Beta 3-adrenergic receptor gene polymorphism and type 2 diabetes in a Caucasian population

Summary
Aim   The β₃-adrenergic receptor (β₃-AR) is suspected to play a key role in the regulation of energy balance by increasing lipolysis and thermogenesis. A mutation in the β₃-AR gene (Trp64Arg) has been associated with the capacity of weight gain and with early onset of noninsulin dependent diabetes mellitus (type 2 diabetes). In this study we investigated the prevalence of the two β₃-AR alleles in a Caucasian population and studied the association between the β₃-AR genotype and metabolic disorders (obesity and type 2 diabetes).
Methods   Genomic DNA extracted from peripheral blood leucocytes of 200 Caucasian subjects (137 subjects with and 63 subjects without type 2 diabetes). The Mva I polymorphism of β₃-AR, which detects the Trp64Arg mutation, was determined by polymerase chain reaction (PCR). We studied the correlation between the Trp64Arg mutation and the body mass index (b.m.i. kg/m²).
Results   There was no significant difference between the patients with type 2 diabetes and control subjects in the frequency of the Arg64 allele (5.5% and 4.8%, respectively). Within the group of type 2 diabetes patients were 14 subjects with the Trp64Arg mutation (b.m.i., mean ± s.d.: 31 ± 8.5 kg/m²) and 123 without the mutation (b.m.i. 29 ± 4.8). There was no association between the β₃-AR gene polymorphism and sex, obesity, blood pressure, glycohaemoglobin concentration, proteinuria.
Conclusion   Our results suggest that the Trp64Arg mutation is not a major determinant of metabolic disorders (type 2 diabetes, obesity) and chronic complications of type 2 diabetes in a Dutch population.     

TRP64ARG polymorphism of the beta 3-adrenergic receptor gene and obesity risk: effect modification by a sedentary lifestyle

Aim: We performed a case–control study to assess the association between obesity risk and the Trp64Arg polymorphism of the β₃-adrenergic receptor gene.
Methods: Obese subjects [n = 159; body mass index (BMI) > 30 kg/m²] and controls (n = 154; BMI < 25 kg/m²) were compared using multivariable logistic regression to control for potential confounders.
Results: A higher obesity risk (adjusted OR: 2.98; 95% CI: 1.00–8.56; p = 0.05) was associated with the Trp64Arg polymorphism among sedentary, but not among more active people.
Conclusions: Our results suggest that the TRP64ARG polymorphism of the ADRB3 seems to be a risk factor for obesity that is dependent on a sedentary lifestyle.     

Polymorphisms of Interleukin-1β and β3-Adrenergic Receptor in Japanese Patients With Nonalcoholic Steatohepatitis

Background: Obesity, hypertriglyceridemia, and diabetes have been reported as frequent complications observed in patients with nonalcoholic steatohepatitis (NASH) in Western countries. The aim of this study was to investigate the genetic predisposition on NASH pathogenesis in the Japanese population.
Methods: Genotypes of two previously described functional polymorphisms—β3-adrenergic receptor 190 T/A polymorphism, which results in Trp64Arg (W64R) amino acid replacement, and interleukin-1β-511 T/C polymorphism in the promoter sequence—were determined in 63 Japanese NASH patients and 100 healthy volunteers using polymerase chain reaction and restriction fragment length polymorphism.
Results: β3-adrenergic receptor R allele frequency and the R/− (W/R and R/R) genotype frequency were significantly higher in NASH patients than those in control subjects. Interleukin-1β-511 T allele frequency and the T/T genotype frequency were significantly higher in NASH patients than those in control subjects. Obesity, hypertriglyceridemia, and hyperinsulinemia were associated with NASH patients with the R/− genotype, whereas an increase in fasting plasma glucose level and a decrease in insulinogenic index were associated with NASH patients with the W/W genotype.
Conclusion: This study confirmed the contribution of obesity, glucose intolerance, and hypertriglyceridemia to NASH development in the Japanese population. In addition to these factors, genetic predispositions to obesity and inflammation in the Japanese population were shown to contribute much to the development of NASH.     

