Journal of Reproduction & Infertility

Journal of Reproduction & Infertility

Genetic Factors of Idiopathic Recurrent Miscarriage in Kazakh Population

Authors
Gulnara S Svyatova
Dinara D Mirzakhmetova
Galina M Berezina
Alexandra V Murtazaliyeva
Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Republic of Kazakhstan
10.18502/jri.v23i1.8451
Abstract
Background: It seems that 50% of the possible causes of recurrent miscarriage do not have any explainable etiology and they require in-depth etiopathogenesis analysis. The purpose of this research was to study polymorphisms relationship of the immune response genes including Val249Ile CX3CR1 (rs3732379), CT60 G/A CTLA4 (rs3087243), and HLA DQA1, DQB1, DRB1 (major histocompatibility complex, class II) with development of idiopathic form of recurrent miscarriage (iRM) in Kazakh population. Methods: TagMan genotyping for 302 patients with iRM and 300 women with normal reproduction was performed. Molecular genetic studies were carried out by the TaqMan method of unified site-specific amplification and real-time genotyping using test systems. Statistical tests and Chi Square were carried out using PLINK, STATA13 software and p˂0.05 was considered statistically significant. Results: It has been shown that carriage of unfavorable genotypes (Val/Ile, Val/Val) by the Val249Ile polymorphism of CX3CR1 gene increases the risk of developing iRM by 1.43 times. Search for associations of genes allelic variants of HLA class 2 complex with iRM revealed 501 allele in DQA1 locus, 0301 in DQB1 locus, 10, 12, 15, 16 alleles in DRB1 locus, which increase the risk of developing iRM in Kazakh population. Conclusion: The highly significant associations of immune response genes with development of iRM in Kazakh population indicate the possible involvement of the immune system interaction of mother cells with syncytiotrophoblast, which is realized by vascular defects and defective embryo implantation, causing termination of pregnancy.
Keywords
gene polymorphism
Genotypes
Implantation
Pregnancy
Reproductive Medicine
Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril. 2020;113(3):533-5.
Wan X, Li L, Liu Z, Fan Z, Yu L. Recurrent spontaneous abortion related to balanced translocation of chromosomes: two case reports. J Med Case Rep. 2021;15(1):270.
Xiang H, Yan H, Sun B, Feng F, Chen P. Decreased expression of long non-coding RNA SNHG7 cause recurrent spontaneous abortion through suppression proliferation and invasion of trophoblast cells via miR-34a. Am J Transl Res. 2019;11(1):463-72.
Wysocka U, Sakowicz A, Jakubowski L, Pinkier I, Rybak-Krzyszkowska M, Alaszewski W, et al. Association between idiopathic recurrent pregnancy loss and genetic polymorphisms in cytokine and matrix metalloproteinase genes. Ginekol Pol. 2021. In press.
Rasti Z, Nasiri M. Association of the+49 A/G polymorphism of CTLA4 gene with idiopathic recurrent spontaneous abortion in women in southwest of Iran. J Reprod Infertil. 2016;17(3):151-6.
Mojarrad M, Hassanzadeh-Nazarabadi M, Tafazoli N. Polymorphism of genes and implantation failure. Int J Mol Cell Med. 2013;2(1):1-8.
Homer HA. Modern management of recurrent miscarriage. Aust N Z J Obstet Gynaecol. 2019;59(1):36-44.
Svyatova GS, Berezina GM. Analysis of GWAS and meta-studies of habitual miscarriage according to world information databases. Obstet Gynecol Perinat. 2018;1(2):140-4.
Svyatova GS, Berezina GM, Murtazaliyeva AV. Association of polymorphisms of cardiovascular system genes with idiopathic recurrent pregnancy loss of Kazakh populations. Rev Latinoamer de Hiperten. 2019;14(4):319-25.
