Download fulltext
HTML
Arasteh, H., Araste, F., Hasan Sheikhha, M., Mehdi Kalantar, S., Farashahi Yazd, E., Reza Ashrafzadeh, H., & Ghasemi, N. (2022). Evaluation of CAG repeat length in the androgen receptor gene and polycystic ovary syndrome risk in Iranian women: A case-control study. International Journal of Reproductive BioMedicine (IJRM), 20(3), 195-202. https://doi.org/10.18502/ijrm.v20i3.10711
https://doi.org/10.18502/ijrm.v20i3.10711
statistics
- 185 Abstract Views
- 97 PDF Views
- 0 HTML Views
authors
-
Hamideh Arasteh
Hamideh Arasteh
Department of Medical Genetics, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
-
Fatemeh Araste
Fatemeh Araste
Department of Medicinal Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
-
Mohammad Hasan Sheikhha
Mohammad Hasan Sheikhha
Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
-
Seyyed Mehdi Kalantar
Seyyed Mehdi Kalantar
Department of Medical Genetics, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
-
Ehsan Farashahi Yazd
Ehsan Farashahi Yazd
Department of Medical Genetics, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
-
Hamid Reza Ashrafzadeh
Hamid Reza Ashrafzadeh
Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
-
Nasrin Ghasemi
Nasrin Ghasemi
Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Published Date
- Apr 21, 2022
Evaluation of CAG repeat length in the androgen receptor gene and polycystic ovary syndrome risk in Iranian women: A case-control study
Abstract
Background: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder, which affects about 15-20% of women of reproductive age. The most important etiopathogenesis factor in its incidence is hyperandrogenism; over 70 candidate genes are known to be associated with this syndrome, such as the androgen receptor (AR) gene which encodes a steroid receptor and is located on the Xq11-12 chromosome. The N-terminus of exon 1 of AR contains a polymorphic trinucleotide repeat (CAG)n region that encodes glutamine tract. There are some studies showing that shorter AR CAG repeats are significantly related to enhanced AR sensitivity.
Objective: This study investigated the frequency of the polymorphic expansion of the trinucleotide CAG repeats of AR in PCOS.
Materials and Methods: 160 Iranian women aged 17-40 yr participated in this casecontrol study: 80 women as PCOS patients and 80 women as healthy controls according to the Rotterdam criteria. Other similar phenotype factors such as hyperandrogenism were not considered as PCOS. The frequency of polymorphic expansion of CAG trinucleotide repeats in PCOS patients was compared with the frequency in non-PCOS controls in using two primer sets for nested polymerase chain reaction. The polymerase chain reaction products were visualized on polyacrylamide gel and then were confirmed by a sequencing process.
Results: The results did not show a significant correlation between the frequency of CAG repeats in AR and PCOS incidence.
Conclusion: In contrast to some previous reports, the present data showed that the CAG length in PCOS cases did not significantly differ from that of controls. So, the AR (CAG)n does not appear to be a major factor for PCOS in Iranian women.
Key words: Androgen receptor, (CAG)n repeats, Polycystic ovary syndrome.
References
[1] Rosenfield RL, Ehrmann DA. The pathogenesis of polycystic ovary syndrome (PCOS): The hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev 2016; 37: 467-520.
[2] Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: A prospective study. J Clin Endocrinol Metab 1998; 83: 3078-3082.
[3] Wild RA, Carmina E, Diamanti-Kandarakis E, Dokras A, Escobar-Morreale HF, Futterweit W, et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: A consensus statement by the androgen excess and polycystic ovary syndrome (AE-PCOS) society. J Clin Endocrinol Metab 2010; 95: 2038-2049.
[4] Setji TL, Brown AJ. Polycystic ovary syndrome: Diagnosis and treatment. Am J Med 2007; 120: 128-132.
[5] Diamanti-Kandarakis E, Piperi Ch, Spina J, Argyrakopoulou G, Papanastasiou L, Bergiele A, et al. Polycystic ovary syndrome: The influence of environmental and genetic factors. Hormones 2006; 5: 17-34.
[6] Legro RS, Driscoll D, Strauss JF, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci USA 1998; 95: 14956- 14960.
