Skip to main content

ADRB3 polymorphism rs4994 (Trp64Arg) associates significantly with bodyweight elevation and dyslipidaemias in Saudis but not rs1801253 (Arg389Gly) polymorphism in ARDB1



In some populations, obesity and body weight related disorders show a correlation with polymorphisms in three subtypes of beta-adrenoceptor (β1, β2, and β3) [ADRB1, ADRB2 and ADRB3] genes. We scanned for the polymorphism of Arg389Gly (rs1801253) in ADRB1 and Trp64Arg (rs4994) in ADRB3 genes in Saudi population to determine association, if any, of these polymorphisms with obesity and related disorders.


We studied 329 non-related adults (33.1% men and 66.9% women), aged 18–36 years. Anthropometric measurements were recorded, and Body mass index (BMI) and waist/hip ratio were calculated; leptin, insulin, lipidogram, and glucose concentrations were determined. ADRB1 and ADRB3 polymorphisms (Arg389Gly and Trp64Arg, respectively) were screened by DNA sequencing. The subjects were divided into three groups according to BMI: normal weight (BMI < 25 kg/m2), overweight (BMI ≥25.1–29.9 kg/m2) subjects, and obese (≥30 kg/m2).


In the age-matched groups of the normal weight, overweight and obese male and female subjects, all anthropometric parameters were found to be significantly higher, and in the obese group, all biochemical parameters were significantly elevated compared to the normal weight controls. The allelic frequency of Gly389 ADRB1 did not differ amongst the three groups, whereas the frequency of Arg64 of ADRB3 gene was significantly higher in the overweight and obese subjects, compared with the normal weight subjects. In addition, subjects carrying Arg64 allele regardless of their BMI had a greater waist and hip circumference, W/H ratio, plasma cholesterol, triglyceride, LDL, leptin, insulin, and glucose level compared to those with the wild-type Trp allele.


The results of this study have shown a significant association between the Trp64Arg polymorphism in ADRB3 gene and the development of overweight and obesity in Saudi populations. It also has an influence on the levels of lipid, insulin, leptin, and glucose, whereas, Arg389Gly polymorphism in ADRB1 is not associated with overweight, obesity or dyslipidaemias in Saudis.


Obesity and diabetes mellitus Type 2 (T2DM) are rapidly growing public health problems in the Saudi population [1, 2]. A high risk of T2DM and cardiovascular complication is also associated with increased obesity [2, 3]. Several epidemiological and clinical studies have shown that human obesity is a multifactorial disorder, with both genetic predisposition and environmental factors contributing to its etiology [4, 5]. Extensive studies have linked different genetic loci to obesity, and strong linkage has between reported between beta (β) adrenoceptor polymorphisms (ADRB) and obesity or weight gain [6,7,8,9,10]. There are three subtypes of ARDB: β-1, β-2, and β-3, and these are involved in development, behavior, smooth muscle tone, heart function, and energy metabolism [11]. The three β -subtypes (β-1, β-2, and β-3) coexist in both white adipose tissue (WAT) and brown adipose tissue (BAT). In WAT, ADRB signaling is thought to stimulate lipolysis in response to fasting, whereas in BAT, it mediates heat production in response to cold exposure or overfeeding via activation of the uncoupling protein-1(UCP1) [12,13,14]. Catecholamines are regulators of lipolysis, and act via β1-, β2-, β3- (stimulatory), and α2- (inhibitory) adrenoceptor subtypes in adipose tissue. Most of the sympathetic nervous system-mediated energy expenditure in skeletal muscles takes place via the coupling of catecholamines with β2-adrenoceptors [15, 16] and plays important roles in energy expenditure and control of body weight [9,10,11,12,13,14,15,16,17]. Recently, it has been shown that ARDBs are polymorphic with single nucleotide polymorphism (SNPs) exerting functional consequences affecting receptor activity and regulation, and hence may contribute to the pathophysiology of obesity and related disorders [7,8,9]. Several studies have shown an association between ADRB polymorphism and BMI, T2DM, hypertension [HT] and dyslipidaemias, while other studies have failed to show such an association [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53].

In our previous report, we have shown a link between obesity-related disorders in Saudi population and Gln27Glu polymorphism in ARDB2 gene [9]. In the present study, we have investigated the relationship between polymorphism in ARDB1 (rs1801253) and ARDB3 (rs4994) genes and obesity and related disorders in the Saudi population.


Study group

The study was approved by the local ethics committee at the Umm Al Qura University, Makkah Al Mukaramah, Saudi Arabia (IRB No. 235). It included randomly chosen 329 unrelated Saudi subjects [men = 109 (33.1%) and women = 220 (66.9%)], from a nationwide population, with ages ranging from 18 to 36 years. Informed written consent was obtained from all study subjects before their participation.

