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Zafari Zangeneh, F., Sarmast Shoushtari, M., Shojaee, S., & Aboutorabi, E. (2020). Investigation Trp64Arg polymorphism of the beta 3-adrenergic receptor gene in nonobese women with polycystic ovarian syndrome. International Journal of Reproductive BioMedicine (IJRM), 18(3), 165–174. https://doi.org/10.18502/ijrm.v18i3.6712
https://doi.org/10.18502/ijrm.v18i3.6712
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Farideh Zafari Zangeneh
Farideh Zafari Zangeneh
Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Maryam Sarmast Shoushtari
Maryam Sarmast Shoushtari
Department of Chemical and Environment, Faculty of Engineering, UPM, Selangor, Malaysia.
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Sahar Shojaee
Sahar Shojaee
Cell Therapy Center, Gandhi Hospital, Tehran, Iran.
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Elahe Aboutorabi
Elahe Aboutorabi
Department of Genetics, Islamic Azad University Science and Research Branch, Tehran, Iran.
Published Date
- Apr 5, 2020
Investigation Trp64Arg polymorphism of the beta 3-adrenergic receptor gene in nonobese women with polycystic ovarian syndrome
Abstract
Background: Polycystic ovary syndrome (PCOS) is a multifactorial and heterogeneous disease that has a potent inheritable component based on familial clustering. Despite many studies in the genetic field of PCOS, the genes that are involved in the causes of this syndrome have not been thoroughly investigated.
Objective: The purpose of this study was to establish the occurrence of the Trp64Arg polymorphism of beta3 adrenergic receptor in non-obese women with PCOS.
Materials and Methods: This cross-sectional study was performed on 100 women with PCOS and normal women as the control group in Imam Khomeini Hospital of Tehran in 2016-2017. Peripheral blood sample (2 cc) was obtained from two groups for genomic DNA based on the gene bank. Polymorphisms were genotyped by of using ADRB3 Trp64Arg. Then the DNA was extracted by genomic kiagen kit. The primer was analyzed for PCR based on gene bank by using Primer3 software and then confirmed by primer Blast tool at NCBI site to conformity to the beta-3 adrenergic receptor gene. The protein changes were assessment by the Clastal W software.
Results: The sequence analysis presented in NCBI, transcript variant 1, with the code NM_000025.2, shows changes in the amino acid sequence of exon 1 in women with PCOS. Polymorphism in the codon 64 encoding the amino acid tryptophan (W) occurred in the nucleotide c.T190C, which changed the nucleotide T to C and then the amino acid sequence of the tryptophan was altered to arginine pW64R.
Conclusion: T-C polymorphism is evident in the codon 64 of the adrenergic β3 receptor in patients with PCOS. Therefore, Beta3 adrenergic receptor gene polymorphism (Thr164Ile) associates with this syndrome in nonobese women.
Key words: Codon 64, Beta-3 adrenergic receptor, Polymorphism, Polycystic ovarian syndrome.
References
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[4] Labbé SM, Caron A, Lanfray D, Monge-Rofarello B, Bartness TJ, Richard D. Hypothalamic control of brown adipose tissue thermogenesis. Front Syst Neurosci 2015; 9: 150.
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[6] Zhang H, Wu J, Yu L. Association of Gln27Glu and Arg16Gly polymorphisms in Beta2-adrenergic receptor gene with obesity susceptibility: A meta-analysis. PLoS One 2014; 9: e100489.
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[11] Xu W, Liu Y, Ye D. Association between IL-33 gene polymorphisms (rs1929992, rs7044343) and systemic lupus erythematosus in a chinese han population. Immunol Invest 2016; 45: 575–583.
[12] Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81: 19–25.
[13] Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elía E, Kessler SH, Kahn PA, et al. Actvation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab 2015; 21: 33–38.
[14] Fratantonio E, Vicari E, Pafumi C, Calogero AE. Genetics of polycystic ovarian syndrome. Reprod Biomed Online 2005; 10: 713–720.
