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Association of Trp64Arg polymorphism of the β3-adrenergic receptor gene and no association of Gln223Arg polymorphism of the leptin receptor gene in Japanese schoolchildren with obesity

Abstract

OBJECTIVE: To investigate whether Trp64Arg polymorphism of the β3-adrenergic receptor (β3-AR) gene and Gln223Arg polymorphism of the leptin receptor (Ob-R) gene are associated with obesity in Japanese schoolchildren.

DESIGN: Population study of participants from a rural town located within 50 km northeast of Tokyo based on school medical examinations.

SUBJECTS: 553 Japanese schoolchildren (291 boys and 262 girls) who were 9–15 y old with a mean age of 11.9±1.8 y.

MEASUREMENTS: DNA was extracted from whole blood and genotyped by PCR-RFLP. Height, weight and blood pressure were measured in school medical examinations. Total cholesterol, triglyceride and HDL-cholesterol concentrations were measured by an autoanalyzer. Obesity index, body mass index (BMI) and LDL-cholesterol concentration were calculated by the respective formulae.

RESULTS: In Trp64Arg polymorphism of the β3-AR gene, the number of obese subjects with Trp/Arg or Arg/Arg genotypes was significantly higher than that of the non-obese subjects (χ2=5.79, P=0.02). The obesity index of subjects with the Arg/Arg or Arg/Trp genotype was significantly higher than that of those with the Trp/Trp genotype (8.2±18.7% vs 4.5±15.8%, P=0.04). Moreover, after adjustments for age and gender, BMI of subjects with the Trp/Arg or Arg/Arg genotype was significantly higher than that of those with the Trp/Trp genotype (19.4±3.6 kg/m2 vs 18.9±3.2 kg/m2, P=0.02). However, no significant differences were observed in the clinical characteristics among the genotype groups of the Ob-R gene.

CONCLUSIONS: Trp64Arg polymorphism of the β3-AR gene appears to be a genetic risk factor for obesity in Japanese children, but Gln223Arg polymorphism of the Ob-R gene does not appear to be associated with obesity.

Introduction

Obesity results from an imbalance between energy intake and expenditure. It is a well-known risk factor for hypertension, abnormality of blood lipid levels, type 2 diabetes mellitus, cardiovascular disease, gallbladder disease and some forms of cancer.1,2,3,4 Manson et al5 noted that body weight is an important determinant of mortality among middle-aged women. Accumulating evidence indicates the strong association between obesity and health problems. Childhood obesity increases the risk of obesity in adulthood. Whitaker et al6 found that obesity is an increasingly important predictor of adult obesity among older children. Moreover, overweight in adolescence predicts a broad range of adverse health effects that are independent of adult weight.7 Therefore, it is important to identify the cause of obesity, and to prevent obesity in childhood.

In humans, a low resting metabolic rate is a risk factor for weight gain and obesity.8,9,10 The β3-adrenergic receptor (β3-AR) has seven transmembrane domains, is coupled with G-protein, and is localized in brown and white adipose tissue. Stimulation of the β3-AR by β-adrenergic agonists activates adenylate cyclase, which increases intracellular concentrations of cyclic AMP and results in increased lipolysis and thermogenesis.11,12,13,14 In 1995, substitution of tryptophan by arginine at position 64 of the human β3-AR gene (Trp64Arg polymorphism of the β3-AR gene) was reported to be associated with the earlier onset of type 2 diabetes mellitus and the tendency to have a lower resting metabolic rate in Pima Indians,15 with abdominal obesity and insulin resistance in Finns,16 and with increased capacity to gain weight in the French.17 In Japanese, it was reported that individuals with the Trp/Trp genotype had a higher body mass index (BMI) and a tendency for an earlier age of onset of type 2 diabetes mellitus.18,19