Anthropometric and biochemical measurements

Anthropometric measurements included the recording of height, weight, waist and hip circumference by standard methods. Body mass index (BMI; kg/m2) and waist-to-hip ratio (WHR) were calculated [54]. For biochemical studies, 20 ml of blood was drawn by venipuncture from an antecubital vein without compression, following an overnight fast, from each subject under study. 10 ml blood was placed in ethylenediaminetetraacetic acid (EDTA) coated tubes, 2 ml in tubes containing fluoride and the rest in plain tubes. All samples were immediately centrifuged at room temperature to collect the plasma/serum. Plasma glucose was determined in duplicate by a glucose-oxidase method adapted to an autoanalyzer (Hitachi 704, Boehringer Mannheim, Germany). Enzymatic methods using commercial kits (Boehringer Mannheim) were used to estimate total serum cholesterol, triglycerides, low-density lipoprotein [LDL] and high-density lipoprotein [HDL]. Plasma insulin and leptin concentrations were estimated by radioimmunoassay (RIA) using Human Insulin Specific RIA kit and Human Leptin RIA Kit, respectively (Linco Research, St Louis, MO).

Genotyping of ADRB1 polymorphism (rs1801253)

The genomic DNAs of all the subjects were extracted from peripheral blood leukocytes using Gentra Systems Kit (Minneapolis, MN, cat # D5500). The DNA fragment containing codon 389 of the ARDB1 gene was amplified by polymerase chain reaction (PCR) using a sense primer (5’-CTCTTCGTCTTCTTCAACTGGCT-3′) and an antisense primer (5’-CAACAAGGAACATCAGCAAGC-3′). The PCR conditions consisted of an initial denaturation step at 95 °C for 15 min, followed by 34 cycles of denaturation at 95 °C for 1 min, annealing at 60 °C for 1 min, and extension at 72 °C for 1 min, with a final extension of 10 min at 72 °C. With these primers, a PCR product was verified on 2% agarose gel electrophoresis. Nucleotide sequencing was carried out by the ABI Big Dye Terminator protocol using ABI 3100 Avant Genetic Analyzer.

Genotyping of ADRB3 polymorphism (rs4994)

The DNA fragment containing codon 64 of the ADRB3 gene was amplified by PCR using a sense primer (5′- CCAGTGGGCTGCCAGGGG-3′) and an antisense primer (5′- GCCAGTGGCGCCCAACGG -3′). The PCR conditions were also the same as mentioned above for ADRB1 studies. Nucleotide sequencing was carried out by the ABI Big Dye Terminator protocol using ABI 3100 Avant Genetic Analyzer.

Statistical analysis

Stat View program for Windows (version 8.0; SAS) was used to conduct all data analyses. Based on the value of BMI, the total population was grouped as normal weight (BMI < 25 kg/m2), overweight (BMI ≥25.1–29.9 kg/m2), and obese (≥30 kg/m2). The data obtained was analyzed separately for each group and is presented as mean ± SEM. The comparisons of anthropometric parameters and biochemical and hormonal variables between overweight, obese and normal weight control subjects were carried out using the independent student’s t-test and ANOVA.

The data were further grouped according to the three genotypes of ARDB1 and ARDB3 genes, and the anthropometric measurements, age, BMI, fasting serum insulin, leptin, glucose level and lipid profile, were compared by the Mann-Whitney U- test. To study the influence of the ARDB1 and ARDB3 genotypes on BMI, multivariable logistic regression was used. The different parameters were correlated using Pearson’s correlation coefficient (r), and the p-value was obtained. Frequency distribution analysis was performed using the chi-square test, and frequencies of the different alleles in different groups (normal, overweight and obese) were compared. Relative risk was estimated by the odds ratios (ORs) and their 95% confidence intervals (CIs), and a p-value ≤0.05 was considered statistically significant.


Obesity-related anthropometric and biochemical characteristics

Using a BMI cut-off point of BMI < 25 kg/m2, BMI ≥ 25.1–29.9 kg/m2) and BMI > 30 kg/m2 for normal weight, overweight and obese, as recommended by the World Health Organization [55] there were 115, 68, 146 individuals in the normal weight, overweight and obese groups, respectively. The anthropometric characteristics of the study subjects are presented in Table 1. All the three groups matched in their age and no statistically significant differences were observed amongst the groups. All other parameters except HDL, were significantly higher in overweight and obese subjects as compared to the normal weight (control) group (p < 0.0001) as shown in Table 1. The results of biochemical and hormonal parameters are presented in Table 2 for the three groups. The value for each parameter was elevated significantly, in the overweight and obese subjects, except HDL, which was significantly lower when compared to the normal weight group (Table 2).

Table 1 Anthropometric characteristics of control, overweight and obese study subjects
Table 2 Comparisons of clinical parameters amongst control, overweight and obese study subjects

Polymorphism in ADRB1 Arg389Gly genotype

The genotype and allele frequencies of the ADRB1 Arg389Gly (rs1801253) polymorphism were calculated in each group and results were compared. There was no significant difference in the genotype and allelic frequency of ADRB1 Arg389Gly between control and obese or overweight subjects, as shown in Table 3. The ADRB1 genotypes (CC, CG, GG) were grouped separately, and the phenotypic characteristics, biochemical and hormonal parameters were calculated separately for each genotype. No significant differences were observed in the results obtained for the three genotypes (Table 4).

