Trp64Arg Mutation Research Articles

The Association of Trp64Arg Polymorphism in the Beta-Adrenergic Receptor With Insulin Resistance: Meta-Analysis.

BackgroundInsulin resistance is a metabolic disorder that occurs in type 2 diabetes mellitus and obesity. Genetic factors such as β3-adrenoceptor polymorphism (Trp64Arg) may be involved in IR and insulin secretion. However, their association is controversial. Therefore, the current meta-analysis was conducted to clarify the relationship between the Trp64Arg and IR.MethodsThe literature search was performed in PubMed, Embase, and Web of Science using the keywords “Receptors, Adrenergic, beta-3, Receptors, Adrenergic, Insulin Resistance, Protein-Coupled Receptor Kinase 3” from 2005 to February 7, 2021. We used a random-effects model to calculate the pooled effect size. We conducted subgroup analysis and regression analysis to identify sources of heterogeneity; and Egger’s test and funnel plot were used to test publication bias. Finally, we conducted a sensitivity analysis.ResultsWe included eight papers with 1,586 subjects. There was a positive correlation between Trp64Arg mutation and insulin level (standardized mean difference = 0.20, 95% confidence intervals: 0.00 to 0.39, I 2 = 57.6%, p = 0.016). However, there was no association between Trp64Arg and the homeostasis model (HOMA-IR) assessment. Egger’s tests showed no publication bias; the sensitivity analysis showed that our results were stable. Regression analysis revealed no source of heterogeneity.ConclusionTrp64Arg may be associated with IR. European ancestry, obesity, plasma insulin level, and test status may be potential factors affecting the relationship between Trp64Arg and IR.

Genotyping Method and Frequency of ADRB3-rs4994 Single Nucleotide Polymorphism Genotypes in Hanoi 3-5 Years Old Chidren

Genotyping Method and Frequency of ADRB3-rs4994 Single Nucleotide Polymorphism Genotypes in Hanoi 3-5 Years Old Chidren

Study of the association of Trp64Arg mutation of beta three adrenergic receptor with obesity in Saudi population

Introduction: Beta three adrenergic receptor (ADRB3) is an adrenergic receptor that induces activation of adenylate cyclase located mainly in adipose tissue and is involved in the thermogenesis of brown fat tissue and in the regulation of lipolysis. Agonists of ADRB3 are found to induce the thermogenesis process of human brown fat tissue and thus believed to be excellent anti-obesity targets. The most studied single nucleotide polymorphism (SNP) of ADRB3 is rs4994. Inconsistent findings have been found in earlier studies about the association of rs4994 polymorphisms with obesity among different populations. The association of ADRB3/rs4994 polymorphism with obesity among the Saudi population is unknown. This study aimed to investigate the association of ADRB3/rs4994 polymorphism with obesity, blood lipids and blood pressure in the Saudi population.
 Method: This study was a case control study involving 88 obese healthy volunteers and 84 non-obese (controls) volunteers recruited from the King Khaled University Hospital (KKUH), Riyadh City, Saudi Arabia. Using KASPTM (Competitive Allele-Specific PCR) the rs4994 genotype for each participant was determined. The frequency, distribution, and association of each genotype with body mass index (BMI) and lipid profile were calculated.
 Results: The distribution of CC, TT and CT genotypes in the study population was 0.37, 0.06 and 0.56, respectively. The heterozygote CT genotype was associated with a reduced risk of obesity (odds ratio (OR)=0.4398, 95%CI=0.2338 to 0.8277, P-value=0.010). It was more frequent in the non-obese participants compared to the obese participants (67.9% vs. 44.3%, respectively). Moreover, participants with the CT genotype had a significantly lower BMI (P=0.004). In contrast, the CC genotype was associated with an increased risk of obesity (OR=2.5, 95%CI=1.3467 to 4.8758, P-value=0.004). The frequency of the CC genotype was higher in obese participants compared to the non-obese ones (46.6% vs. 28.6%, respectively). Participants with the CC genotype demonstrated a significantly higher BMI than participants with the CT or TT genotypes (Q= 4.5, P=0.004). The TT genotype had no significant effects on the participants’ BMI (OR=2.9, 95%CI=0.7563 to 11.5759, P value=0.11), and it was higher in obese compared to non-obese participants (9.1% vs. 3.6%, respectively). No significant effect of ADRB3/rs4994 polymorphism on blood lipid profile or blood pressure was observed.
 Conclusion: The findings of this study suggested that the heterozygote CT genotype of the ADRB3/rs4994 polymorphism is associated with a reduced risk of obesity among the Saudi population. In the future, larger scale studies are required to further confirm these observations.