[7] Xita N, Tsatsoulis A. Fetal programming of polycystic ovary syndrome by androgen excess: Evidence from experimental, clinical, and genetic association studies. J Clin Endocrinol Metab 2006; 91: 1660-1666.
[8] Castillo-Higuera T, Alarcón-Granados MC, Marin-Suarez J, Moreno-Ortiz H, Esteban-Pérez CI, Ferrebuz-Cardozo AJ, et al. A comprehensive overview of common polymorphic variants in genes related to polycystic ovary syndrome. Reprod Sci 2021; 28: 2399-2412.
[9] Panda PK, Rane R, Ravichandran R, Singh Sh, Panchal H. Genetics of PCOS: A systematic bioinformatics approach to unveil the proteins responsible for PCOS. Genom Data 2016; 8: 52-60.
[10] Baculescu N. The role of androgen receptor activity mediated by the CAG repeat polymorphism in the pathogenesis of PCOS. J Med Life 2013; 6: 18-25.
[11] La Spada AR, Roling DB, Harding AE, Warner CL, Spiegel R, Hausmanowa-Petrusewicz I, et al. Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. Nat Genet 1992; 2: 301-304.
[12] Greenland KJ, Beilin J, Castro J, Varghese PN, Zajac JD. Polymorphic CAG repeat length in the androgen receptor gene and association with neurodegeneration in a heterozygous female carrier of Kennedy’s disease. J Neurol 2004; 251: 35-41.
[13] Slattery ML, Sweeney C, Murtaugh M, Ma KhN, Wolff RK, Potter JD, et al. Associations between ERα, ERβ, and AR genotypes and colon and rectal cancer. Cancer Epidemiol Biomarkers Prev 2005; 14: 2936-2942.
[14] Mifsud A, Ramirez S, Yong EL. Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries. J Clin Endocrinol Metab 2000; 85: 3484-3488.
[15] Shah NA, Antoine HJ, Pall M, Taylor KD, Azziz R, Goodarzi MO. Association of androgen receptor CAG repeat polymorphism and polycystic ovary syndrome. J Clin Endocrinol Metab 2008; 93: 1939-1945.
[16] Jääskeläinen J, Korhonen S, Voutilainen R, Hippeläinen M, Heinonen S. Androgen receptor gene CAG length polymorphism in women with polycystic ovary syndrome. Fertil Steril 2005; 83: 1724-1728.
[17] Rotterdam ESHRE/ASRM-Sponsored PCOS conswnsus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19: 41-47.
[18] Tsai YC, Simoneau AR, Spruck CH, Nichols PW, Steven K, Buckley JD, et al. Mosaicism in human epithelium: Macroscopic monoclonal patches cover the urothelium. J Urol 1995; 153: 1697-1700.
[19] Schüring AN, Welp A, Gromoll J, Zitzmann M, Sonntag B, Nieschlag E, et al. Role of the CAG repeat polymorphism of the androgen receptor gene in polycystic ovary syndrome (PCOS). Exp Clin Endocrinol Diabetes 2012; 120: 73-79.
[20] Gur EB, Karadeniz M, Turan GA. Fetal programming of polycystic ovary syndrome. World J Diabetes 2015; 6: 936- 942.
[21] Choong CS, Kemppainen JA, Zhou ZX, Wilson EM. Reduced androgen receptor gene expression with first exon CAG repeat expansion. Mol Endocrinol 1996; 10: 1527-1535.
[22] Xita N, Georgiou I, Lazaros L, Psofaki V, Kolios G, Tsatsoulis A. The role of sex hormone-binding globulin and androgen receptor gene variants in the development of polycystic ovary syndrome. Hum Reprod 2008; 23: 693-698.
[23] Laisk T, Haller-Kikkatalo K, Laanpere M, Jakovlev Ü, Peters M, Karro H, et al. Androgen receptor epigenetic variations influence early follicular phase gonadotropin levels. Acta Obstet Gynecol Scand 2010; 89: 1557-1563.
[24] Radian S, Baculescu N, Aflorei D, Gussi I, Vladoiu S, Ianas O, et al. CAG repeat alleles of the androgen receptor are associated with polycystic ovary syndrome (PCOS) in the Romanian population. Endocrine 2010; 22: 498.