Table 3 Distribution of the genotypes, allele’s frequencies and odd ratio of the ADRB1 Arg389Gly polymorphism in control, overweight and obese subjects
Table 4 Phenotypic characteristics of subjects grouped according to ADRB1 polymorphism at Codon 389

Polymorphism in ADRB3 Trp64Arg genotype

The frequencies of Trp64Arg (rs4994) alleles and genotypes were calculated. The overweight and obese subjects had a significantly higher genotype and allele frequency of Arg64 compared with normal weight subjects. The genotype and allele frequencies in the total group, are presented in Table 5 with the OR, CI, χ2 and p-value. Furthermore, the study groups were separated according to their Trp64Arg genotypes (TT, TC, CC), and the phenotypic characteristics were obtained. The value of the different parameters in the different genotypes is presented in Table 6. This Table shows that the subjects carrying Arg64 in the homozygous state had a greater BMI, waist and hip circumference, W/H ratio, cholesterol, triglyceride, LDL-C, and plasma leptin, insulin, and glucose compared with those with the Trp64Trp and Trp64Arg genotypes, and the difference was significant. However, the decrease in HDL level was not statistically significant (p-value = 0.335) in individuals with different ADRB3 genotypes (Table 6).

Table 5 The genotypes and allele frequencies of ADRB3 Trp64Arg polymorphism in control, overweight and obese subjects
Table 6 Phenotypic Characteristics of subjects grouped according to ADRB3 polymorphism at Codon 64


This is the first study to report the relationship between ADRB1 and ADRB3 gene polymorphism and obesity-related phenotypes in the Saudi population. Since in our previous report, we had observed an association between Gln27Glu polymorphism of ADRB2 gene, obesity, and other related disorders in Saudi population [9] our interest was to explore if any association existed between ADRB1 (rs1801253) and ADRB3 (rs4994) and these abnormalities. Hence, during this study, a large cohort of 329 subjects was genotyped for Gly389Arg in ADRB1 (rs1801253) and Trp64Arg in ADRB3 (rs4994) genes and the association of the variant allele with metabolic parameters were analyzed. The results of our investigation have clearly highlighted the strong association with ADRB3 polymorphism, where the mutant Arg allele in ADRB3, significantly associates with a greater body weight and higher BMI, elevated leptin and dyslipidaemias both in heterozygous and homozygous. It also results in elevated blood glucose level and hyperinsulinaemia. However, the ADRB1 polymorphism Arg389Gly, shows no association either with the BMI or related disorders. The ADRB1 is a candidate gene for obesity due to its role in catecholamine mediated energy homeostasis. In 2008, Ohshiro and coworkers had shown a strong association between mutations in the ADRB1 and massive obesity in Japanese [56]. In obese individuals, the degree of weight loss during a very low calorie diet has been shown to correlate with changes in ADRB1 protein concentration in adipose tissue [57, 58]. An investigation involving a population cohort of 761 women indicated that women carrying the Gly49 genotype had greater elevation in BMI over 15 years compared to those with the Ser49 genotype [59]. Dionne et al., [7] reported that Gly389Arg exhibited a strong relationship with obesity in Caucasian women. In contrast, some studies have reported the Arg389Gly polymorphism had no significant relationship to obesity in Danish [21], Swedish [60] and Japanese [56] subjects, suggesting that it has no role in human obesity. Masuo and Lambert [10] have reviewed various studies about the relationship of polymorphism in either Gly49-Gly389 or Ser49Gly- Arg389Gly in ADRB1 with obesity or obesity related disorders and have reported contradicting findings among different populations which means that the relationship of ADRB1 polymorphism to obesity could vary between different populations. In fact, our findings for Arg389 Gly polymorphism in ADRB1 amongst Saudi population are in line with earlier published reports [7, 21, 61, 62] and suggest that ADRB1 Arg389Gly polymorphisms do not contribute to obesity and related disorders in the Saudi population.

The ADRB3 gene is expressed in adipose tissues and stimulates the mobilization of lipids from the WAT and increases thermo-genesis in BAT [10]. Mutation of ADRB3 in WAT could slow lipolysis and thereby cause the retention of lipids in adipocytes and may contribute to visceral obesity in humans. Interestingly, extensive studies have investigated the role of Trp64Arg (rs4994) in the development of obesity, T2DM, hypertension (HT), cardiovascular disease CAD, dyslipidaemias. Table 7 summarizes some of the studies reported from different populations and shows that there are extensive contradictions between populations, between genders and within different female age groups. Some studies suggest a strong relationship between obesity and Trp64Arg polymorphism in some populations [20, 26,27,28, 31,32,33, 35, 37,38,39,40, 45, 48, 51, 61,61,65]. Whereas, other studies on same or different populations have failed to show any association [21, 36, 41, 46, 49, 50, 52]. Even within the same population there are contradictory reports (Table 7). This makes the study of Trp64Arg polymorphism necessary in every population. The present study has found a strong relationship between obesity and Trp64Arg polymorphism in the Saudi population. This is a similar association that we have shown earlier to exist between Gln27Glu polymorphism in ADRB2 gene and obesity related disorders such as hypertriglyceridemia, hyperinsulinemia, and hyperleptinemia in Saudis [9].