The mutation of Trp64Arg in β3-adrenoreceptor-encoding gene is significantly associated with increased hypertension risk and elevated blood pressure: a meta-analysis.

This meta-analysis was implemented to test the association of a missense mutation, Trp64Arg, in β3-adrenoreceptor-encoding gene (ADRB3) with both hypertension risk and blood pressure (BP) changes. A systematic search of three publicly-available databases was launched to look for articles published as of December 2016. Qualification appraisal and data extraction were independently done by two researchers. Pooled estimates were expressed as odds ratio (OR) or weighted mean difference (WMD), and their 95% confidence intervals (95% CIs). There were separately 21 (3750/4225 patients/controls) and 17 (6100 subjects) individual studies for hypertension risk and BP changes. Integral analyses revealed that Trp64Arg mutation was associated with the significantly increased risk of hypertension, and particularly, the 64Trp/64Arg heterozygote carriers were 1.23-times more likely to develop hypertension compared with the 64Trp/64Trp homozygote carriers (OR = 1.23, 95% CI: 1.02∼1.46, P = 0.021). Publication bias was extremely low for all integral comparisons. In stratified analyses, significance was spotted in populations of Chinese descent, in retrospective studies, in hospital-based studies, in age-matched case-control studies, in studies enrolling patients with mean body mass index < 25 kg/m2 and in studies with total sample size ≥ 240. Heterogeneity was improved for most stratified comparisons. Further in hypertensive patients, the 64Trp/64Arg heterozygote carriers had significantly higher systolic (WMD = 0.87 mmHg, 95% CI: 0.39∼1.35, P < 0.001) and diastolic (WMD = 0.88 mmHg, 95% CI: 0.59∼1.17, P < 0.001) BP than 64Trp/64Trp homozygote carriers. Altogether, ADRB3 gene Trp64Arg mutation was significantly associated with an increased predisposition toward hypertension and elevated systolic/diastolic BP in hypertensive patients, suggesting that Trp64Arg is an important hypertension-susceptibility marker.

Metabolic syndrome and ADRB3 gene polymorphism in severely obese patients from South Italy

To evaluate the prevalence of beta(3)-adrenergic receptor (ADRB3) Trp64Arg polymorphism and its relationship with the metabolic syndrome in severe obesity. Cross-sectional outpatients study. In 265 (100 men) severely obese non-diabetic subjects and 78 (25 men) healthy volunteers, genomic DNA was isolated from peripheral leukocytes. In obese patients, plasma concentrations of leptin, lipids, glucose and insulin, the homeostasis model assessment index and blood pressure have been measured. The Trp64Arg mutation was identified with the real-time TaqMan method. Neither genotype distribution nor allele frequency differed between the two groups. The metabolic syndrome prevalence was 59% in obese subjects, and was higher in men than in women (65 vs 55%: P=0.03). The body mass index (BMI) was related to age tertiles (beta=0.08; P<0.001; multiple linear regression) in Trp64Arg-positive obese subjects. We confirm the high prevalence of the metabolic syndrome among severely obese subjects. ADRB3 polymorphism was significantly related to insulin resistance only in obese male subjects. Moreover, increased BMI was related to age in obese subjects with the ADRB3 polymorphism.

Comparison of Body Fat Distribution and Blood Lipid Profiles according to Trp64Arg Polymorphism for the .BETA.3-Adrenergic Receptor Gene in Korean Middle-Aged Women

The aim of this study was to determine whether there was an association between body fat distribution, blood lipid profiles, and beta 3-adrenergic receptor gene polymorphism in Korean middle-aged women. Subjects were grouped according to BMI as obese (> or = 5 BMI, n = 95) or non-obese (BMI<25, n = 93). The Trp64Arg mutation of the beta 3-adrenergic receptor gene was detected by PCR-RFLP. Skinfold thickness, body circumference, intra-abdominal fat area by CT, and blood lipid profiles were also measured. Data were compared using ANOVA, Bonferroni t-test, and Chi-square. Significance for statistical analyses were set at p<0.05. In the obese group, 63.16% were Trp64Trp homozygotes and 36.84% were Trp64Arg heterozygotes, compared to 80.65% who were Trp64Trp homozygotes and 19.35% who were Trp64Arg heterozygotes in the non-obese group. These results indicated a significant (chi-square = 4.943, p<0.05) difference between the two groups. Frequency of the Arg64 allele in the obese group (16.84%) showed a significant (chi-square = 4.185, p<0.05) difference as compared to the non-obese group (9.68%). Skinfold thickness and body circumference of the Trp64Arg heterozygote group showed a consistent increase as compared to the Trp64Trp homozygote group. Visceral fat area and VSR of Trp64Arg heterozygote group showed a higher tendency than Trp64Trp homozygotes in the obese group, but these differences were not statistically significant. In conclusion, the Trp64Arg polymorphism of the beta 3-adrenergic receptor gene is associated with obesity in middle-aged Korean women, but it is difficult to suggest the prominent association of the Trp64Arg polymorphism of the beta 3-adrenergic receptor gene with prevalence of abdominal obesity or dyslipidemia in Korean middle-aged women.

Meta‐Analysis of the Association of the Trp64Arg Polymorphism in the β3 Adrenergic Receptor with Insulin Resistance

To clarify the possible association between the Trp64Arg polymorphism and insulin resistance (IR). Articles evaluating the effect of the Trp64Arg polymorphism on IR were identified on the MEDLINE and PubMed databases from 1995 to February, 2004. After extraction of relevant data, main and subgroup meta-analyses were performed to assess the differences in IR indices between Trp/Trp and Trp/Arg genotypes. Forty eligible papers containing 56 subgroups were included in this meta-analysis. Among a total of 12,805 subjects, 21.9% had Trp64Arg mutation: 20.8%, heterozygotes and 1.1%, homozygotes. Significant associations were found between this mutation and some indices of IR. The weighted mean difference in fasting insulin, 120-minute insulin level after oral glucose tolerance test, and homeostasis model assessment between Arg64 and Trp64 was 0.23 [95% confidence interval (CI), 0.05 to 0.42] pM, 0.89 (95% CI, 0.30 to 1.48) pM, and 0.55 (95% CI, 0.14 to 0.96), respectively. Subgroup analysis further indicated that this significant association existed only in the Asian population (p < 0.01) and in the obese (p = 0.02) and diabetes subgroups (p = 0.03). Numerous studies have been conducted to examine the relationship between the beta3-adrenergic receptor Trp64Arg polymorphism and components of IR syndrome. However, the results have been inconsistent and have led to controversy about whether this polymorphism is associated with these clinical features. The current meta-analysis demonstrated the moderate effects of the Trp64Arg polymorphism on IR in the Asian population and in obese and diabetic subgroups.

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.

Difficulty in losing weight by behavioral intervention for women with Trp64Arg polymorphism of the beta3-adrenergic receptor gene.

