Polymorphic CAG and GGN repeats in Cryptorchidism patient risk: A meta-analytical study
Abstract
Genetic mutations in the androgen receptor (AR) gene have been identified as the cause of androgen insensitivity syndrome. These mutations are linked to inconsistent development of the Wolffian duct and may result in conditions such as micropenis, hypospadias, and cryptorchidism. The androgen receptor has two polymorphic sites located in exon 1, which consists of varying amounts of CAG and GGN repeats. These repetitions lead to the formation of polyglutamine and polyglycine stretches of varied lengths. Increased CAG repeats lead to a decrease in androgen receptor transcriptional activity, but the impact of GGN triplets is less well understood. This research examined the CAG and GGN repeat lengths in males who had a past medical record of cryptorchidism. Prospective and retrospective observational studies from PubMed, Science Direct, and Embase were systematically searched up to 15th November 2020. Primary outcomes were analyzed using a fixed or random effect model regarding its heterogeneity and continued with multilevel modeling of each polymorphism and ethnicity. CAG and GGN repeat polymorphism was found to be significantly different compared to control in contributing to cryptorchidism (CAG: 0.55 [CI 95%=0.19-0.91]; p-value=0.003 and GGN 0.90 [CI95%=0.65-1.15]; p value<0.000). In conclusion, CAG and GGN repeat polymorphism have an essential role in the incidence of cryptorchidism.
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References
Bogaert, V., Vanbillemont, G., Taes, Y., De Bacquer, D., Deschepper, E., Van Steen, K., & Kaufman, J. M. (2009). Small effect of the androgen receptor gene GGN repeat polymorphism on serum testosterone levels in healthy men. European journal of endocrinology, 161(1), 171-177.
Delli Muti, N., Tirabassi, G., Buldreghini, E., Lenzi, A., & Balercia, G. (2014). Synergistic effect of androgen receptor (CAG repeat length) and endothelial nitric oxide synthase (Glu298Asp variant) gene polymorphisms on seminal parameters in men with idiopathic oligoasthenozoospermia. Endocrine, 47, 322-324.
Eisermann, K., Wang, D., Jing, Y., Pascal, L. E., & Wang, Z. (2013). Androgen receptor gene mutation, rearrangement, polymorphism. Translational andrology and urology, 2(3), 137.
Grigorova, M., Punab, M., Kahre, T., Ivandi, M., Tõnisson, N., Poolamets, O., ... & Laan, M. (2017). The number of CAG and GGN triplet repeats in the Androgen Receptor gene exert combinatorial effect on hormonal and sperm parameters in young men. Andrology, 5(3), 495-504.
Gurney, J. K., McGlynn, K. A., Stanley, J., Merriman, T., Signal, V., Shaw, C., ... & Sarfati, D. (2017). Risk factors for cryptorchidism. Nature Reviews Urology, 14(9), 534-548. Hamdi, S. M., Almont, T., Galinier, P., Mieusset, R., & Thonneau, P. (2017). Altered secretion of Sertoli cells hormones in 2‐year‐old prepubertal cryptorchid boys: a cross‐sectional study. Andrology, 5(4), 783-789.
Huang, G., Shan, W., Zeng, L., & Huang, L. (2015). Androgen receptor gene CAG repeat polymorphism and risk of isolated hypospadias: results from a meta-analysis. Genet Mol Res, 14(1), 1580-1588.
Hutson, J. M., Southwell, B. R., Li, R., Lie, G., Ismail, K., Harisis, G., & Chen, N. (2013). The regulation of testicular descent and the effects of cryptorchidism. Endocrine Reviews, 34(5), 725-752.
Katagiri, Y., Neri, Q. V., Takeuchi, T., Moy, F., Sills, E. S., & Palermo, G. D. (2006). Androgen receptor CAG polymorphism (Xq11-12) status and human spermatogenesis: a prospective analysis of infertile males and their offspring conceived by intracytoplasmic sperm injection. International journal of molecular medicine, 18(3), 405-413.
Kollin, C., & Ritzen, E. M. (2014). Cryptorchidism: a clinical perspective. Pediatric endocrinology reviews: PER, 11, 240-250.
Koster, R., Mitra, N., D'Andrea, K., Vardhanabhuti, S., Chung, C. C., Wang, Z., ... & Kanetsky, P. A. (2014). Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors. Human molecular genetics, 23(22), 6061-6068.
Lanciotti, L., Cofini, M., Leonardi, A., Bertozzi, M., Penta, L., & Esposito, S. (2019). Different clinical presentations and management in complete androgen insensitivity syndrome (CAIS). International journal of environmental research and public health, 16(7), 1268.
Mosaad, Y. M., Shahin, D., Elkholy, A. A. M., Mosbah, A., & Badawy, W. (2012). CAG repeat length in androgen receptor gene and male infertility in Egyptian patients. Andrologia, 44(1), 26-33.
Nenonen, H., Björk, C., Skjaerpe, P. A., Giwercman, A., Rylander, L., Svartberg, J., & Giwercman, Y. L. (2009). CAG repeat number is not inversely associated with androgen receptor activity in vitro. MHR: Basic science of reproductive medicine, 16(3), 153-157.
Rodprasert, W., Virtanen, H. E., Mäkelä, J. A., & Toppari, J. (2020). Hypogonadism and cryptorchidism. Frontiers in endocrinology, 10, 495250.
Rodríguez, F., Godoy, M. J., Ortiz, E., Benítez‐Filselcker, A., López, M. T., Cassorla, F., & Castro, A. (2024). CAG and GGN repeat polymorphisms in the androgen receptor gene of a Chilean pediatric cohort with idiopathic inguinal cryptorchidism. Andrology, 12(2), 289-296.
Skakkebaek, N. E., Rajpert-De Meyts, E., Buck Louis, G. M., Toppari, J., Andersson, A. M., Eisenberg, M. L., ... & Juul, A. (2016). Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility. Physiological reviews, 96(1), 55-97.
Tirabassi, G., Delli Muti, N., Buldreghini, E., Lenzi, A., & Balercia, G. (2014). Central body fat changes in men affected by post-surgical hypogonadotropic hypogonadism undergoing testosterone replacement therapy are modulated by androgen receptor CAG polymorphism. Nutrition, Metabolism and Cardiovascular Diseases, 24(8), 908-913.
Wang, Q., Ge, X., Wang, H. X., Shi, Q. M., Ding, Z., & Xu, L. C. (2018). Association of androgen receptor gene CAG and GGN repeat polymorphism with cryptorchidism: a meta-analysis. Andrologia, 50(1), e12909.
Wilhelm, D., Yang, J. X., & Thomas, P. (2013). Mammalian sex determination and gonad development. Current topics in developmental biology, 106, 89-121.
Zitzmann, M., & Nieschlag, E. (2003). The CAG repeat polymorphism within the androgen receptor gene and maleness 1. International journal of andrology, 26(2), 76-83.
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