Table 7 Studies reporting the association of Trp64Arg (rs4994) with obesity and obesity-related disorders in different populations

The ADRB2 and ARDB3 gene polymorphisms may act as predictive markers for obesity and obesity related disorders in Saudis.


Our present results shows for the first time that obesity and related disorders in Saudis are linked to polymorphism of Trp64Arg (rs4994) in ADRB3 gene but not to Arg389Gly (rs1801253) in ARDB1 gene.



β1-adrenoceptor, β3


β2 beta-adrenoceptor


β3 beta-adrenoceptor




Brown adipose tissue


Body mass index


Cardiovascular disease


95% confidence interval


Ethylenediaminetetraacetic acid




High-density lipoprotein



kg/m2 :

Kilogram/m square


Low-density lipoprotein








Odds ratio




Polymerase chain reaction




Pearson’s correlation coefficient




Standard Error of the Mean


Single nucleotide polymorphism


Diabetes mellitus Type 2




Uncoupling protein-1


White adipose tissue


Waist-to-hip ratio


  1. Warsy AS, El-Hazmi MA. Diabetes mellitus, hypertension and obesity-common multifactorial disorders in Saudis. East Mediterr Health J. 1999;5(6):1236–42. PubMed PMID: 11924118

    PubMed  CAS  Google Scholar 

  2. El-Hazmi MA, Warsy AS. Prevalence of overweight and obesity in diabetic and non-diabetic Saudis. East Mediterr Health J. 2000;6(2–3):276–82. PubMed PMID: 11556013

    PubMed  CAS  Google Scholar 

  3. Mokdad AH, Bowman BA, Engelgau MM, Vinicor F. The continuing epidemics of obesity and diabetes in the United States. JAMA. 1997;286(10):1195–200.

    Article  Google Scholar 

  4. Masuo K, Mikami H, Ogihara T. Tuck ML familial obesity, sympathetic activation and blood pressure level. Blood Press. 2001;10(4):199–204.

    Article  PubMed  CAS  Google Scholar 

  5. Cui J, Hopper JL, Harrap SB. Genes and family environment explain correlations between blood pressure and body mass index. Hypertension. 2002;40(1):7–12.

    Article  PubMed  CAS  Google Scholar 

  6. Biery AJ, Ebbesson SO, Shuldiner AR, Boyer BB. The beta(3)-adrenergic receptor TRP64ARG polymorphism and obesity in Alaskan Eskimos. Int J Obes Relat Metab Disord. 1997;21(12):1176–9.

    Article  PubMed  CAS  Google Scholar 

  7. Dionne IJ, Garant MJ, Nolan AA, Pollin TI, Lewis DG, Shuldiner AR, Poehlman ET. Association between obesity and a polymorphism in the beta(1)-adrenoceptor gene (Gly389Arg ADRB1) in Caucasian women. Int J Obes Relat Metab Disord. 2002;26(5):633–9.

    Article  PubMed  CAS  Google Scholar 

  8. Pereira AC, Floriano MS, Mota GF, Cunha RS, Herkenhoff FL, Mill JG, Krieger JE. Beta2 adrenoceptor functional gene variants, obesity, and blood pressure level interactions in the general population. Hypertension. 2003;42(4):685–92.

    Article  PubMed  CAS  Google Scholar 

  9. Daghestani MH, Warsy A, Daghestani MH, Al-Odaib AN, Eldali A, Al-Eisa NA, Al-Zahrani S. The Gln27Glu polymorphism in beta2-adrenergic receptor gene is linked to hypertriglyceridemia, hyperinsulinemia and hyperleptinemia in Saudis. Lipids Health Dis. 2010;9:90–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Masuo K, Lambert GW. Relationships of adrenoceptor polymorphisms with obesity. J Obes. 2011;2011:609485. Epub 2011 Apr 4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Skeberdis VA. Structure and function of beta3-adrenergic receptors. Med (Kaunas). 2004;40(5):407–13.

    Google Scholar 

  12. Lafontan M, Berlan M. Fat cell adrenergic receptor and the control of white and brown fat cell function. J Lipid Res. 1993;34(7):1057–91.

    PubMed  CAS  Google Scholar 

  13. Blaak EE, van Baak MA, Kempen KP, Saris WH. Role of alpha- and beta-adrenoceptors in sympathetically mediated thermogenesis. Am J Phys. 1993;264(1):E11–7.

