J Korean Med Sci.  2022 Nov;37(46):e336. 10.3346/jkms.2022.37.e336.

Identification of Single Nucleotide Polymorphisms as Biomarkers for Recurrent Pregnancy Loss in Korean Women

Affiliations
  • 1Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
  • 2Bundang Cheil Women’s Hospital, Seongnam, Korea
  • 3Institute of Women’s Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
  • 4Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
  • 5Seoul Clinical Laboratories Healthcare Co., Ltd., Yongin, Korea

Abstract

Background
Single nucleotide polymorphisms (SNPs) are reportedly associated with repeated abortion. Thus, genetic analysis based on race is the key to developing accurate diagnostic tests. This study analyzed the genetic polymorphisms of recurrent pregnancy loss (RPL) patients among Korean women compared to the controls.
Methods
In 53 women of RPL group and 50 controls, the genetic analysis was performed. The genotype distribution and allele frequency were analyzed statistically for the difference between the two groups. The association between each SNP marker and RPL risk was analyzed.
Results
The genotypes of LEPR, endothelial nitric oxide synthase (eNOS), KDR, miR-27a, miR-449b, and tumor necrosis factor-alpha (TNF-α) were analyzed using odds ratio (OR) with 95% confidence intervals (CIs). Only the AG genotype of miR-449b (A>G) polymorphism showed significant association with the risk of RPL when compared to the AA genotype (OR, 2.39). The combination of GG/AG+GG/CA+AA genotypes for eNOS/ miR-449b/TNF-α was associated with 7.36-fold higher risk of RPL (OR, 7.36). The GG/ AG+GG combination for eNOS/miR-449b showed 2.43-fold higher risk for RPL (OR, 2.43). The combination of AG+GG/CA+AA genotypes for miR-449b/TNF-α showed a significant association with the risk of RPL (OR, 7.60). From the haplotype-based analysis, the G-G-A haplotype of eNOS/miR-449b/TNF-α and the G-A haplotype of miR-449b/TNF-α were associated with increased risk of RPL (OR, 19.31; OR, 22.08, respectively).
Conclusion
There is a significant association between the risk of RPL and miR-449b/TNF-α combination, and therefore, genetic analysis for specific combined genotypes can be an important screening method for RPL in Korean women.

Keyword

Plasma; MicroRNAs; Pregnancy; Recurrent Pregnancy Loss; Miscarriage

Figure

  • Fig. 1 Odds ratio of genotype combinations with significantly increased odds compared to reference. Odds ratio with 95% confidence interval in log scale.eNOS = endothelial nitric oxide synthase, TNF = tumor necrosis factor.


