnoea index > or = 10. Using receiver-operating characteristic curves analysis, the most powerful predictor variable was Wv32 (W 0.758, p<0.0001), followed by Wv16 (W 0.729, p<0.0001) and Wv64 (W 0.700, p<0.0001). Classification and Regression Trees methodology generated a decision tree for OSAS prediction including all levels of Wv coefficients, from Wv2 to Wv256 with a sensitivity reaching 92.4% and a specificity of 90.1% (percentage of agreement 91.2%) with this nonparametric analysis. Time-frequency parameters calculated using wavelet transform and extracted from the nocturnal heart period analysis appeared as powerful tools for obstructive sleep apnoea syndrome diagnosis.     

Sleep and daytime sleepiness in upper airway resistance syndrome compared to obstructive sleep apnoea syndrome.

This study has investigated differences in the nocturnal sleep and daytime sleepiness among patients with obstructive sleep apnoea syndrome (OSAS), upper airway resistance (UARS), sleep hypopnoea syndrome, and normal control subjects, using sleep scoring and spectral activity analysis of the electroencephalogram (EEG). Twelve nonobese males with UARS aged 30-60 yrs were recruited. These subjects were strictly matched for age and body mass index with twelve OSAS patients, 12 sleep hypopnoea syndrome patients, and 12 normal controls, all male. Daytime sleepiness was evaluated using the Epworth Sleepiness Scale (ESS) and the Multiple Sleep Latency Test (MSLT). The macrostructure of sleep was determined using international criteria and spectral analysis of the sleep EEG was obtained from a central lead. The sleep macrostructure of OSAS and UARS patients was significantly different from that of controls. These patients were also sleepier during the daytime than controls. Complaints of tiredness and daytime sleepiness, ESS and MSLT scores were similar in the different patient groups. Mild dysmorphia was present in all three patient groups. However, nocturnal sleep was significantly different among the different groups. OSAS patients had significantly more awake time during sleep than the UARS patients. The spectral activity of the total sleep time of the patient groups also differed significantly from that of controls. When the sleep spectral activity of UARS and OSAS patients were compared, OSAS patients had less slow wave sleep activity than UARS patients. UARS patients had a significantly higher absolute power in the 7-9 Hz bandwidth than OSAS patients. The absolute delta power over the different sleep cycles was also different between controls and patients, and between UARS and OSAS patients. There are clear differences in the macrostructure and spectral activity of sleep between upper airway resistance and obstructive sleep apnoea syndrome patients, demonstrated by differences in the cortical activity recorded in the central lead during sleep. Despite these nocturnal sleep differences, the tests of subjective daytime sleepiness are not significantly different.     

Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities.

Considerable evidence is available in support of an independent association between obstructive sleep apnoea syndrome (OSAS) and cardiovascular disease, which is particularly strong for systemic arterial hypertension and growing for ischaemic heart disease, stroke, heart failure, atrial fibrillation and cardiac sudden death. The pathogenesis of cardiovascular disease in OSAS is not completely understood but likely to be multifactorial, involving a diverse range of mechanisms including sympathetic nervous system overactivity, selective activation of inflammatory molecular pathways, endothelial dysfunction, abnormal coagulation and metabolic dysregulation, the latter particularly involving insulin resistance and disordered lipid metabolism. The present report, which arose out of a European Union Cooperation in the field of Scientific and Technical Research (COST) action on OSAS (COST B26), reviews the current evidence for an independent association and proposes research priorities to identify the underlying mechanisms involved, with a view to identifying novel therapeutic strategies. Large-scale collaborative studies of carefully defined patient populations with obstructive sleep apnoea syndrome, adequately controlled for potential confounders, are needed. Such studies carry the prospect of evaluating potential interactions between different basic mechanisms operating in obstructive sleep apnoea syndrome and cardiovascular disease, and interactions with other related disorders, such as obesity, diabetes and dyslipidaemia. Furthermore, translational studies involving cell culture and animal models linked to studies of obstructive sleep apnoea syndrome patients are necessary to integrate basic mechanisms with the clinical disorder.     