    CAS  Google Scholar 

  14. Hagström-Toft E, Enoksson S, Moberg E, Bolinder J, Arner P. Beta-adrenergic regulation of lipolysis and blood flow in human skeletal muscle in vivo. Am J Phys. 1998;275(1):E909–16.

    Google Scholar 

  15. Monroe MB, Seals DR, Shapiro LF, Bell C, Johnson D, Parker JP. Direct evidence for tonic sympathetic support of resting metabolic rate in healthy adult humans. Am J Physiol Endocrinol Metab. 2001;280(5):E740–4.

    Article  PubMed  CAS  Google Scholar 

  16. Iwashita S, Tanida M, Terui N, Ootsuka Y, Shu M, Kang D, Suzuki M. Direct measurement of renal sympathetic nervous activity in high-fat diet-related hypertensive rats. Life Sci. 2002;71(5):537–46.

    Article  PubMed  CAS  Google Scholar 

  17. Enoksson S, Talbot M, Rife F, Tamborlane WV, Shervin RS, Caprio S. Impaired in vivo stimulation of lipolysis in adipose tissue by selective beta2-adrenergic agonist in obese adolescent girls. Diabetes. 2000;49(12):2149–53.

    Article  PubMed  CAS  Google Scholar 

  18. Large V, Hellstrom L, Reynisdottir S, Longvist F, Eriksson P, Lannfelt L, Arner P. Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. J Clin Invest. 1997;100(12):3005–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Hellström L, Large V, Reynisdottir S, Wahrenberg H, Arner P. The different effects of a Gln27Glu beta 2-adrenoceptor gene polymorphism on obesity in males and in females. J Intern Med. 1999;245(3):253–9.

    Article  PubMed  Google Scholar 

  20. Masuo K, Katsuya T, Fu Y, Rakugi H, Ogihara T, Tuck ML. Beta2- and beta3-adrenergic receptor polymorphisms are related to the onset of weight gain and blood pressure elevation over 5 years. Circulation. 2005;111(25):3429–34.

    Article  PubMed  CAS  Google Scholar 

  21. Gjesing AP, Andersen G, Albrechtsen A, Glümer C, Borch-Johnsen K, Jørgensen T, Hansen T, Pedersen O. Studies of associations between the Arg389Gly polymorphism of the beta1-adrenergic receptor gene (ADRB1) and hypertension and obesity in 7677 Danish white subjects. Diabet Med. 2007;24(4):392–7.

    Article  PubMed  CAS  Google Scholar 

  22. Nonen S, Yamamoto I, Liu J, Maeda M, Motomura T, Igarashi T, Fujio Y, Azuma J. Adrenergic beta1 receptor polymorphism (Ser49Gly) is associated with obesity in type II diabetic patients. Biol Pharm Bull. 2008;31(2):295–8.

    Article  PubMed  CAS  Google Scholar 

  23. Kim JY, Lee SS. The effects of uncoupling protein 1 and beta3-adrenergic receptor gene polymorphisms on weight loss and lipid profiles in obese women. Int J Vitam Nutr Res. 2010;80(2):87–96.

    Article  PubMed  CAS  Google Scholar 

  24. Yamakita M, Ando D, Tang S, Yamagata Z. The Trp64Arg polymorphism of the beta3-adrenergic receptor gene is associated with weight changes in obese Japanese men: a 4-year follow-up study. J Physiol Anthropol. 2010;29(4):133–9.

    Article  PubMed  Google Scholar 

  25. Ruiz JR, Larrarte E, Margareto J, Ares R, Labayen I. The Arg 389 Gly beta1-adrenergic receptor gene polymorphism and human fat cell lipolysis. Int J Obes Relat Metab Disord. 2011;25(11):1599–603.

    Google Scholar 

  26. Ryuk JA, Zhang X, Ko BS, Daily JW, Park S. Association of β3-adrenergic receptor rs4994 polymorphisms with the risk of type 2 diabetes: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2017;129:86–96. Epub 2017 May 5. PubMed PMID: 28521197

    Article  PubMed  CAS  Google Scholar 

  27. Yang H, Cai D, Zhu Q, Wu D, Wang Q, Wang Z. The mutation of Trp64Arg in β3-adrenoreceptor-encoding gene is significantly associated with increased hypertension risk and elevated blood pressure: a meta-analysis. Oncotarget. 2017; [Epub ahead of print] PubMed PMID:28404887

  28. Csernus K, Pauler G, Erhardt É, Lányi É, Molnár D. Effects of energy expenditure gene polymorphisms on obesity-related traits in obese children. Obes Res Clin Pract. 2015;9(2):133–40. Epub 2014 Jul 8. PubMed PMID: 25081806