[15] Jahanfar S, Eden JA. Genetic and non-genetic theories on the etiology of polycystic ovary Syndrome. Gynecol Endocronol 1996; 10: 357–364.
[16] Obermayer-Pietsch B, Trummer C, Schwetz V, Schweighofer N, Pieber T. Genetics of insulin resistance in polycystic ovary syndrome. Curr Opin Clin Nutr Metab Care 2015; 18: 401–406.
[17] Dadachanji R, Shaikh N, Mukherjee S. Genetic variants associated with hyperandrogenemia in pcos pathophysiology. Genet Res Int 2018; 2018: 7624932.
[18] De Leo V, Musacchio MC, Cappelli V, Massaro MG, Morgante G, Petraglia F. Genetic, hormonal and metabolic aspects of PCOS: an update. Reprod Biol Endocrinol 2016; 14: 38.
[19] Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. The androgen excess and PCOS society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009; 91: 456–488.
[20] Bartelt A, Heeren J. Adipose tissue browning and metabolic health. Nat Rev Endocrinol 2014; 10: 24–36.
[21] Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009; 360: 1509–1517.
[22] Pfannenberg C, Werner MK, Ripkens S, Stef I, Deckert A, Schmadl M, et al. Impact of age on the relationships of brown adipose tissue with sex and adiposity in humans. Diabetes 2010; 59: 1789–1793.
[23] Wang Q, Zhang M, Ning G, Gu W, Su T, Xu M, et al. Brown adipose tissue in humans is activated by elevated plasma catecholamines levels and is inversely related to central obesity. PLoS One 2011; 6: e21006.
[24] 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 (Lond) 2008; 32: 1240–1249.
[25] Baturin AK, Pogozheva AV, Sorokina EIu, Makurina ON, Tutel’ian VA. The Trp64Arg polymorphism of beta3- adrenoreceptor gene study in persons with overweight and obesity. Vopr Pitan 2012; 81: 23–27.
[26] Nolsøe RL, Hamid YH, Pociot F, Paulsen S, Andersen KM, Borch-Johnsen K, et al. Association of a microsatellite in FASL to type II diabetes and of the FAS-670G>A genotype to insulin resistance. Genes Immun 2006; 7: 316–321.
[27] Li YY, Lu XZ, Wang H, Zhou YH, Yang XX, Geng HY, et al. ADRB3 Gene Trp64Arg polymorphism and essential hypertension: A meta-analysis including 9,555 subjects. Front Genet 2018; 9: 106–115.
[28] 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 metaanalysis. Diabetes Res Clin Pract 2017; 129: 86–96.
[29] Guan L, Cui X, Zhou H. Meta-analysis of the association between the Trp64Arg polymorphism of the beta-3 adrenergic receptor and susceptibility to gestational diabetes mellitus. J Obstet Gynaecol 2018; 38: 172–176.
[30] Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 2008; 454: 1000–1004.
[31] Mund RA, Frishman WH. Brown adipose tissue thermogenesis: β3-adrenoreceptors as a potential target for the treatment of obesity in humans. Cardiol Rev 2013; 21: 265–269.
[32] Fujisawa T, Ikegami H, Yamato E, Takeawa K, Nakagawa Y, Hamada Y, et al. Association of Trp64Arg mutation of the β3-adrenergic-receptor with NIDDM and body weight gain. Diabetologia 1996; 39: 349–352.
[33] Berthoud HR. Mind versus metabolism in the control of food intake and energy balance. Physiol Behav 2004; 81: 781–793.
[34] Richardson RD, Omachi K, Kermani R, Woods SC. Intraventricular insulin potentiates the anorexic effect of corticotropin releasing hormone in rats. Am J Physiol Regul Integr Comp Physiol 2002; 283: R1321–R1326.
[35] Lu B, Diz-Chaves Y, Markovic D, Contarino A, Penicaud L, Fanelli F, et al. The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms. Int J Obes (Lond). 2015; 39: 408–17.