Leptin, the circulating product of the ob gene, is secreted by adipose tissue20 and its expression rises with increasing fat stores in humans.21 The leptin receptor (Ob-R), the diabetes (db) gene product, is a single transmembrane protein that is a member of the class 1 cytokine receptor family.22 The receptor has a widespread tissue distribution in several alternatively spliced isoforms, one of which, the Ob-Rb isoform, is expressed most abundantly in the hypothalamus. Leptin and Ob-R constitute an important feedback system linking the hypothalamus and adiposity. It has been recognized that leptin is an adipocyte-derived blood-borne satiety factor that acts on Ob-R in the hypothalamus, thereby regulating food intake and energy expenditure.23 Montague et al24 reported that in two children of Pakistani origin, leptin deficiency due to a mutation in the leptin gene was associated with early-onset obesity. However, it is likely that this mutation is not a major contribution to obesity. Clément et al25 detected a G to A base substitution of exon 16 in the human leptin Ob-R gene, and reported that a homozygous mutation resulted in a truncated Ob-R lacking both the transmembrane and the intracellular domains. Although this mutation caused obesity, it was not detected in 402 normal weight or obese Caucasians. It follows from this that this mutation is not a common one, but a functional Ob-R is required for the regulation of body weight. In the Zucker fa/fa rat, a missense mutation in a highly conserved extracellular domain of the receptor leads to elevated plasma leptin concentrations and obesity.26,27 It is possible that Ob-R gene mutations or polymorphism contribute to human obesity. Therefore, many studies of the Ob-R gene in humans were performed, and some revealed several sequence polymorphisms in African-Americans, Caucasians and Pima Indians.28,29 A substitution of glutamine for arginine at position 223 in the extracellular domain of the human Ob-R gene (Gln223Arg polymorphism of the Ob-R gene) was found exclusively in 20 obese Pima Indians, except for a single individual.29 This amino acid substitution lies 46 amino acids upstream from the missense mutation found in the fatty Zucker rat.27 This polymorphism is also common in Japanese.30 However, it is not clear whether leptin activity is influenced by this polymorphism.

Few prior studies have assessed the influence of Trp64Arg polymorphism of the β3-AR gene and Gln223Arg polymorphism of the Ob-R gene on obesity in childhood. In this study, we investigated the relationships of β3-AR gene and Ob-R gene polymorphisms with obesity in Japanese schoolchildren.

Methods

Subjects

This study is based on school medical examinations performed on a senior class of an elementary school and one junior-high school in another school district in a rural town located 50 km northeast of Tokyo. A total of 553 Japanese schoolchildren (291 boys and 262 girls), 9–15 y old with a mean age (±s.d.) of 11.9±1.8 y, participated in this study. Informed consent was obtained from the subjects, their parents and the school principals before the blood was collected, and 98% of the subjects agreed to participate in this study.

Obesity index ((real weight−standard weight)/ standard weight×100) was calculated using the standard weight for Japanese children, which was proposed by the Ministry of Education in Japan and determined according to age, gender and stature.31 Non-obesity was defined as obesity index between −20% and +20%. Obesity was defined as obesity index of more than +20%. Slight, moderate and morbid obesity were defined as obesity indices of +20+30%, +30+50% and more than +50%, respectively. Body mass index (BMI) was calculated according to the formula, (real weight (kg)/height2 (m2)). Blood pressure (BP) was measured by an auto-hemodynamometer in the sitting position after 5 min rest.

Laboratory tests

Blood samples were obtained in the morning after an overnight fast. Total cholesterol (TC), triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) were measured by an autoanalyzer. Low-density lipoprotein cholesterol (LDL-C) was calculated by Friedewald's formula.32

Genotyping of the Trp64Arg polymorphism of the β3-AR gene and the Gln223Arg polymorphism of the Ob-R gene

Genomic DNA was extracted from peripheral blood leukocytes according to the methods described.33 The β3-AR genotype was determined by polymerase chain reaction–restriction fragment length polymorphism (PCR-R-LP) analysis as described by Widén et al.16 The Ob-R genotype was determined by PCR-R-LP analysis as described by Gotoda et al.34

Statistical analysis

All data are expressed as mean±standard deviation (s.d.). One-way analysis of variance (ANOVA), Kruskal–Wallis test, unpaired t-test, Mann–Whitney test, analysis of covariance (ANCOVA) and test were used to estimate the effects of each genotype on quantitative and qualitative variables. TG was logarithmically transformed before the analysis. Statistical analyses were performed using SPSS 6.1 software and StatView 4.5 software. Statistical significant was established at the P<0.05 level.

Results

Characteristics

Table 1 presents physical and clinical characteristics of the subjects. Numbers (%) of subjects with slight, moderate and morbid obesity were 37 (6.7%), 40 (7.2%) and 13 (2.4%), respectively.

Table 1 Physical and clinical characteristics of subjects

Genotype and allele frequencies of the β3-AR gene and effect of the β3-AR genotype on obesity

The distributions of the β3-AR genotype, allele frequencies and odds ratio for obesity are shown in Table 2. The frequencies of the Trp/Trp, Trp/Arg and Arg/Arg genotypes of the β3-AR gene were 339 (61.3%), 190 (34.4%) and 24 (4.3%), respectively. The allelic frequencies of Trp64 and Arg64 were 0.785 and 0.215. The overall genotype distributions did not deviate significantly from the Hardy–Weinberg equilibrium. The odds ratio (95% confidence interval CI) for obesity of the Arg64 allele was 1.6 (2.2–1.1). The Trp/Arg or Arg/Arg genotype groups were present in 169 of the 463 non-obese subjects (36.5%), and 45 of the 90 obese subjects (50.0%). The difference was significant (χ2=5.79, P=0.02).