    Article  PubMed  Google Scholar 

  29. Burguete-Garcia AI, Martinez-Nava GA, Valladares-Salgado A, Bermudez Morales VH, Estrada-Velasco B, Wacher N, et al. Association of β1 and β3 adrenergic receptors gene polymorphisms with insulin resistance and high lipid profiles related to type 2 diabetes and metabolic syndrome. Nutr Hosp. 2014;29(6):1327–34. PubMed PMID: 24972470

    Article  PubMed  CAS  Google Scholar 

  30. Kumar S, Mishra A, Srivastava A, Mittal T, Garg N, Mittal B. Significant role of ADRB3 rs4994 towards the development of coronary artery disease. Coron Artery Dis. 2014;25(1):29–34. PubMed PMID:24201118

    Article  PubMed  Google Scholar 

  31. Brondani LA, Duarte GC, Canani LH, Crispim D. The presence of at least three alleles of the ADRB3 Trp64Arg (C/T) and UCP1 -3826A/G polymorphisms is associated with protection to overweight/obesity and with higher high-density lipoprotein cholesterol levels in Caucasian-Brazilian patients with type 2 diabetes. Metab Syndr Relat Disord. 2014;12(1):16–24. Epub 2013 Oct 18. PubMed PMID: 24138564

    Article  PubMed  CAS  Google Scholar 

  32. Oguri K, Tachi T, Matsuoka T. Visceral fat accumulation and metabolic syndrome in children: the impact of Trp64Arg polymorphism of the beta3-adrenergic receptor gene. Acta Paediatr. 2013;102(6):613–9. Epub 2013 Jan 22. PubMed PMID: 23282015

    Article  PubMed  CAS  Google Scholar 

  33. Baturin AK, Pogozheva AV, Sorokina EI, Makurina ON, Tutel'ian VA. The Trp64Arg polymorphism of beta3-adrenoreceptor gene study in persons with overweight and obesity. Vopr Pitan. 2012;81(2):23–7. PubMed PMID:22774474

    PubMed  CAS  Google Scholar 

  34. Sasayama D, Hori H, Teraishi T, Hattori K, Ota M, Tatsumi M, Higuchi T, Amano N, Kunugi H. Possible impact of ADRB3 Trp64Arg polymorphism on BMI in patients with schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2012;38(2):341–4. Epub 2012 May 17. PubMed PMID: 22609474

    Article  CAS  Google Scholar 

  35. Takeuchi S, Katoh T, Yamauchi T, Kuroda Y. ADRB3 polymorphism associated with BMI gain in Japanese men. Exp Diabetes Res. 2012:973561. Epub 2012 Apr 8. PubMed PMID: 22550477; PubMed Central.PMCID: PMC3328897

  36. Chou YC, Tsai CN, Lee YS, Pei JS. Association of adrenergic receptor gene polymorphisms with adolescent obesity in Taiwan. Pediatr Int. 2012;54(1):111–6. PubMed PMID: 22115535

    Article  PubMed  CAS  Google Scholar 

  37. Mirrakhimov AE, Kerimkulova AS, Lunegova OS, Moldokeeva CB, Zalesskaya YV, Abilova SS, et al. An association betweenTRP64ARG polymorphism of the B3 adrenoreceptor gene and some metabolic disturbances. Cardiovasc Diabetol. 2011;10:89. PubMed PMID: 21992420; PubMed Central PMCID: PMC3215178

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Malik SG, Saraswati MR, Suastika K, Trimarsanto H, Oktavianthi S, Sudoyo H. Association of beta3-adrenergic receptor (ADRB3) Trp64Arg gene polymorphism with obesity and metabolic syndrome in the Balinese: a pilot study. BMC Res Notes. 2011;4:167. PubMed PMID: 21619577; PubMed Central PMCID: PMC3121622

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Cruz M, Valladares-Salgado A, Garcia-Mena J, Ross K, Edwards M, Angeles-Martinez J, et al. Candidate gene association study conditioning on individual ancestry in patients with type 2 diabetes and metabolic syndrome from Mexico City. Diabetes Metab Res Rev. 2010;26(4):261–70. PubMed PMID: 20503258

    Article  PubMed  CAS  Google Scholar 

  40. Kurokawa N, Young EH, Oka Y, Satoh H, Wareham NJ, Sandhu MS, et al. The ADRB3 Trp64Arg variant and BMI: a meta-analysis of 44 833 individuals. Int J Obes. 2008;32(8):1240–9. Epub 2008 Jun 24. Review. PubMed PMID: 18574485

    Article  CAS  Google Scholar 

  41. Rooyen JM, Pretorius PJ, Britz M, Huisman HW, Schutte AE, Towers GW, et al. Genetic polymorphisms of beta2- and beta3-adrenergic receptor genes associated with characteristics of the metabolic syndrome in black south African women. Exp Clin Endocrinol Diabetes. 2008;116(4):236–40. PubMed PMID: 18393130