[36] Smith SR, de Jonge L, Pelleymounter M, Nguyen T, Harris R, York D, et al. Peripheral administration of human corticotropin-releasing hormone: a novel method to increase energy expenditure and fat oxidation in man. J Clin Endocrinol Metab 2001; 86: 1991–1998.
[37] Mastorakos G, Karoutsou EI, Mizamtsidi M. Corticotropin releasing hormone and the immune/inflammatory response. Eur J Endocrinol 2006; 155: S77–S84.
[38] Kiapekou E, Zapanti E, Mastorakos G, Loutradis D. Update on the role of ovarian corticotropin-releasing hormone. Ann NY Acad Sci 2010; 1205: 225–229.
[39] Zangeneh FZ, Naghizadeh MM, Bagheri M, Jafarabadi M. Are CRH & NGF as psychoneuroimmune regulators in women with polycystic ovary syndrome? Gynecol Endocrinol 2017; 33: 227–233.
[40] Solinas G, Summermatter S, Mainieri D, Gubler M, Montani JP, Seydoux J, et al. Corticotropin-releasing hormone directly stimulates thermogenesis in skeletal muscle possibly through substrate cycling between de novo lipogenesis and lipid oxidation. Endocrinology 2006; 147: 31–38.
[41] Wu S, Divall S, Nwaopara A, Radovick S, Wondisford F, Ko C, et al. Obesity-induced infertility and hyperandrogenism are corrected by deletion of the insulin receptor in the ovarian theca cell. Diabetes 2014; 63: 1270–1282.
[42] Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 2012; 33: 981– 1030.
[43] Baptiste CG, Battista MC, Trottier A, Baillargeon JP. Insulin and hyperandrogenism in women with polycystic ovary syndrome. J Steroid Biochem Mol Biol 2010; 122: 42–52.
[44] Flaa A, Aksnes TA, Kjeldsen SE, Eide I, Rostrup M. Increased sympathetic reactivity may predict insulin resistance: an 18-year follow-up study. Metabolism 2008; 57: 1422–1427.
[45] Zafari Zangeneh F, Naghizadeh MM, Masoumi M. Polycystic ovary syndrome and circulating inflammatory markers. Int J Reprod Biomed 2017; 15: 375–382.
[46] Baranwal A, Mirbolooki MR, Mukherjee J. Initial assessment of β3-adrenoceptor-activated brown adipose tissue in streptozotocin-induced type 1 diabetes rodent model using [18F] fluorodeoxyglucose positron emission tomography/computed tomography. Molecular Imaging 2015; 14: 561–566.
[47] Arch JR, Wilson S. Prospects for beta 3-adrenoceptor agonists in the treatment of obesity and diabetes. Int J Obes Relat Metab Disord 1996; 20: 191–199.
[48] Sawa M, Harada H. Recent developments in the design of orally bioavailable beta3-adrenergic receptor agonists. Curr Med Chem 2006; 13: 25–37.
[2] Dumesic DA, Padmanabhan V, Abbott DH. Polycystic ovary syndrome and oocyte developmental competence. Obstet Gynecol Surv 2008; 63: 39–48.
[3] Richard JE, López-Ferreras L, Chanclón B, Eerola K, Micalle P, Skibicka KP, et al. CNS β3-adrenergic receptor activation regulates feeding behavior, white fat browning, and body weight. Am J Physiol Endocrinol Metab 2017; 313: E344–E358.
[4] Labbé SM, Caron A, Lanfray D, Monge-Rofarello B, Bartness TJ, Richard D. Hypothalamic control of brown adipose tissue thermogenesis. Front Syst Neurosci 2015; 9: 150.
[5] Hadri KE, Charon C, Pairault J, Hauguel-De Mouzon S, Quignard-Boulangé A, Fève B. Down-regulation of beta3- adrenergic receptor expression in rat adipose tissue during the fasted/fed transition: evidence for a role of insulin. Biochem J 1997; 323: 359–364.
[6] Zhang H, Wu J, Yu L. Association of Gln27Glu and Arg16Gly polymorphisms in Beta2-adrenergic receptor gene with obesity susceptibility: A meta-analysis. PLoS One 2014; 9: e100489.
[7] 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.
[8] Weyer C, Gautier JF, Danforth E Jr. Development of beta 3-adrenoceptor agonists for the treatment of obesity and diabetes–an update. Diabetes Metab 1999; 25: 11–21.
[9] Atia A, Abdullah A, Alrawaiq N. Overview of the role of B2-adrenergic receptor variants in human hypertension. International Journal of PharmTech Research 2014; 6: 1611–1615.
[10] Reihsaus E, Innis M, MacIntyre N, Liggett SB. Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol 1993; 8: 334–339.
[11] Xu W, Liu Y, Ye D. Association between IL-33 gene polymorphisms (rs1929992, rs7044343) and systemic lupus erythematosus in a chinese han population. Immunol Invest 2016; 45: 575–583.
[12] Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81: 19–25.
[13] Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elía E, Kessler SH, Kahn PA, et al. Actvation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab 2015; 21: 33–38.
[14] Fratantonio E, Vicari E, Pafumi C, Calogero AE. Genetics of polycystic ovarian syndrome. Reprod Biomed Online 2005; 10: 713–720.
[15] Jahanfar S, Eden JA. Genetic and non-genetic theories on the etiology of polycystic ovary Syndrome. Gynecol Endocronol 1996; 10: 357–364.
[16] Obermayer-Pietsch B, Trummer C, Schwetz V, Schweighofer N, Pieber T. Genetics of insulin resistance in polycystic ovary syndrome. Curr Opin Clin Nutr Metab Care 2015; 18: 401–406.
[17] Dadachanji R, Shaikh N, Mukherjee S. Genetic variants associated with hyperandrogenemia in pcos pathophysiology. Genet Res Int 2018; 2018: 7624932.
[18] De Leo V, Musacchio MC, Cappelli V, Massaro MG, Morgante G, Petraglia F. Genetic, hormonal and metabolic aspects of PCOS: an update. Reprod Biol Endocrinol 2016; 14: 38.
[19] Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. The androgen excess and PCOS society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009; 91: 456–488.
[20] Bartelt A, Heeren J. Adipose tissue browning and metabolic health. Nat Rev Endocrinol 2014; 10: 24–36.
[21] Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009; 360: 1509–1517.
[22] Pfannenberg C, Werner MK, Ripkens S, Stef I, Deckert A, Schmadl M, et al. Impact of age on the relationships of brown adipose tissue with sex and adiposity in humans. Diabetes 2010; 59: 1789–1793.
[23] Wang Q, Zhang M, Ning G, Gu W, Su T, Xu M, et al. Brown adipose tissue in humans is activated by elevated plasma catecholamines levels and is inversely related to central obesity. PLoS One 2011; 6: e21006.
[24] 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 (Lond) 2008; 32: 1240–1249.
[25] Baturin AK, Pogozheva AV, Sorokina EIu, Makurina ON, Tutel’ian VA. The Trp64Arg polymorphism of beta3- adrenoreceptor gene study in persons with overweight and obesity. Vopr Pitan 2012; 81: 23–27.
[26] Nolsøe RL, Hamid YH, Pociot F, Paulsen S, Andersen KM, Borch-Johnsen K, et al. Association of a microsatellite in FASL to type II diabetes and of the FAS-670G>A genotype to insulin resistance. Genes Immun 2006; 7: 316–321.
[27] Li YY, Lu XZ, Wang H, Zhou YH, Yang XX, Geng HY, et al. ADRB3 Gene Trp64Arg polymorphism and essential hypertension: A meta-analysis including 9,555 subjects. Front Genet 2018; 9: 106–115.
[28] 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 metaanalysis. Diabetes Res Clin Pract 2017; 129: 86–96.
[29] Guan L, Cui X, Zhou H. Meta-analysis of the association between the Trp64Arg polymorphism of the beta-3 adrenergic receptor and susceptibility to gestational diabetes mellitus. J Obstet Gynaecol 2018; 38: 172–176.