Ahmadi S, Rostamzadeh J, Khosravi D, Shariati P, Shakiba N. Association of CTLA-4 gene 49 A/G polymorphism with the incidence of type 1 diabetes mellitus in the Iranian Kurdish population. Pak J Biol Sci. 2013;16(24):1929-35.
Misra MK, Mishra A, Phadke SR, Agrawal S. Association of functional genetic variants of CTLA4 with reduced serum CTLA4 protein levels and increased risk of idiopathic recurrent miscarriages. Fertil Steril. 2016;106(5):1115-23.e6.
Tutchenko TM, Burka OA, Samilyk VS, Trokhymovych OV, Krotik OI, Gromova OL. Time to reduce the rate of idiopathic recurrent pregnancy losses. Reprod Endocrin. 2021;55:21-8.
Colley E, Hamilton S, Smith P, Morgan NV, Coomarasamy A, Allen S. Potential genetic causes of miscarriage in euploid pregnancies: A systematic review. Hum Reprod Update. 2019;25(4):452-72.
Atia TA. Overview of genetic causes of recurrent miscarriage and the diagnostic approach. Biocell. 2019;43(4):253-62.
Grimstad F, Krieg S. Immunogenetic contributions to recurrent pregnancy loss. J Assist Reprod Genet. 2016;33(7):833-47.
Meuleman T, Lashley LE, Dekkers OM, van Lith JM, Claas FH, Bloemenkamp KW. HLA associations and HLA sharing in recurrent miscarriage: a systematic review and meta-analysis. Hum Immunol. 2015;76(5):362-73.
Lowe M, Payton A, Verma A, Worthington J, Gemmell I, Hamilton P, et al. Associations between human leukocyte antigens and renal function. Sci Rep. 2021;11(1):3158.
Ali S, Majid S, Niamat Ali M, Taing S, El-Serehy H, Al-Misned FA. Evaluation of etiology and pregnancy outcome in recurrent miscarriage patients. Saudi J Biol Sci. 2020;27(10):2809-17.
Aruna M, Nagaraja T, Andal Bhaskar S, Tarakeswari S, Reddy К, Thangaraj L. Novel alleles of HLA-DQ and – DR loci show association with recurrent miscarriages among South Indian women. Hum Reprod. 2011;26(4):765-74.
El Hachem H, Crepaux V, May-Panloup P, Descamps P, Legendre G, Bouet PE. Recurrent pregnancy loss: current perspectives. Int J Womens Health. 2017;9:331-45.
Arias-Sosa LA, Acosta ID, Lucena-Quevedo E, Moreno-Ortiz H, Esteban-Pérez C, Forero-Castro M. Genetic and epigenetic variations associated with idiopathic recurrent pregnancy loss. J Assist Reprod Gen. 2018;35(3):355-66.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Gen. 2007;81(3):559-75.
Wang XP, Li QD, Ma ZW, Hong Y, Zhao AM, Di W, et al. [A/G polymorphism at position 49 in exon 1 of CTLA-4 gene in Chinese women with unexplained recurrent spontaneous abortion]. Zhonghua Fu Chan Ke Za Zhi. 2006;41(3):155-8. Chinese.
Parveen F, Faridi RM, Singh BS. Analysis of CCR5 and CX3CR1 gene polymorphisms in association with unexplained recurrent miscarriages among north Indian women. Cytokine. 2011;56(2):239-44.
Larsen CE, Alper CA. The genetics of HLA-associated disease. Curr Opin Immunol. 2004;16(5):660-7.
Segal S, Hill AV. Genetic susceptibility to infectious disease. Trends Microbiol. 2003;11(9):445-8.
Gordeeva LA, Shabaldin AV, Glushkov AN, Glushkova OA, Makarchenko OS. Association HLA-DRB1 with reproductive pathology in women. Med Immunol. 2007;9(6):643-8.
Tkach IR, Sosnina KO, Huleyuk NL, Terpylyak OI. Contribution of chromosomal abnormalities and genes of the major histocompatibility complex to early pregnancy losses. Biopolym Cell. 2015;31(1):38-45.
Iskhakov AT, Asatova MM, Rasulova MI. HLA profiles for miscarriage. Immunology. 1996;1:27-28.
Boldyreva MN, Bartseva OB, Kurilo LF, Tkachenko ER, Alekseev LP, Adamyan LV. Connection of the HLA-DRB1 genotype with reproductive failures. Reprod Issues. 2010;6:59-63.
Journal of Reproduction & Infertility
Volume 23, Issue 1
Winter 2022
Pages 39-45