    Article  PubMed  CAS  Google Scholar 

  42. Dunajska K, Lwow F, Milewicz A, Jedrzejuk D, Laczmanski L, Belowska-Bien K, et al. Beta(3)-adrenergic receptor polymorphism and metabolic syndrome in postmenopausal women. Gynecol Endocrinol. 2008;24(3):133–8. PubMed PMID: 18335327

    Article  PubMed  CAS  Google Scholar 

  43. Zafarmand MH, van der Schouw YT, Grobbee DE, de Leeuw PW, Bots ML. T64A polymorphism in beta3-adrenergic receptor gene (ADRB3) and coronary heart disease: a case-cohort study and meta-analysis. J Intern Med. 2008;263(1):79–89. PubMed PMID: 18088254

    Article  PubMed  CAS  Google Scholar 

  44. Morcillo S, Cardona F, Rojo-Martínez G, Almaraz MC, Esteva I, Ruiz-De-Adana MS, et al. Effect of the combination of the variants -75G/a APOA1 and Trp64Arg ADRB3 on the risk of type 2 diabetes (DM2). Clin Endocrinol. 2008;68(1):102–7. Epub 2007 Aug 28. PubMed PMID: 17727676

    Article  CAS  Google Scholar 

  45. Tamaki S, Nakamura Y, Tabara Y, Okamura T, Kita Y, Kadowaki T, et al. Relationship between metabolic syndrome and Trp64arg polymorphism of the beta-adrenergic receptor gene in a general sample: the Shigaraki study. Hypertens Res. 2006;29(11):891–6. PubMed PMID: 17345789

    Article  PubMed  CAS  Google Scholar 

  46. Bracale R, Pasanisi F, Labruna G, Finelli C, Nardelli C, Buono P, et al. Metabolic syndrome and ADRB3 gene polymorphism in severely obese patients from South Italy. Eur J Clin Nutr. 2007;61(10):1213–9. Epub 2007 Feb 14. PubMed PMID: 17299491

    Article  PubMed  CAS  Google Scholar 

  47. Wang CY, Nguyen ND, Morrison NA, Eisman JA, Center JR, Nguyen TV. Beta3-adrenergic receptor gene, body mass index, bone mineral density and fracture risk in elderly men and women: the Dubbo osteoporosis epidemiology study (DOES). BMC Med Genet. 2006;7:57. PubMed PMID: 16820065; PubMed Central PMCID: PMC1559683

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Matsushita Y, Yokoyama T, Yoshiike N, Matsumura Y, Date C, Kawahara K, et al. 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. J Clin Endocrinol Metab. 2003;88(12):5914–20.

    Article  PubMed  CAS  Google Scholar 

  49. Santos JL, Pérez-Bravo F, Martínez JA, Montalvo D, Albala C, Carrasco E. No evidence for an association between genetic polymorphisms of beta(2)- and beta(3)-adrenergic receptor genes with body mass index in Aymara natives from Chile. Nutrition. 2002;18(3):255–8. PubMed PMID: 11882399

    Article  PubMed  CAS  Google Scholar 

  50. Kurokawa N, Nakai K, Kameo S, Liu ZM, Satoh H. Association of BMI with the beta3-adrenergic receptor gene polymorphism in Japanese: meta-analysis. Obes Res. 2001;9(12):741–5. PubMed PMID: 11743057

    Article  PubMed  CAS  Google Scholar 

  51. Lowe WL Jr, Rotimi CN, Luke A, Guo X, Zhu X, Comuzzie AG, et al. The beta 3-adrenergic receptor gene and obesity in a population sample of African Americans. Int J Obes Relat Metab Disord. 2001;25(1):54–60. PubMed PMID: 11244458

    Article  PubMed  CAS  Google Scholar 

  52. Gagnon J, Mauriège P, Roy S, Sjöström D, Chagnon YC, Dionne FT, et al. The Trp64Arg mutation of the beta3 adrenergic receptor gene has no effect on obesity phenotypes in the Québec family study and Swedish obese subjects cohorts. J Clin Invest. 1996;98(9):2086–93. PubMed PMID: 8903328; PubMed Central PMCID: PMC507653

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Hameed I, Masoodi SR, Afroze D, Naykoo NA, Bhat RA, Ganai BA. Trp homozygotes at codon 64 of ADRB3 gene are protected against the risk of type 2 diabetes in the Kashmiri population. Genet Test Mol Biomarkers. 2013;17(10):775–9. Epub 2013 Aug 22. PubMed PMID: 23968135

    Article  PubMed  CAS  Google Scholar 

  54. WHO. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser. 2000;0:i-xii, 1–253.

    Google Scholar 

  55. Ohshiro Y, Hayashi M, Yabiku K, Ueda K, Wakasaki H, Ishigame M, et al. Mutations in the β1 adrenergic receptor gene and massive obesity in Japanese. Diab Res Clin Prac. 2008;80(2):213–7.

    Article  CAS  Google Scholar 

  56. Rasmussen M, Belza A, Almdal T, Toubro S, Bratholm P, Astrup A, et al. Change in beta1-adrenergic receptor protein concentration in adipose tissue correlates with diet-induced weight loss. Clin Sci (Lond). 2005;108(4):323–9.