Table 2 β3-AR and Ob-R genotypes, allele frequency, and odds ratios for obesity

Clinical characteristics of subjects according to the Trp64Arg genotype of the β3-AR gene are shown in Table 3. The obesity index of subjects with the Trp/Arg or Arg/Arg genotype was significantly higher than that of those with the Trp/Trp genotype (8.2±18.7 vs 4.5±15.8%, P=0.04). Furthermore, the obesity index of subjects with the Trp/Arg or Arg/Arg genotype was higher than that of those with the Trp/Trp genotype (P=0.02), after adjustments for age and gender. BMI did not significantly differ between subjects with the Trp/Arg or Arg/Arg genotype and those with the Trp/Trp genotype (19.4±3.6 vs 18.9±3.2 kg/m2). However, after adjustments for age and gender, BMI of subjects with the Trp/Arg or Arg/Arg genotype was significantly higher than that of those with the Trp/Trp genotype (P=0.02). Diastolic blood pressure (DBP) of subjects with the Trp/Arg or Arg/Arg genotype was significantly higher than that of those with the Trp/Trp genotype (61.4±8.5 vs 59.9±8.4 mmHg, P=0.04), but, after adjustments for age, gender and obesity index, no significant difference was observed in DBP between the two groups.

Table 3 Clinical characteristics of subjects according to Trp64Arg genotype of the β3-AR gene and Gln223Arg genotype of the Ob-R gene

Genotype and allele frequencies of the Ob-R gene and effect of the Ob-R genotype on obesity

The distributions of the Ob-R genotype, allele frequencies and odds ratio for obesity are shown in Table 2. The frequencies of the Gln/Gln, Gln/Arg and Arg/Arg genotypes of the Ob-R gene were 15 (2.7%), 134 (24.2%) and 404 (73.1%), respectively. The allelic frequencies of Gln223 and Arg223 were 0.148 and 0.852. The overall genotype distributions did not deviate significantly from the Hardy–Weinberg equilibrium. The odds ratio (95% CI) for obesity of the Arg223 allele was 0.9 (1.4–0.6). The Arg/Arg genotype was present in 341 of the 463 non-obese subjects (73.7%), and 63 of the 90 obese subjects (70.0%). The difference was not significant (χ2=0.51, P=0.475).

Clinical characteristics of subjects according to the Gln223Arg genotype of the Ob-R gene are shown in Table 3. No significant difference was observed in the clinical characteristics among the genotype groups, or between the Gln/Gln or Gln/Arg genotype and the Arg/Arg genotype.

Effect of the β3-AR genotype and the Ob-R genotype on serum lipid

Serum lipid value, according to the Trp64Arg genotype of the β3-AR gene and Gln223Arg genotype of the Ob-R gene are shown in Table 4. There were no significant differences in TC, TG, HDL-C and LDL-C among the β3-AR and the Ob-R genotype groups.

Table 4 Serum lipid according to Trp64Arg genotype of the β3-AR gene and Gln223Arg genotype of the Ob-R gene

Discussion

Association of Trp64Arg polymorphism of the β3-AR gene and Gln223Arg polymorphism of the Ob-R gene with obesity has already been investigated in some studies. Several studies have reported significant associations between Trp64Arg polymorphism of the β3-AR gene and obesity or weight gain, while other studies have reported no association, thus association of Trp64Arg polymorphism of the β3-AR gene with obesity or weight gain is controversial.15,16,17,18,19,35,36,37,38,39,40,41,42,43,45 Few studies have been conducted on the effects of this polymorphism on obesity in children. Obesity is influenced by both environmental and genetic factors. Few Japanese schoolchildren have a habit of drinking and smoking of this age. They usually take exercise regularly at school. Thus, in children, the difference of environmental factors such as drinking and exercise is probably less than in adults. This study was conducted to ascertain whether Trp64Arg polymorphism of the β3-AR gene and Gln223Arg polymorphism of the Ob-R gene influence obesity in children.