[25] Hickey T, Chandy A, Norman R. The androgen receptor CAG repeat polymorphism and X-chromosome inactivation in Australian Caucasian women with infertility related to polycystic ovary syndrome. J Clin Endocrinol Metab 2002; 87: 161-165.
[26] Dasgupta Sh, Sirisha PVS, Neelaveni K, Anuradha K, Reddy AG, Thangaraj K, et al. Androgen receptor CAG repeat polymorphism and epigenetic influence among the south Indian women with polycystic ovary syndrome. PLoS One 2010; 5: e12401.
[27] Wang R, Goodarzi MO, Xiong T, Wang D, Azziz R, Zhang H. Negative association between androgen receptor gene CAG repeat polymorphism and polycystic ovary syndrome? A systematic review and meta-analysis. Mol Hum Reprod 2012; 18: 498-509.
[28] Bruns CM, Baum ST, Colman RJ, Eisner JR, Kemnitz JW, Weindruch R, et al. Insulin resistance and impaired insulin secretion in prenatally androgenized male rhesus monkeys. J Clin Endocrinol Metab 2004; 89: 6218-6223.
[29] Zhu JQ, Zhu L, Liang XW, Xing FQ, Schatten H, Sun QY. Demethylation of LHR in dehydroepiandrosteroneinduced mouse model of polycystic ovary syndrome. Mol Hum Reprod 2010; 16: 260-266.
[30] Lange EM, Sarma AV, Ray A, Wang Y, Ho LA, Anderson SA, et al. The androgen receptor CAG and GGN repeat polymorphisms and prostate cancer susceptibility in African-American men: Results from the Flint Men’s Health Study. J Hum Genet 2008; 53: 220-226.
[2] Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: A prospective study. J Clin Endocrinol Metab 1998; 83: 3078-3082.
[3] Wild RA, Carmina E, Diamanti-Kandarakis E, Dokras A, Escobar-Morreale HF, Futterweit W, et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: A consensus statement by the androgen excess and polycystic ovary syndrome (AE-PCOS) society. J Clin Endocrinol Metab 2010; 95: 2038-2049.
[4] Setji TL, Brown AJ. Polycystic ovary syndrome: Diagnosis and treatment. Am J Med 2007; 120: 128-132.
[5] Diamanti-Kandarakis E, Piperi Ch, Spina J, Argyrakopoulou G, Papanastasiou L, Bergiele A, et al. Polycystic ovary syndrome: The influence of environmental and genetic factors. Hormones 2006; 5: 17-34.
[6] Legro RS, Driscoll D, Strauss JF, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci USA 1998; 95: 14956- 14960.
[7] Xita N, Tsatsoulis A. Fetal programming of polycystic ovary syndrome by androgen excess: Evidence from experimental, clinical, and genetic association studies. J Clin Endocrinol Metab 2006; 91: 1660-1666.
[8] Castillo-Higuera T, Alarcón-Granados MC, Marin-Suarez J, Moreno-Ortiz H, Esteban-Pérez CI, Ferrebuz-Cardozo AJ, et al. A comprehensive overview of common polymorphic variants in genes related to polycystic ovary syndrome. Reprod Sci 2021; 28: 2399-2412.
[9] Panda PK, Rane R, Ravichandran R, Singh Sh, Panchal H. Genetics of PCOS: A systematic bioinformatics approach to unveil the proteins responsible for PCOS. Genom Data 2016; 8: 52-60.
[10] Baculescu N. The role of androgen receptor activity mediated by the CAG repeat polymorphism in the pathogenesis of PCOS. J Med Life 2013; 6: 18-25.
[11] La Spada AR, Roling DB, Harding AE, Warner CL, Spiegel R, Hausmanowa-Petrusewicz I, et al. Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. Nat Genet 1992; 2: 301-304.
[12] Greenland KJ, Beilin J, Castro J, Varghese PN, Zajac JD. Polymorphic CAG repeat length in the androgen receptor gene and association with neurodegeneration in a heterozygous female carrier of Kennedy’s disease. J Neurol 2004; 251: 35-41.
[13] Slattery ML, Sweeney C, Murtaugh M, Ma KhN, Wolff RK, Potter JD, et al. Associations between ERα, ERβ, and AR genotypes and colon and rectal cancer. Cancer Epidemiol Biomarkers Prev 2005; 14: 2936-2942.