    Article  CAS  Google Scholar 

  57. Masuo K. Roles of Beta2- and Beta3-adrenoceptor polymorphisms in hypertension and metabolic syndrome. Int J Hypertens. 2010:832821. Published online 2010 Oct 21. doi:

  58. Linné Y, Dahlman I, Hoffstedt J. beta1-adrenoceptor gene polymorphism predicts long-term changes in body weight. Int J Obes. 2005;29(5):458–62.

    Article  CAS  Google Scholar 

  59. Rydén M, Hoffstedt J, Eriksson P, Bringman S, Arner P. The Arg 389 Gly beta1-adrenergic receptor gene polymorphism and human fat cell lipolysis. Int J Obes Relat Metab Disord. 2001;25(11):1599–603.

    Article  PubMed  Google Scholar 

  60. Clement K, Vaisse C, Manning BS, Basdevant A, Guy-Grand B, Ruiz J, et al. Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. N Engl J Med. 1995;333(6):352–4.

    Article  PubMed  CAS  Google Scholar 

  61. Sakane N, Yoshida T, Umekawa T, Kogure A, Takakura Y, Kondo M. Effects of Trp64Arg mutation in the beta 3-adrenergic receptor gene on weight loss, body fat distribution, glycemic control, and insulin resistance in obese type 2 diabetic patients. Diabetes Care. 1997;20(12):1887–90.

    Article  PubMed  CAS  Google Scholar 

  62. Umekawa T, Yoshida T, Sakane N, Kogure A, Kondo M, Honjyo H. Trp64Arg mutation of beta3-adrenoceptor gene deteriorates lipolysis induced by beta3-adrenoceptor agonist in human omental adipocytes. Diabetes. 1999;48(1):117–20.

    Article  PubMed  CAS  Google Scholar 

  63. Endo K, Yanagi H, Hirano C, Hamaguchi H, Tsuchiya S, Tomura S. Association of Trp64Arg polymorphism of the beta3-adrenergic receptor gene and no association of Gln223Arg polymorphism of the leptin receptor gene in Japanese school children with obesity. Int J Obes Relat Metab Disord. 2002;24(4):443–9.

    Article  CAS  Google Scholar 

  64. Oizumi T, Daimon M, Saitoh T, Kameda W, Yamaguchi H, Ohnuma H, et al. Funagata diabetes study. Genotype Arg/Arg, but not Trp/Arg, of the Trp64Arg polymorphism of the beta(3)-adrenergic receptor is associated with type 2 diabetes and obesity in a large Japanese sample. Diabetes Care. 2001;24(9):1579–83.

    Article  PubMed  CAS  Google Scholar 

  65. Kawaguchi H, Masuo K, Katsuya T, Sugimoto K, Rakugi H, Ogihara T, et al. beta2- and beta3-adrenoceptor polymorphisms relate to subsequent weight gain and blood pressure elevation in obese normotensive individuals. Hypertens Res. 2006;29(12):951–9.

    Article  PubMed  CAS  Google Scholar 

Download references


The authors extend their appreciation to the National Plan for Science, Technology and Innovation (MAARIFAH), King Abdul-Aziz City for Science and Technology, Kingdom of Saudi Arabia, grant Number No 08-MED 604-2.


This Work was funded by the National Plan for Science, Technology and Innovation (MAARIFAH), King Abdul-Aziz City for Science and Technology, Kingdom of Saudi Arabia, grant Number No 08-MED 604-2.

Availability of data and materials

All data is available with the authors and can be provided when required.

Author information

Authors and Affiliations



MD1, ZKH, MHE and AW designed the experiment, carried all the experiments, prepared the tables and drafted the manuscript. MD2 and MD3 arranged the subjects/samples of the study. MD and AW drafted of the manuscript. AME, ZKH and MHE participated in the manuscript revision. AME and AW performed all the statistical analysis. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Arjumand Warsy.

Ethics declarations

Ethics approval and consent to participate

The ethical approval for this study was obtained from the local Institutional Review Board (IRB) at the Umm Al Qura University, Makkah Al Mukaramah, Saudi Arabia (IRB No. 235). Written informed consent was obtained from all study subjects before their participation.

Consent for publication

All authors have read and agreed to the contents of the manuscript and approved the submission.

Competing interests

The authors declare no conflicts of interest, state that the manuscript has not been published or submitted elsewhere, state that the work complies with Ethical Policies of the Journal and the work has been conducted under internationally accepted ethical standards after relevant ethical review.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Daghestani, M., Daghestani, M., Daghistani, M. et al. ADRB3 polymorphism rs4994 (Trp64Arg) associates significantly with bodyweight elevation and dyslipidaemias in Saudis but not rs1801253 (Arg389Gly) polymorphism in ARDB1. Lipids Health Dis 17, 58 (2018).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: