Frequency of the rs 14035 polymorphism of RAN gen in recurrent pregnancy loss: A case-control study

Abstract

Background: Genetic factors could account for recurrent pregnancy loss (RPL). The RAN gene is a member of the ”large RAS family” and a small GTPase that is essential for the translocation of Ribonucleic acid (RNA) and proteins through the nuclear pore. Mutation in the RAN constitutive gene could stop DNA synthesis and alter the expression of genes in the uterus, likely playing a role in recurrent miscarriage.


Objective: The aim was to investigate the frequency of RAN (rs 14035) polymorphism in women with RPL compared with women without abortion history.


Materials and Methods: In this case-control study, 100 women with at least two consecutive miscarriages before the 20th wk of gestation and having spouses with karyotype and normal sperm parameters as the case group and 100 women with no history of abortion and having at least one successful pregnancy and normal delivery as the control group. The groups were age matched (20-40 yr). The rs 14035 polymorphism of RAN gene was investigated by Polymerase Chain Reaction- Restriction Fragment Length poly morphism technique and the frequency of which was compared between the two groups.


Results: The frequency of TT, TC, and CC genotypes of RAN gene polymorphism in the case group were 9%, 40%, and 51%, respectively, and in the control group were 11%, 38%, and 51%, respectively. There was no significant difference in the genotypes between two groups (p = 0.882).


Conclusion: According to our results, it seems that RAN polymorphism (rs 14035) is not associated with the risk of RPL in this study population.


Key words: RAN gene, Repeated abortion, Polymorphism, PCR-RFLP.

References
[1] Sierra S, Stephenson M. Genetics of recurrent pregnancy loss. Semin Reprod Med 2006; 24: 17–24.

[2] Meka A, Reddy BM. Recurrent spontaneous abortions: an overview of genetic and non-genetic backgrounds. Int J Hum Genet 2006; 6: 109–117.

[3] Moore MS, Blobel G. A G protein involved in nucleocytoplasmic transport: the role of Ran. Trends Biochem Sci 1994; 19: 211–216.

[4] Sazer S, Dasso M. The ran decathlon: multiple roles of Ran. J Cell Sci 2000; 113: 1111–1118.

[5] Fotoohi M, Ghasemi N, Mirghanizadeh SA, Vakili M, Samadi M. Association between HLA-E gene polymorphism and unexplained recurrent spontaneous abortion (RSA) in Iranian women. Int J Reprod Biomed 2016; 14: 477–482.

[6] Arjmand F, Ghasemi N, Mirghanizadeh SA, Samadi M. The balance of the immune system between HLA-G and NK cells in unexplained recurrent spontaneous abortion and polymorphisms analysis. Immunol Res 2016; 64: 785–790.

[7] Abdollahi E, Tavasolian F, Ghasemi N, Mirghanizadeh SA, Azizi M, Ghoryani M, et al. Association between lower frequency of R381Q variant (rs11209026) in IL-23 receptor gene and increased risk of recurrent spontaneous abortion (RSA). J Immunotoxicol 2015; 12: 317–321.

[8] Zahraei M, Sheikhha MH, Kalantar SM, Ghasemi N, Jahaninejad T, Rajabi S, et al. The association of arylendosulfatase 1 (SULF1) gene polymorphism with recurrent miscarriage. J Assist Reprod Genet 2014; 31: 157–161.

[9] Teremmahi Ardestani M, Nodushan HH, Aflatoonian A, Ghasemi N, Sheikhha MH. Case control study of the factor V Leiden and factor II G20210A mutation frequency in women with recurrent pregnancy loss. Iran J Reprod Med 2013; 11: 61–64.

[10] O’Toole AS, Miller S, Haines N, Zink MC, Serra MJ. Comprehensive thermodynamic analysis of 3′ doublenucleotide overhangs neighboring Watson-Crick terminal base pairs. Nucleic Acids Res 2006; 34: 3338–33344.

[11] Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120: 15–20.

[12] Tohidi N, Ghorbian S. [Investigating the association of RAN (rs 14035) and XPO5 (rs 2257082) genes polymorphisms with the recurrent pregnancy loss in women referred to Imam Khomeini Hospital of Ardabil During 2015-2017 years.] J Rafsanjan Univ Med Sci 2018; 17: 201–212. (in Persian)

[13] Jung YW, Jeon YJ, Rah H, Kim JH, Shin JE, Choi DH, et al. Genetic variants in microRNA machinery genes are associate with idiopathic recurrent pregnancy loss risk. PloS One 2014; 9: e95803–e95811.

[14] Fallah-Sohy A, Zaker Bostanabad S, Mirza Ahmadi S. [Investigation of relationship between MicroRNA Machinery Genes polymorphism (RAN rs14035, DICER rs3742330) and recurrent spontaneous abortion in city of Tehran.] New Cell Mol Biotech J 2018; 8: 23–30. (in Persian).

[15] Tabibnejad N, Sheikhha MH, Ghasemi N, Fesahat F, Soleimani M, Aflatoonian A. Association between early embryo morphokinetics plus cumulus cell gene expression and assisted reproduction outcomes in polycystic ovary syndrome women. Reprod Biomed Online 2019; 38: 139–151.

[16] Rah H, Jeon YJ, Lee BE, Kim JO, Shim SH, Lee WS, et al. Association of polymorphisms in microRNA machinery genes (DROSHA, DICER1, RAN, and XPO5) with risk of idiopathic primary ovarian insufficiency in Korean women. Menopause 2013; 20: 1067–1073.

[17] Jeon YJ, Choi YS, Rah H, Kim SY, Choi DH, Cha SH, et al. Association study of microRNA polymorphisms with risk of idiopathic recurrent spontaneous abortion in Korean women. Gene 2012; 494: 168–173.

[18] Fu M, Xu WM, Qin TZ, Xu KH. The association between the polymorphisms of mirna biogenesis related genes (DICER, DROSHA and RAN) and unexplained recurrent spontaneous abortion in chinese women. Sichuan Da Xue Xue Bao Yi Xue Ban 2017; 48: 880–885.

[19] Kotlabova K, Doucha J, Hromadnikova I. Placentalspecific microRNA in maternal circulation-identification of appropriate pregnancy-associated microRNAs with diagnostic potential. J Reprod Immunol 2011; 89: 185–191.

[20] Chakrabarty A, Tranguch S, Daikoku T, Jensen K, Furneaux H, Dey SK. MicroRNA regulation of cyclooxygenase-2 during embryo implantation. Proc Nati Acad Sci USA 2007; 104: 15144–15149.

[21] Enquobahrie DA, Abetew DF, Sorensen TK, Willoughby D, Chidambaram K, Williams MA. Placental microRNA expression in pregnancies complicated by preeclampsia. Am J Obstet Gynecol 2011; 204: 178. e12–e21.

[22] Choi YS, Kwon H, Kim JH, Shin JE, Choi Y, Yoon TK, et al. Haplotype-based association of ACE I/D, AT1R 1166A> C, and AGT M235T polymorphisms in reninangiotensin- aldosterone system genes in Korean women with idiopathic recurrent spontaneous abortions. Eur J Obstet Gynecol Reprod Biol 2011; 158: 225–228.

[23] Donker RB, Mouillet JF, Nelson DM, Sadovsky Y. The expression of Argonaute2 and related microRNA biogenesis proteins in normal and hypoxic trophoblasts. Mol Hum Reprod 2007; 13: 273–279.