[14] Mifsud A, Ramirez S, Yong EL. Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries. J Clin Endocrinol Metab 2000; 85: 3484-3488.
[15] Shah NA, Antoine HJ, Pall M, Taylor KD, Azziz R, Goodarzi MO. Association of androgen receptor CAG repeat polymorphism and polycystic ovary syndrome. J Clin Endocrinol Metab 2008; 93: 1939-1945.
[16] Jääskeläinen J, Korhonen S, Voutilainen R, Hippeläinen M, Heinonen S. Androgen receptor gene CAG length polymorphism in women with polycystic ovary syndrome. Fertil Steril 2005; 83: 1724-1728.
[17] Rotterdam ESHRE/ASRM-Sponsored PCOS conswnsus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19: 41-47.
[18] Tsai YC, Simoneau AR, Spruck CH, Nichols PW, Steven K, Buckley JD, et al. Mosaicism in human epithelium: Macroscopic monoclonal patches cover the urothelium. J Urol 1995; 153: 1697-1700.
[19] Schüring AN, Welp A, Gromoll J, Zitzmann M, Sonntag B, Nieschlag E, et al. Role of the CAG repeat polymorphism of the androgen receptor gene in polycystic ovary syndrome (PCOS). Exp Clin Endocrinol Diabetes 2012; 120: 73-79.
[20] Gur EB, Karadeniz M, Turan GA. Fetal programming of polycystic ovary syndrome. World J Diabetes 2015; 6: 936- 942.
[21] Choong CS, Kemppainen JA, Zhou ZX, Wilson EM. Reduced androgen receptor gene expression with first exon CAG repeat expansion. Mol Endocrinol 1996; 10: 1527-1535.
[22] Xita N, Georgiou I, Lazaros L, Psofaki V, Kolios G, Tsatsoulis A. The role of sex hormone-binding globulin and androgen receptor gene variants in the development of polycystic ovary syndrome. Hum Reprod 2008; 23: 693-698.
[23] Laisk T, Haller-Kikkatalo K, Laanpere M, Jakovlev Ü, Peters M, Karro H, et al. Androgen receptor epigenetic variations influence early follicular phase gonadotropin levels. Acta Obstet Gynecol Scand 2010; 89: 1557-1563.
[24] Radian S, Baculescu N, Aflorei D, Gussi I, Vladoiu S, Ianas O, et al. CAG repeat alleles of the androgen receptor are associated with polycystic ovary syndrome (PCOS) in the Romanian population. Endocrine 2010; 22: 498.
[25] Hickey T, Chandy A, Norman R. The androgen receptor CAG repeat polymorphism and X-chromosome inactivation in Australian Caucasian women with infertility related to polycystic ovary syndrome. J Clin Endocrinol Metab 2002; 87: 161-165.
[26] Dasgupta Sh, Sirisha PVS, Neelaveni K, Anuradha K, Reddy AG, Thangaraj K, et al. Androgen receptor CAG repeat polymorphism and epigenetic influence among the south Indian women with polycystic ovary syndrome. PLoS One 2010; 5: e12401.
[27] Wang R, Goodarzi MO, Xiong T, Wang D, Azziz R, Zhang H. Negative association between androgen receptor gene CAG repeat polymorphism and polycystic ovary syndrome? A systematic review and meta-analysis. Mol Hum Reprod 2012; 18: 498-509.
[28] Bruns CM, Baum ST, Colman RJ, Eisner JR, Kemnitz JW, Weindruch R, et al. Insulin resistance and impaired insulin secretion in prenatally androgenized male rhesus monkeys. J Clin Endocrinol Metab 2004; 89: 6218-6223.
[29] Zhu JQ, Zhu L, Liang XW, Xing FQ, Schatten H, Sun QY. Demethylation of LHR in dehydroepiandrosteroneinduced mouse model of polycystic ovary syndrome. Mol Hum Reprod 2010; 16: 260-266.
[30] Lange EM, Sarma AV, Ray A, Wang Y, Ho LA, Anderson SA, et al. The androgen receptor CAG and GGN repeat polymorphisms and prostate cancer susceptibility in African-American men: Results from the Flint Men’s Health Study. J Hum Genet 2008; 53: 220-226.