Trp64Arg mutation in the beta(3)-adrenergic receptor (beta(3)AR) gene is relatively common in Japanese people. However, it has not been clear whether persons with Trp64Arg mutation in the beta(3)AR gene tend to have obesity and difficulty in losing weight even with a restricted diet and exercise. We investigated the response of body weight and metabolic factors to behavioral intervention in Japanese women with Trp64Arg mutation in the beta(3)AR gene. A 3-month behavioral intervention study using a combination of diet and exercise programs. A total of 76 perimenopausal women with no clinical symptoms (age: 54.7+/-7.7 y, body mass index (BMI): 21.0-33.0 kg/m(2)). Anthropometric measurements (weight, height, body fat, waist circumference, hip circumference, skin fold, resting energy expenditure and blood pressure) and metabolic measurements (serum levels of cholesterol, triglyceride, phospholipid, nonesterified fatty acid, glucose, insulin and leptin) and determination of the beta(3)AR genotype by polymerase chain reaction followed by BstNI digestion. At the baseline of BMI, body weight, body fat, waist circumference, hip circumference, the arm skin fold, resting energy expenditure, or blood lipid and glucose profiles, there was no significant difference in participants with/without mutation of the beta(3)AR gene. The intervention yielded a body weight reduction in 69 and 48%, and induced a significant difference in weight loss (-0.74 and -0.01 kg) for women with wild-type and Trp64Arg mutation, respectively. Significant differences of anthropometric parameters were found in body weight, BMI, waist and hip circumferences and blood pressure of wild type by the intervention. However, women with Trp64Arg mutation did not show significant changes in these anthropometric parameters, except for hip circumference. A significant difference was found in high-density lipoprotein cholesterol (HDL-C) and in the low-density lipoprotein cholesterol/HDL-C ratio in both genotypes. The results of the present study suggest that the Trp64Arg mutation of the beta(3)AR gene is associated with difficulty in losing weight through behavioral intervention, although it is not related to obesity-related phenotypes and resting energy expenditure before the intervention.

Effect of Trp64Arg mutation in the β3-adrenoceptor gene on body fat distribution, glycemic control and lipids in response to hypocaloric diets in men with coronary artery disease

This study aimed to investigate whether the Trp64Arg mutation of the β3-adrenoceptor gene affects abdominal fat mobilization and endocrinal function in overweight-obese men with coronary artery disease (CAD) during 12 weeks’ mild weight reduction (–300kcal/d). Seventy participants were subdivided into ‘without-mutation’ group and ‘with-mutation’ group. After the intervention, the average weight and body mass index of the subjects without mutation (n = 50) and with mutation (n = 20) similarly decreased by about 5% (p < 0.001). In without-mutation group, the areas of total and visceral fats at both 1 st and 4 th lumbar vertebra (L1, L4) and that of subcutaneous fat at L1 level were significantly reduced. Fasting insulin and lipid profiles were also improved only in this group. However, with-mutation group showed a significant reduction only in mid thigh fat area. In conclusion, the Trp64Arg mutation during mild weight reduction makes difficult not only abdominal fat loss but also improvements in insulin and lipid profiles in CAD men despite similar weight reduction in both without- and with-mutation groups.

Effects of uncoupling protein 1 and ß3-adrenergic receptor gene polymorphisms on body size and serum lipid concentrations in Japanese women

Objectives: To investigate whether the −3826 A–G point mutation of the uncoupling protein 1 (UCP1) gene and the Trp64Arg mutation of the ß3-adrenergic receptor (ß3-AR) gene are associated with increased susceptibility to weight gain and hyperlipidemia in postmenopausal women. Methods: We genotyped 312 Japanese women for UCP1 and ß3-AR gene polymorphisms, and investigated their effects on anthropometrical parameters, serum lipid concentrations, and their changes after 4 years. Results: Although body mass index (BMI), serum triglyceride, total cholesterol, and low-density lipoprotein levels were significantly higher and high-density lipoprotein levels significantly lower in postmenopausal ( n=182) than in premenopausal ( n=99) women, there was no significant difference in these parameters between carriers and non-carriers of the G allele in the postmenopausal women. In the premenopausal women, BMI and the 4-year change in body weight (BW) of carriers of the G allele were significantly higher than those of non-carriers of the G allele ( P=0.022 and 0.048, respectively). In the postmenopausal women, the 4-year change in the level of serum triglyceride of carriers of the G allele was significantly higher ( P=0.049), and the change of high-density lipoprotein was significantly lower ( P=0.020) than those of non-carriers of the G allele. The ß3-AR polymorphism showed no apparent affect on these parameters. Conclusions: The −3826 A–G polymorphism of the UCP1 gene is associated with an increase in BW of premenopausal women and with the 4-year changes in serum triglyceride and high-density lipoprotein levels in postmenopausal women.