Association of Trp64Arg polymorphism of the beta3-adrenergic receptor gene and no association of Gln223Arg polymorphism of the leptin receptor gene in Japanese schoolchildren with obesity

OBJECTIVE: To investigate whether Trp64Arg polymorphism of the beta3-adrenergic receptor (beta3-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 beta3-AR gene, the number of obese subjects with Trp/Arg or Arg/Arg genotypes was significantly higher than that of the non-obese subjects (chi2=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 beta3-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.     

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.     

Association of a single nucleotide polymorphism in the secreted frizzled-related protein 4 (sFRP4) gene with bone mineral density

Background:   Wnt-β-catenin signaling pathway is involved in the regulation of bone mineral density (BMD). Secreted frizzled-related protein (sFRP) 4 that antagonize Wnt signals may modulate Wnt-β-catenin signaling pathway in the bone. Therefore, we analyzed expression of sFRP4 mRNA in primary osteoblasts and the association of a single nucleotide polymorphism (SNP) in the sFRP4 gene with BMD.
Methods:   Expression levels of sFRP4 mRNA were analyzed during the culture course of rat primary osteoblasts. Association of a SNP in the sFRP4 gene at Arg262 (CGC to CGT) with BMD was examined in 372 healthy post-menopausal Japanese women.
Results:   sFRP4 mRNA was detected and increased during the differentiation of rat primary osteoblasts. As an association study of the SNP in the sFRP4 gene, the subjects without the T allele (CC; n  = 129) had significantly higher lumbar BMD than the subjects bearing at least one T allele (TT + CT; n  = 243) (Z score; 0.054 versus −0.324; P  = 0.0188).
Conclusion:   sFRP4 mRNA was expressed and regulated in primary osteoblasts. A genetic variation at the sFRP4 gene locus is associated with BMD, suggesting an involvement of sFRP4 gene in the bone metabolism.     

Synergistic effect of polymorphisms in uncoupling protein 1 and β3-adrenergic receptor genes on basal metabolic rate in obese Finns

Summary The polymorphisms in the uncoupling protein 1 (UCP1, A to G) and β ₃-adrenergic receptor (β ₃-AR, Trp64Arg) genes have been suggested to be associated with an increased tendency to gain weight. We investigated the frequency of the A to G polymorphism of the UCP1 gene and its effect on basal metabolic rate (BMR) among obese Finns. We also examined the effects of the simultaneous occurrence of the polymorphisms in the UCP1 and β ₃-AR genes on BMR. Altogether 170 obese subjects (29 men, 141 women, BMI 34.7 ± 3.8 kg/m², age 43 ± 8 years, mean ± SD) participated in the study. The A to G substitution of the UCP1 gene was verified by digestion of the PCR product with Bcl I. The frequency of the A to G polymorphism of the UCP1 gene in obese subjects did not differ significantly from the population-based control subjects (5 vs 1 % for homozygotes (GG) and 35 vs 42 % for heterozygotes (AG), p = 0.077, for trend). BMR adjusted for lean body mass, age and sex (adjBMR) was similar among the three UCP1 gene genotypes of obese subjects (AA n = 90, AG n = 72 or GG n = 8). However, the subjects with the polymorphisms in both UCP1 and β ₃-AR genes (n = 18) had a 79 kcal/day (95 % CI 30–128) lower adjBMR than the subjects without these polymorphisms (n = 76) (1551 ± 77 vs 1629 ± 141 kcal/day, p = 0.002). Furthermore, adjBMR was 63 kcal/day (95 % CI 7–118 kcal/day) lower in the subjects with both polymorphisms (n = 18) compared with the subjects (n = 14) who had only the polymorphism in the β ₃-AR gene (1551 ± 77 vs 1613 ± 76 kcal/day, p = 0.028). The A to G polymorphism of the UCP1 gene did not have an independent effect on BMR, but its simultaneous existence with the Trp64Arg polymorphism of the β ₃-AR gene resulted in more lowered BMR than the Trp64Arg polymorphism of β ₃-AR gene alone. [Diabetologia (1998) 41: 357–361] Received: 12 June 1997 and in final revised form: 7 November 1997     