[30] Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 2008; 454: 1000–1004.
[31] Mund RA, Frishman WH. Brown adipose tissue thermogenesis: β3-adrenoreceptors as a potential target for the treatment of obesity in humans. Cardiol Rev 2013; 21: 265–269.
[32] Fujisawa T, Ikegami H, Yamato E, Takeawa K, Nakagawa Y, Hamada Y, et al. Association of Trp64Arg mutation of the β3-adrenergic-receptor with NIDDM and body weight gain. Diabetologia 1996; 39: 349–352.
[33] Berthoud HR. Mind versus metabolism in the control of food intake and energy balance. Physiol Behav 2004; 81: 781–793.
[34] Richardson RD, Omachi K, Kermani R, Woods SC. Intraventricular insulin potentiates the anorexic effect of corticotropin releasing hormone in rats. Am J Physiol Regul Integr Comp Physiol 2002; 283: R1321–R1326.
[35] Lu B, Diz-Chaves Y, Markovic D, Contarino A, Penicaud L, Fanelli F, et al. The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms. Int J Obes (Lond). 2015; 39: 408–17.
[36] Smith SR, de Jonge L, Pelleymounter M, Nguyen T, Harris R, York D, et al. Peripheral administration of human corticotropin-releasing hormone: a novel method to increase energy expenditure and fat oxidation in man. J Clin Endocrinol Metab 2001; 86: 1991–1998.
[37] Mastorakos G, Karoutsou EI, Mizamtsidi M. Corticotropin releasing hormone and the immune/inflammatory response. Eur J Endocrinol 2006; 155: S77–S84.
[38] Kiapekou E, Zapanti E, Mastorakos G, Loutradis D. Update on the role of ovarian corticotropin-releasing hormone. Ann NY Acad Sci 2010; 1205: 225–229.
[39] Zangeneh FZ, Naghizadeh MM, Bagheri M, Jafarabadi M. Are CRH & NGF as psychoneuroimmune regulators in women with polycystic ovary syndrome? Gynecol Endocrinol 2017; 33: 227–233.
[40] Solinas G, Summermatter S, Mainieri D, Gubler M, Montani JP, Seydoux J, et al. Corticotropin-releasing hormone directly stimulates thermogenesis in skeletal muscle possibly through substrate cycling between de novo lipogenesis and lipid oxidation. Endocrinology 2006; 147: 31–38.
[41] Wu S, Divall S, Nwaopara A, Radovick S, Wondisford F, Ko C, et al. Obesity-induced infertility and hyperandrogenism are corrected by deletion of the insulin receptor in the ovarian theca cell. Diabetes 2014; 63: 1270–1282.
[42] Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 2012; 33: 981– 1030.
[43] Baptiste CG, Battista MC, Trottier A, Baillargeon JP. Insulin and hyperandrogenism in women with polycystic ovary syndrome. J Steroid Biochem Mol Biol 2010; 122: 42–52.
[44] Flaa A, Aksnes TA, Kjeldsen SE, Eide I, Rostrup M. Increased sympathetic reactivity may predict insulin resistance: an 18-year follow-up study. Metabolism 2008; 57: 1422–1427.
[45] Zafari Zangeneh F, Naghizadeh MM, Masoumi M. Polycystic ovary syndrome and circulating inflammatory markers. Int J Reprod Biomed 2017; 15: 375–382.
[46] Baranwal A, Mirbolooki MR, Mukherjee J. Initial assessment of β3-adrenoceptor-activated brown adipose tissue in streptozotocin-induced type 1 diabetes rodent model using [18F] fluorodeoxyglucose positron emission tomography/computed tomography. Molecular Imaging 2015; 14: 561–566.
[47] Arch JR, Wilson S. Prospects for beta 3-adrenoceptor agonists in the treatment of obesity and diabetes. Int J Obes Relat Metab Disord 1996; 20: 191–199.
[48] Sawa M, Harada H. Recent developments in the design of orally bioavailable beta3-adrenergic receptor agonists. Curr Med Chem 2006; 13: 25–37.