Effect of Trp64Arg mutation of the beta3-adrenergic receptor gene and C161T substitution of the peroxisome proliferator activated receptor gamma gene on obesity in Japanese children.

Obesity is a multifactorial syndrome influenced by both genetic and behavioral factors. Trp64Arg mutation of the beta3-adrenergic receptor (AR) gene and C161T substitution of the peroxisome proliferator-activated receptor (PPAR) gamma gene have been reported to be associated with obesity or lipid metabolism in adults. However, the effects of these mutations on children have not yet been clarified. For this reason, we studied the effects of Trp64Arg mutation of the beta3-AR gene and C161T substitution of the PPARgamma gene on obesity in Japanese children. In order to determine the effects of Trp64Arg mutation of the beta3-AR gene and C161T substitution of the PPARgamma gene on obesity in children, 105 obese Japanese children were screened by the polymerase chain reaction and restriction fragment-length polymorphism analysis. Plasma lipid, apolipo-protein (apo), glucose, insulin and leptin levels were also determined. Obese boys with Trp64Arg showed a higher obesity index and lower plasma levels of high-density lipoprotein cholesterol (HDL-C), apoA-I and apoA-II than those of them without the mutation. Obese boys with both mutations showed a higher plasma leptin level than those with only the beta3-AR gene mutation or PPARgamma gene mutation. No significant effect of these mutations was found in obese girls. All of these data suggest that Trp64Arg mutation of the beta3-AR gene might affect obesity and HDL metabolism in obese boys. In contrast, C161T mutation of the PPARgamma gene, by itself, is unlikely to influence obesity, lipid metabolism or plasma leptin levels.

Multiple symmetric lipomatosis may be the consequence of defective noradrenergic modulation of proliferation and differentiation of brown fat cells.

Multiple symmetric lipomatosis (MSL) is an inherited disorder in which enlarging and unencapsulated lipomas symmetrically develop in the subcutaneous tissue of the neck, shoulders, mammary, and truncal regions. In some cases, it is associated with mitochondrial DNA abnormalities. The pathogenesis of MSL is completely unknown, although the fat deposits may be due to a neoplastic-like proliferation of functionally defective brown adipocytes. It has recently been demonstrated that the beta(3)-adrenergic receptor is the functionally relevant adrenergic receptor subtype in brown adipocytes and that its stimulation by noradrenaline (NA) modulates the expression of genes, such as uncoupling protein (UCP)-1 and inducible nitric oxide synthase (iNOS), involved in fat cell proliferation and differentiation. Furthermore, Trp64Arg mutation of the beta(3)-adrenoceptor has been implicated in lower NA activity in adipose tissues. The aim of this study was to investigate the molecular and functional characteristics of MSL adipocytes and to analyse the effects of nitric oxide (NO) on the proliferation/differentiation of MSL adipocytes in culture, and the relevance of putative noradrenergic deficit in the development of lipomas in MSL patients. Cultured MSL adipocytes were able to synthesize UCP-1 (the selective marker of brown adipocytes), but unlike that of normally functioning brown fat cells, the expression of the UCP-1 gene was not significantly induced by NA. NA is also defective in inducing iNOS gene expression, thus leading to reduced NO production and a consequent reduction in the anti-proliferative, adipogenic (mitochondrial biogenesis) effects of NA on MSL cells. Furthermore, the transcriptional peroxisome proliferator-activated receptor gamma co-activator-1 (PGC-1), which plays a key role in the sympathetic-stimulated mitochondrial biogenesis of brown adipocytes, is expressed but not induced by NA in MSL cells, as it is in brown adipocytes. The study did not find any association between beta(3)-adrenoceptor gene polymorphism and noradrenergic signalling defects in MSL subjects with or without mitochondrial DNA mutations.