Variants in the human beta 1-, beta 2-, and beta 3-adrenergic receptor genes are not associated with morbid obesity in children and adolescents

AIM: beta-adrenergic receptors (beta-ARs) are of key importance for the regulation of lipolysis and thermogenesis by catecholamines. Genetic defects in expression or function of beta(1)- beta(2)- and/or beta(3)-AR could affect energy homeostasis and predispose an individual towards the development of obesity. We therefore investigated the possible association of polymorphisms in the beta-adrenergic receptor genes with early onset obesity. METHODS: Frequencies of the following variants were assessed in extremely obese children and healthy underweight controls: Gly/Ser in codon 49 and Arg/Gly in codon 389 of the beta(1)-AR, Arg/Gly in codon 16 and Gln/Glu in codon 27 of the beta(2)-AR, Trp/Arg in codon 64 of the beta(3)-AR. RESULTS: The Ser49 allele in the beta(1)-AR gene was found at a frequency of 0.131 in obese and 0.136 in lean subjects (p = 0.835), while the Gly389 allele in the beta(1)-AR had a frequency of 0.319 in obese and 0.328 in lean subjects (p = 0.802). Gly16 in the beta(2)-AR was found with a frequency of 0.590 in obese and 0.611 in lean subjects (p = 0.591) and the Glu27 allele in the beta(2)-AR had a frequency of 0.380 in obese and 0.420 in lean subjects (p = 0.298). CONCLUSION: We did not detect significant differences for allele and carrier frequencies of individual polymorphisms. Together with previously obtained data on genotype distribution of a beta(3)-AR variant in the same study group, no significant differences were found between obese and lean subjects for the distribution of individuals with variants in none, one, two or all three beta-ARs. Our data make it unlikely that polymorphisms in beta-ARs are involved in the pathogenesis of early onset obesity.     

Elevated serum leptin in patients with coronary artery disease: no association with the Trp64Arg polymorphism of the beta3-adrenergic receptor

BACKGROUND: Serum leptin is associated with the occurrence of cardiovascular risk factors but it is unknown whether leptin is also associated with cardiovascular disease. Another open question is whether the Trp64Arg polymorphism of the beta3-adrenergic receptor (beta3-AR) is a determinant of circulating leptin. OBJECTIVES: We measured serum leptin concentrations in a large group of patients with angiographically assessed coronary artery disease (CAD) and investigated the relationship between the Trp64Arg polymorphism of the beta3-adrenergic receptor (AR) and serum leptin. PATIENTS AND METHODS: Leptin was measured in the fasting state in 1000 consecutive patients with angiographically confirmed CAD by radioimmunoassay. The codon 64 T/C polymorphism of the beta3-AR gene was analysed by the polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) technique. Controls were 1000 age-, gender- and weight-matched subjects without clinical signs of CAD. RESULTS: Serum leptin concentrations were significantly higher in patients with CAD than in those without CAD (median: 6.8 vs 6.1 ng/ml, P < 0.001). In a multiple regression analysis leptin was found to be a determinant of CAD (P = 0.005) along with established risk factors. No differences in serum leptin were observed between wild-type and heterozygous carriers of the Trp64Arg mutation of the beta3-AR gene, whereas the small group of homozygous carriers had higher leptin due to their higher BMI. In a multiple linear regression analysis, body mass index, gender and fasting insulin were the main significant determinants of serum leptin, whereas the beta3-AR polymorphism had no effect. CONCLUSIONS: Patients with coronary artery disease exhibit higher serum leptin concentrations than age- and gender-matched controls of comparable BMI, indicating that leptin could contribute to the development of cardiovascular disease, possibly via activation of the sympathetic nervous system. The Trp64Arg variant of the beta3-adrenoceptor did not influence serum leptin.     