Previous reports have suggested that allele frequency of the Arg64 of the β3-AR gene was higher in Japanese than in Caucasians, African-Americans and Mexican-Americans, although the frequency of the Arg64 of the β3-AR was highest in Pima Indians.15,16,17,18,35,36,37,38,39,40,41,42,43,44,45

These findings suggested that polymorphism may play an important role in Japanese as well as in Pima Indians. Some studies attempted to clarify the association between the polymorphism and obesity in Japanese. For example, Kadowaki et al18 reported that in non-diabetic and obese subjects, BMI in subjects with the Arg/Arg genotype was significantly higher than in those with the Trp/Trp genotype, and Fujisawa et al19 also reported that the Arg/Arg genotype was accompanied by a significantly higher BMI than the Arg/Trp and Trp/Trp genotypes. On the other hand, Ueda et al,38 Azuma et al39 and Sun et al40 suggested that Trp64Arg polymorphism of the β3-AR gene does not appear to be associated with obesity. In Germany, Hinny et al43 investigated whether Trp64Arg polymorphism of the β3-AR gene results in a genetic predisposition to the development of obesity in children, adolescents and young adults. Their data indicated that the Arg/Trp genotype is not of major importance in regulation of body weight.

BMI is the common index for obesity in Western countries, especially in adults; however, it is reported that BMI is influenced by age and gender. The cutoff value of BMI for obesity has not been established in children, although the Expert Committee on Clinical Guidelines for Overweight in Adolescent Preventive Services has attempted to established the criteria of BMI for overweight or obesity.46 In Japan, there is no established cutoff value of BMI for childhood obesity, so we used BMI after adjustment for age and gender. Moreover, obesity index is the most common method to measure obesity in Japanese schoolchildren,31 and many reports have indicated that the obesity index has a good association with the severity of complications for obesity.47,48 For these reasons we used obesity index to indicate the obesity. In the present study, the frequency of the Trp/Arg or Arg/Arg genotypes in obese subjects was significantly higher than that in the non-obese subjects. Moreover, the obesity index and BMI of subjects with the Arg/Arg, or Arg/Trp genotypes were significantly higher than in those with the Trp/Trp genotype. Our data provides evidence that the Trp64Arg polymorphism of the β3-AR gene is a genetic risk factor for obesity in Japanese children. The difference between previous results and our data may be due to ethnicity, the small scale of the study population or the age of the subjects.

Recently, molecular mechanisms of the Trp64Arg mutation of the β3-AR gene were studied using an in vitro transfection technique, which shared that the response to various β3-adrenergic agonists, (ie maximal cAMP accumulation) of the cell with the mutated receptor was significantly reduced.49 In addition, Umekawa et al50 reported that the Trp64Arg mutation of the β3-AR gene was associated with lower lipolytic activities induced by a β3-adrenergic agonist. These data suggested that the lower response to β3-adrenergic stimulation in the Trp64Arg mutation of the β3-AR gene was an important key for the association with obesity.

The Gln223Arg polymorphism of the Ob-R gene was found exclusively in nine obese Pima Indians among 20 samples,29 and this polymorphism lies 46 amino acids upstream from the missense mutation found in the fatty Zucker rat.27 Thereafter, several investigations in ethnic populations, including Japanese subjects, on whether this polymorphism is associated with obesity, have been published. Previous reports have suggested that allele frequency of the Arg223 of the Ob-R gene was higher in Japanese (0.838–0.872) than in Caucasians (0.421–0.440) and in Pima Indians (0.750).29,30,33,51,52 These studies showed that allele frequency varies among ethnic groups and that the polymorphism is not associated with obesity. In this study, we observed an allele frequency similar to that reported by Matsuoka et al.30 Our data suggest that the Gln223Arg polymorphism of the Ob-R gene is not associated with obesity. Several other polymorphisms have been found for the Ob-R gene.30 Further studies are needed to determine association between the polymorphisms of the Ob-R gene and obesity.

In the current study, the DBP subjects of subjects with the Trp/Arg, Arg/Arg genotype of the β3-AR gene was significantly higher than that of those with the Trp/Trp genotype before adjustments for age, gender and obesity index. However, after adjustments for age, gender and obesity index, no significant difference was observed between two groups. It is of interest that Widén et al, 16 Kadowaki et al18 and Sakane et al37 reported with the Arg64 allele had higher BP than those with the Trp/Trp genotype in adults. They did not adjust BP for BMI in their papers. Since hypertension is associated with obesity,1 further studies are required to clarify the association between polymorphism of the β3-AR gene and

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Acknowledgements

This work was supported by a grant for scientific research from the Ministry of Education (09772047, 11770191).

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Correspondence to H Yanagi.

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Endo, K., Yanagi, H., Hirano, C. et al. Association of Trp64Arg polymorphism of the β3-adrenergic receptor gene and no association of Gln223Arg polymorphism of the leptin receptor gene in Japanese schoolchildren with obesity. Int J Obes 24, 443–449 (2000). https://doi.org/10.1038/sj.ijo.0801177

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Keywords

  • β3-adrenergic receptor gene
  • leptin receptor gene
  • polymorphism
  • obesity
  • schoolchildren

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