The Risk of Obesity and the Trp64Arg Polymorphism of the β3-Adrenergic Receptor: Effect Modification by Age

Aim: To examine the association between the risk of obesity and the Trp64Arg polymorphism of the β₃-adrenergic receptor gene. Methods: A case-control study was conducted. The case series encompassed 159 subjects with a body mass index >30 kg/m² (obesity) and no other major diseases except for type 2 diabetes, and the controls were 154 healthy subjects with a body mass index <25 kg/m². 313 Spanish subjects between 20 and 60 years of age were screened for the Trp64Arg mutation. Results: The prevalence of the Trp64Arg mutation was similar among cases (19.5%) and control subjects (16.2%). The association between the risk of obesity and the Trp64Arg mutation was estimated using multivariate logistic regression. A higher odds ratio of 3.84 (95% CI 1.33–11.12) for the mutation was found among younger individuals (20–35 years), while no increased risk was apparent among older participants (35–60 years). Moreover, when the model was adjusted for gender, age, and leisure-time physical activity, the product-term for interaction (effect modification) between age and the presence of the Trp64Arg mutation was statistically significant (likelihood ratio test p = 0.035). Conclusion: Individuals aged 20–35 years who are Trp64Arg carriers had a substantially higher risk of developing obesity, independent of their sex or leisure-time physical activity.

Impact of polymorphisms of human beta-adrenergic receptor gene on changes in height during growth hormone treatment.

The aim of this study was to investigate the occurrence of polymorphisms of the beta-adrenergic receptor gene in short children and to evaluate the possible influence of the polymorphisms on changes in height and obesity index in response to GH treatment. Of the 75 children enrolled in the study, 40 completed at least 5 years of GH treatment. The genotype distribution of the beta2 and 3-adrenergic receptor polymorphisms in the study population did not differ significantly from those reported in non-obese subjects. There were no significant differences in the SD score for height at any given time-point between the group with and without the Trp64Arg mutation of the beta3-adrenergic receptor gene. In relation to the Glyl6Arg polymorphism of the beta2-adrenergic receptor gene, the mean SD score for height increased significantly during GH treatment in children with Argl6Arg and Glyl6Arg. In those with Glyl6Gly, the score did not show any significant increase during all 5 years of GH treatment. In both the groups with and without the Trp64Arg mutation, the changes in obesity index did not reach statistical significance at any time-point. Only children with Glyl6Gly had a significantly higher baseline mean obesity index than those with Glyl6Arg. The index also decreased markedly from 21.9% to 5.8% in these children during the first 4 years of GH treatment. Thus, when the impact of the polymorphisms of these two receptor genes was studied simultaneously, it appeared that only the beta2-adrenergic receptor polymorphism had an important role to play in modulating the regulation of growth rate and energy expenditure in short children.

Association of a mutation in the β3‐adrenergic receptor gene with obesity and response to dietary intervention in Chinese children

This study aimed to determine whether the Trp64Arg mutation in the β3‐adrenergic receptor (β3‐adr) gene is related to childhood obesity and the response to dietary intervention for obesity. The study included 311 healthy children aged 8‐11 y selected at random from 4 primary schools in Beijing. Fasting insulin and lipids were measured and anthropometry was carried out for all samples. The mutation of the β3‐adr gene was determined by polymerase chain reaction‐restriction fragment length polymorphism analysis. Forty‐seven obese children were selected and divided into two groups. One group received dietary intervention (36 subjects); the other served as the control group (11 subjects). After 3 mo of dietary intervention, anthropometry was carried out again in 47 obese children. The frequency of the mutated allele was similar in 73 overweight and 238 normal‐weight children (0.18 and 0.17, respectively). Adjusted for age and sex, there was no significant difference in body mass index (BMI) and the levels of fasting lipids and insulin between those with and without the mutation of the 311 children. However, after 3 mo of dietary intervention, increases in weight and BMI were significantly lower in obese children without the mutation than in the control group (2.41 ± 0.56 vs 4.43 ± 0.70, p &lt; 0.05; 0.48 ± 0.24 vs 1.55 ± 0.35, p &lt; 0.05, respectively), but the changes in weight and BMI in obese children with the mutation were similar to the results in the controls (4.32 ± 0.69 vs 4.43 ± 0.70; 1.47 ± 0.32 vs 1.55 ± 0.35). Conclusion: The Trp64Arg mutation of the β3‐adr gene may predict the result of dietary intervention in obese children to some extent, but it was not a major factor affecting weight in Chinese children.

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

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). 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. 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. 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.