A mutation of the b3-adrenergic receptor is associated with visceral obesity but decreased serum triglyceride

Summary The Trp64Arg mutation of the β3-adrenergic receptor (β3AR) is prevalent in several ethnic groups and is associated with weight gain, and some features of syndrome X such as insulin resistance and dyslipidaemia. Nevertheless, it is not known at present whether this mutation is associated with visceral obesity, which is an important risk factor for the development of hypertension, dyslipidaemia, insulin resistance, non-insulin-dependent diabetes mellitus, and atherosclerosis. To investigate whether this mutation may contribute to visceral obesity, we studied the relationships between β3AR genotypes and clinical phenotypes. The Trp64Arg allele of β3AR was examined in 278 Japanese men with respect to variables relating to visceral obesity assessed by computerised tomography. To detect the Trp64Arg mutation, polymerase chain reaction-restriction fragment length polymorphism analysis using Bst NI digestion was performed. This mutation was more frequently observed in subjects with higher body mass index (BMI) (p = 0.02). Moreover, in 120 subjects with a moderate degree of obesity (22 M BMI < 26.4 kg/m²), the mutation (homozygotes and heterozygotes) was associated with visceral obesity (higher ratio of visceral to subcutaneous fat area; V/S) (p = 0.03). Furthermore, the Trp64Arg allele was more frequent in subjects with lower serum triglyceride levels (p = 0.02) and the Trp64Arg homozygotes, but not heterozygotes, exhibited lower triglyceride levels. Thus, this mutation appears to be associated with visceral obesity but with lower serum triglyceride. It is suggested that those with the mutation may describe a subset of subjects characterized by decreased lipolysis in visceral adipose tissue. [Diabetologia (1997) 40: 469–472] Received: 6 December 1996 and in revised form: 17 January 1997     

Relation of beta3-adrenergic receptor gene mutation to total body fat but not percent body fat and insulin levels in Thais.

A Trp64Arg mutation in the beta3-adrenergic receptor gene has been implicated in the pathophysiology of non-insulin-dependent diabetes mellitus and obesity. However, the findings have been controversial due to the use of different populations and different methods for the estimation of body fat. In the present study, the prevalence of Trp64Arg mutation of the beta3-adrenergic receptor gene was determined and its relation to body fat as assessed by dual-energy x-ray absorptiometry (DEXA) was evaluated in Thai men and women. The effect on insulin sensitivity as assessed by the serum insulin to glucose ratio was also examined. The subjects were 76 men and 135 women aged 20 to 80 years. Body fat and its regional distribution were assessed by DEXA. Mutation in the beta3-adrenergic receptor gene was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism. Data are expressed as the mean +/- SEM. Fifty-nine subjects (28.0%) had the Trp64Arg mutation in the beta3-adrenergic receptor gene; 54 (25.6%) were heterozygotes and five (2.4%) were homozygotes. The gene frequency of Trp64Arg mutation was 15.2% in these subjects. In women, Trp64Arg mutation was not associated with the difference in total body fat (Trp/Arg or Arg/Arg, 19.4 +/- 1.0 kg; Trp/Trp, 19.2 +/- 0.6 kg) or percent body fat (Trp/Arg or Arg/Arg, 34.6% +/- 1.2%; Trp/Trp, 34.3% +/- 0.6%). In contrast to the findings in women, men with Trp64Arg mutation had lower total body fat after controlling for age (Trp/Arg or Arg/Arg, 13.2 +/- 1.1 kg; Trp/Trp, 15.8 +/- 0.7 kg; P < .05). However, no difference was found in percent body fat (Trp/Arg or Arg/Arg, 20.9% +/- 1.3%; Trp/Trp, 23.3% +/- 0.7%). No difference in the fasting insulin resistance index (FIRI) was found between subjects with and without Trp64Arg mutation. The data suggest that Trp64Arg mutation of the beta3-adrenergic receptor is common in Thais and appears to exert effects on total body fat but not percent body fat in men. Trp64Arg mutation is not associated with insulin resistance as assessed by the FIRI in Thais.