Association of a single-nucleotide polymorphism in the promoter region of leukemia inhibitory factor receptor gene with low bone mineral density in adult women

Background:   Osteoporosis is believed to result from the interaction among multiple environmental and genetic determinants that regulate bone-mineral density (BMD).
Methods:   To investigate a potentially predisposing genetic factor in the onset of osteoporosis, we looked for a possible association between BMD in adult Japanese women and known polymorphisms in the leukemia inhibitory factor receptor gene (LIFR).
Results:   An association analysis of chromosomes from 384 volunteer subjects revealed significant correlation between the −603T > C variant of LIFR and radial BMD ( r  = 0.11, P  = 0.032) in this test population. Comparisons of mean values of adjusted radial BMD among separate genotypic groups implied an allelic dosage effect, because homozygous carriers of T alleles of that SNP had the highest adjusted BMDs (0.403 ± 0.054 g/cm²); women homozygous for the C-allele had the lowest (0.373 ± 0.042 g/cm²), and heterozygous individuals had intermediate scores (0.394 ± 0.056 g/cm²).
Conclusion:   This polymorphism in LIFR may be an important determinant of predisposition to postmenopausal osteoporosis.     

Beta(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 beta(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 beta(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 beta(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 beta(3)-AR gene variant between obese and non obese subjects for each gender. However, among obese males (body mass index > or =24.2 kg/m(2)), with the beta(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 beta(3)-AR gene variant either in the obese and non-obese group. We suggest that the beta(3)-AR gene variant is not important as an obesity-inducing factor in Japanese. However, in males, when obesity becomes obvious, the beta(3)-AR gene variant is considered to influence the enhancement of insulin resistance, in association with visceral obesity.     

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     

The Trp64Arg polymorphism of the beta3-adrenergic receptor gene is associated with increased small dense low-density lipoprotein in a rural Japanese population: the Mima study

The presence of small dense low-density lipoprotein (sdLDL) is closely associated with an increased risk of developing coronary artery disease. The Trp64Arg polymorphism of the beta(3)-adrenergic receptor (beta(3)-AR) gene is a genetic marker for obesity-related traits. However, any possible association between this polymorphism and sdLDL profiles is unclear. The objective of this study is to investigate the effects of the polymorphism of the beta(3)-AR gene on LDL particle size and sdLDL in a rural Japanese population. Among 277 subjects, body mass index, blood pressure, fasting serum insulin levels, and insulin resistance index (fasting glucose x fasting insulin/405) were determined. The polymorphism of the beta(3)-AR gene was assessed by polymerase chain reaction-restriction fragment length polymorphism using buccal samples. Low-density lipoprotein particle size and sdLDL were measured with the electrophoretic separation of lipoproteins on the LipoPrint System (Quantimetrix, Redondo Beach, CA). The frequency of the beta(3)-AR allele was 0.19. In Arg carriers (Trp/Arg or Arg/Arg), the mean value of LDL particle size was smaller than that of non-Arg carriers (Trp/Trp) (P < .05). The area percentage of sdLDL was higher in Arg carriers (P < .05) than in non-Arg carriers. A multiple regression analysis showed that the area percentage of sdLDL was correlated with the polymorphism of the beta(3)-AR gene (P < .05), independently of age, sex, body mass index, smoking, and insulin resistance index. The present findings suggest that the beta(3)-AR gene polymorphism plays a role in the genetic predisposition to increased sdLDL, independently of insulin resistance.     

b3-adrenergic-receptor polymorphism: a genetic marker for visceral fat obesity and the insulin resistance syndrome

Summary We investigated whether the polymorphism of the β ₃-adrenergic receptor (β ₃-AR) gene, which is associated with insulin resistance in non-diabetic subjects and an earlier onset of non-insulin-dependent diabetes mellitus in Pima Indians, was associated with visceral fat obesity and features of the insulin resistance syndrome in Japanese premenopausal obese women. There was no difference between 131 obese women and 256 control subjects (0.23 vs 0.17, p = 0.112) in the frequency of the Arg⁶⁴ allele. The visceral fat area measured by computerised tomography scan was greater in homozygous Arg⁶⁴Arg (172 ± 17 cm², n = 6) and heterozygous Trp⁶⁴Arg (178 ± 47 cm², n = 48) women than in women homozygous for the Trp⁶⁴Trp (121 ± 46 cm², n = 77) genotype (p < 0.01). This was also reflected by increased total body fat but not by increased body mass index. The association between the Trp⁶⁴ allele and visceral fat mass by multiple regression analysis, was independent of age, body mass index and total fat mass (p < 0.004). Moreover, homozygous carriers of the Arg⁶⁴ allele had higher systolic blood pressure, higher fasting and post-load glucose and insulin concentrations, higher cholesterol, and triglyceride and lower HDL-cholesterol concentrations than homozygous carriers of the Trp⁶⁴ allele. Some of these differences were also observed between heterozygous Trp⁶⁴Arg and homozygous Trp⁶⁴Trp genotypes (glucose tolerance, insulin and cholesterol concentration). We conclude that in obese women the β ₃-AR polymorphism may be used as a genetic marker for visceral fat obesity and the insulin resistance syndrome. [Diabetologia (1997) 40: 200–204] Received: 24 April 1996 and in final revised form: 22 October 1996     

肾上腺素能β3受体基因多态性与冠心病及冠状动脉病变程度的相关性研究

目的探讨肾上腺素能β3受体（β3-AR）基因多态性与冠心病及冠状动脉病变的相关关系。方法选择冠心病患者120例,114名健康者为对照。应用聚合酶链反应-限制性片段长度多态性（PCR—RFLP）检测分析肾上腺素能良受体基因型,比较对照组与冠心病组的基因型及等位基因频率之间的差异,同时对冠心病患者中不同β3肾上腺素能受体基因型的冠状动脉病变程度进行比较。结果①冠心病组和对照组Trp64Trp、Trp64Arg和Arg64Arg的基因型频率分别为68．3％、30．0％、1．6％和69．2％、29．8％、0．9％。冠心病组Arg等位基因频率（16．6％）与对照组频率（15．8％）近似（P〉0．05）,突变频率两组相比差异无统计学意义。②冠心病不同冠脉病变支数亚组间多态性分布差异无统计学意义（χ^2=0．471,P=0．790）。结论肾上腺素能艮受体基因多态性与冠心病及不同冠脉病变支数无相关性。     

Association of Trp64Arg mutation of the β3-adrenergic-receptor with NIDDM and body weight gain

Summary A possible pathogenic mutation in the 3-adrenergic-receptor gene (Trp64Arg) has been reported to be associated with an earlier age of onset of non-insulin-dependent diabetes mellitus (NIDDM) and clinical features of the insulin resistance syndrome in Pima Indian, Finnish and French subjects. Since marked heterogeneity has been reported in the association of mutations of candidate genes with NIDDM between Japanese and other ethnic groups, we investigated the association of Trp64Arg with NIDDM in Japanese subjects. The allele frequency of the mutation (Arg) was slightly, but not significantly, higher in NIDDM than in control subjects (70 out of 342 alleles [20.5%] vs 40 out of 248 [16.1%], respectively, p>0.2). When our data were combined with those of Pima Indian and Finnish subjects, however, the Arg/Arg genotype was significantly associated with NIDDM as compared with the other two genotypes (p<0.005, relative risk [RR] 2.13, 95% confidence interval [CI] 1.28–3.55). The Arg allele was also associated with NIDDM (p<0.05, RR 1.27, 95% CI 1.06–1.52). Japanese subjects homozygous for the mutation had a significantly higher body mass index (mean ± SD25.5±3.9 kg/ m²) than heterozygotes (22.6±4.1, p<0.05) and normal homozygotes (22.8±3.8, p<0.05). NIDDM patients homozygous for the mutation tended to have an earlier age of onset of NIDDM than those with other genotypes. These data suggest that the Trp64Arg mutation not only contributes to weight gain and age-at-onset of NIDDM but is also associated with susceptibility to NIDDM.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - 3-AR 3-adrenergic-receptor - Trp64Arg a mutation in the 3-adrenergic-receptor gene causing a Trp to Arg change at codon 64 - BMI body mass index - ADRB3 3-adrenergic receptor gene - PCR polymerase chain reaction - RFLP restriction fragment length polymorphism - RR relative risk - CI confidence interval     

Phenotypic characterization of the beta3-adrenergic receptor mutation and the uncoupling protein 1 polymorphism in Japanese men.

The Trp64Arg mutation of the beta3-adrenergic receptor (beta3AR) gene and A to G polymorphism of the uncoupling protein 1 (UCP1) gene are reported to be associated with weight gain, and both have been shown to have an additive effect on weight gain in Caucasians. Racial differences have also been noted in the beta3AR mutation; however, the effect of UCP1 polymorphism on body weight is not obvious in the Japanese. Thus, we investigated the association of genetic variations in beta3AR and UCP1 genes and the additive effects of these two genes in 214 Japanese men. The frequency of the Trp64Arg allele was 0.19, and serum triglyceride was significantly higher in Arg64 homozygotes versus Trp64 homozygotes. The frequency of the G allele was 0.51, and the body mass index (BMI) was significantly higher in subjects with the G allele (GG homozygotes and AG heterozygotes) versus those without it (AA homozygotes). The beta3AR mutation and UCP1 polymorphism were not found to have additive effects, and they were not related to glucose tolerance patterns and insulin resistance. Our results suggest that the beta3AR mutation is associated with hypertriglyceridemia and the UCP1 polymorphism may be a weak contributing factor to obesity in Japanese men.     

Association of tumor necrosis factor receptor 1 gene polymorphism with bone mineral density

Background:   Estrogen deficiency in postmenopausal women causes an increased production of proinflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α. These cytokines are associated with an increase of bone turnover and an acceleration of bone loss. Tumor necrosis factor-α is known to promote osteoclastogenesis via TNFR1, one of the tumor necrosis factor receptors (TNFR). Therefore, the purpose of the present report was to investigate the association of TNFR1 gene polymorphism with bone mineral density (BMD) in postmenopausal Japanese women.
Methods:   The question of whether a polymorphism of the TNFR1 gene would correlate with osteoporosis in 320 unrelated healthy postmenopausal women in Japan, was investigated. A single nucleotide polymorphism (SNP) located at Pro12 (CCA to CCG) in exon 1 of TNFR1 was utilized.
Results:   The subjects were categorized into three genotypes: AA, AG, and GG. The frequency of each genotype was 72.2%, 23.8%, and 4.0%, respectively. The association of this polymorphism with BMD of the lumbar spine and total body, and several bone metabolic markers was then examined. Concerning the TNFR1 gene, the AA group had significantly low total body BMD, compared with the AG + GG group (Z score; 0.285 vs 0.568; P  = 0.03), although BMD of the lumbar spine was not statistically different.
Conclusion:   These results suggest an association between this SNP of the TNFR1 gene and BMD, and an involvement of TNFR1 in postmenopausal osteoporosis among Japanese.     

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     

The Trp64Arg beta3-adrenergic receptor amino-acid variant is not associated with overweight and type 2 diabetes mellitus in Polish population.

The Trp64Arg amino-acid variant of the beta3 adrenoreceptor gene may be associated with a genetic predisposition to human obesity and related disorders, including type 2 diabetes mellitus. This relationship has been reported in various ethnic groups, however it was not extensively studied in Polish population. Therefore, the aim of the study was to investigate the association of Trp64Arg polymorphism of the beta3 adrenergic receptor gene with overweight and type 2 diabetes mellitus in polish subjects. The Trp64Arg polymorphism was determined by PCR-based MspI restriction fragment length polymorphism (PCR-RFLP). The study population consisted of 358 subjects, among whom 200 were diagnosed as overweight (BMI > 27 kg/m (2)). Among overweight subjects 111 presented with type 2 diabetes mellitus and 89 with normal glucose metabolism. All study participants were unrelated Caucasians and inhabited the city of Lodz, Poland. The frequency of the Arg allele did not differ significantly between overweight and normal weight patients (13 % vs. 11 %, OR 1.17, CI 0.74 - 1.85). The same applied to overweight diabetic patients vs. overweight patients without diabetes mellitus (13 % vs. 13 %, OR 0.97, CI 0.54 - 1.76). The obtained results suggest no association between Trp64Arg polymorphism of the beta3-AR gene and the incidence of overweight and type 2 diabetes mellitus in Polish population.