Gender specific associations of the Trp64Arg mutation in the β3‐adrenergic receptor gene with obesity‐related phenotypes in a Mediterranean population: interaction with a common lipoprotein lipase gene variation

Abstract. Corella D, Guillén M, Portolés O, Sorlí JV, Alonso V, Folch J, Sáiz C (School of Medicine, University of Valencia, Valencia, Spain). Gender specific associations of the Trp64Arg mutation in the β3‐adrenergic receptor gene with obesity‐related phenotypes in a Mediterranean population: interaction with a common lipoprotein lipase gene variation. J Intern Med 2001; 250: 348–360. Objective. To investigate the association between the Trp64Arg β3‐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 &lt; 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.

β 3-adrenergic receptor gene variant is associated with upper body obesity only in obese Japanese-American men but not in women

We investigated gender differences in the relationships between the Trp64Arg variant of the β 3-adrenergic receptor (AR) gene in obesity and insulin resistance in nondiabetic subjects. In 476 nondiabetic Japanese-Americans (M/F=204/272), the Trp64Arg variant of the β 3-AR gene was examined. The presence or absence of the Trp64Arg mutation was examined in DNA separated from leukocytes in peripheral blood using the PCR-RFLP method. The frequency of abnormal allele of the β 3-AR gene was 0.18 for males and 0.17 for females, almost the same as the reported values in Japanese. There was no difference in the frequency of the β 3-AR gene variant between obese and non obese subjects for each gender. However, among obese males (body mass index ≥24.2 kg/m 2), with the β 3-AR gene mutation, the waist-to-hip ratio, fasting insulin, 2-h insulin, total insulin, and HOMA, an index of insulin resistance, were all significantly higher than obese males without the mutation . In females, the index of obesity, insulin resistance, or lipid metabolism did not differ significantly between the subjects with or without the β 3-AR gene variant either in the obese and non-obese group. We suggest that the β 3-AR gene variant is not important as an obesity-inducing factor in Japanese. However, in males, when obesity becomes obvious, the β 3-AR gene variant is considered to influence the enhancement of insulin resistance, in association with visceral obesity.

Relationship of the Trp64Arg polymorphism of the beta3-adrenoceptor gene to central adiposity and high blood pressure: interaction with age. Cross-sectional and longitudinal findings of the Olivetti Prospective Heart Study.

The association of the Trp64Arg polymorphism of the beta3-adrenoceptor (beta3-AR) gene with high blood pressure, central adiposity and other features of the metabolic syndrome was investigated in a large unselected sample of a white male working population in Southern Italy (n = 979). In the whole population, subjects heterozygous for the Trp64Arg mutation (11.2%) were not different from the homozygous Trp64Trp for any of the variables investigated. However, upon stratification for age, among men in the upper tertile of age (> 53 years), the Trp64Arg genotype was associated with higher waist: hip ratio (0.992 +/- 0.021 versus 0.982 +/- 0.037, P< 0.05), serum uric acid (6.34 +/- 1.50 versus 5.75 +/- 1.30 micromol/l, P < 0.05) and systolic blood pressure (144.3 +/- 19.4 versus 136.9 +/- 18.9 mmHg, P< 0.05) compared with the wild-type homozygotes. Accordingly, in the same age group, the carriers of Trp64Arg genotype were more often in the upper tertile of abdominal adiposity (69.7 versus 43.7%, P< 0.02) and serum uric acid (56.3 versus 34.8%, P < 0.02) and were more often hypertensive (68.6 versus 57.6%, P< 0.058) than the Trp64Trp homozygotes. No such differences were observed in younger age groups. No association was found with fasting serum insulin and the homeostasis model assessment (HOMA) index of insulin resistance. Furthermore, in a subgroup of 457 men for whom retrospective 20-year follow-up data were available, the variant genotype was associated with a higher probability of developing overweight (44.7 versus 27.0%, P < 0.05) and a trend to higher blood pressure (52.6 versus 38.4%, P = 0.09) over 20 years. We conclude that the Trp64Arg variant of the beta3-AR receptor predicts a greater tendency to develop abdominal adiposity and high blood pressure with advancing age.