Reference

1. Larsen EC, Christiansen OB, Kolte AM, Macklon N. New insights into mechanisms behind miscarriage. BMC Med. 2013; 11(1):154. PMID: 23803387.
2. Ford HB, Schust DJ. Recurrent pregnancy loss: etiology, diagnosis, and therapy. Rev Obstet Gynecol. 2009; 2(2):76–83. PMID: 19609401.
3. García-Enguídanos A, Calle ME, Valero J, Luna S, Domínguez-Rojas V. Risk factors in miscarriage: a review. Eur J Obstet Gynecol Reprod Biol. 2002; 102(2):111–119. PMID: 11950476.
4. Definitions of infertility and recurrent pregnancy loss. Fertil Steril. 2008; 90(5):Suppl. S60. PMID: 19007647.
5. Branch DW, Gibson M, Silver RM. Clinical practice. Recurrent miscarriage. N Engl J Med. 2010; 363(18):1740–1747. PMID: 20979474.
6. Mark HF. Cytogenetics of reproductive wastage: from conception to birth. Medical Cytogenetics. New York, NY, USA: Marcel Dekker;2000. p. 213–246.
7. Khonina NA, Broitman EV, Shevela EY, Pasman NM, Chernykh ER. Mixed lymphocyte reaction blocking factors (MLR-Bf) as potential biomarker for indication and efficacy of paternal lymphocyte immunization in recurrent spontaneous abortion. Arch Gynecol Obstet. 2013; 288(4):933–937. PMID: 23558562.
8. Murugappan G, Shahine L, Lathi RB. Antimullerian hormone is a predictor of live birth in patients with recurrent pregnancy loss. Fertil Res Pract. 2019; 5(1):2. PMID: 30923623.
9. Kim MS, Gu BH, Song S, Choi BC, Cha DH, Baek KH. ITI-H4, as a biomarker in the serum of recurrent pregnancy loss (RPL) patients. Mol Biosyst. 2011; 7(5):1430–1440. PMID: 21331437.
10. Bahia W, Soltani I, Abidi A, Haddad A, Ferchichi S, Menif S, et al. Identification of genes and miRNA associated with idiopathic recurrent pregnancy loss: an exploratory data mining study. BMC Med Genomics. 2020; 13(1):75. PMID: 32487076.
11. Nagirnaja L, Palta P, Kasak L, Rull K, Christiansen OB, Nielsen HS, et al. Structural genomic variation as risk factor for idiopathic recurrent miscarriage. Hum Mutat. 2014; 35(8):972–982. PMID: 24827138.
12. O’Toole AS, Miller S, Haines N, Zink MC, Serra MJ. Comprehensive thermodynamic analysis of 3′ double-nucleotide overhangs neighboring Watson-Crick terminal base pairs. Nucleic Acids Res. 2006; 34(11):3338–3344. PMID: 16820533.
13. Rah H, Chung KW, Ko KH, Kim ES, Kim JO, Sakong JH, et al. miR-27a and miR-449b polymorphisms associated with a risk of idiopathic recurrent pregnancy loss. PLoS One. 2017; 12(5):e0177160. PMID: 28489914.
14. Rah H, Jeon YJ, Lee BE, Choi DH, Yoon TK, Lee WS, et al. Association of kinase insert domain-containing receptor (KDR) gene polymorphisms with idiopathic recurrent spontaneous abortion in Korean women. Fertil Steril. 2013; 99(3):753–760.e8. PMID: 23158831.
15. Jang HG, Choi Y, Kim JO, Jeon YJ, Rah H, Cho SH, et al. Polymorphisms in tumor necrosis factor-alpha (-863C>A, -857C>T and +488G>A) are associated with idiopathic recurrent pregnancy loss in Korean women. Hum Immunol. 2016; 77(6):506–511. PMID: 27083536.
16. Shin SJ, Lee HH, Cha SH, Kim JH, Shim SH, Choi DH, et al. Endothelial nitric oxide synthase gene polymorphisms (-786T>C, 4a4b, 894G>T) and haplotypes in Korean patients with recurrent spontaneous abortion. Eur J Obstet Gynecol Reprod Biol. 2010; 152(1):64–67. PMID: 20728041.
17. Müller A, Wagner J, Hodžić A, Maver A, Škrlec I, Heffer M, et al. Genetic variation in leptin and leptin receptor genes is a risk factor for idiopathic recurrent spontaneous abortion. Croat Med J. 2016; 57(6):566–571. PMID: 28051281.
18. Bamshad M. Genetic influences on health: does race matter? JAMA. 2005; 294(8):937–946. PMID: 16118384.
19. Di Prima FA, Valenti O, Hyseni E, Giorgio E, Faraci M, Renda E, et al. Antiphospholipid Syndrome during pregnancy: the state of the art. J Prenat Med. 2011; 5(2):41–53. PMID: 22439075.
20. Gaiday AN, Tussupkaliyev AB, Bermagambetova SK, Zhumagulova SS, Sarsembayeva LK, Dossimbetova MB, et al. Effect of homocysteine on pregnancy: a systematic review. Chem Biol Interact. 2018; 293:70–76. PMID: 30053452.
21. Asanidze E, Kristesashvili J, Andguladze S. Correlation between levels of homocysteine, anti-mullerian hormone and insulin resistance in PCOS patients with recurrent miscarriage. Georgian Med News. 2019; (290):25–29.
22. Rull K, Nagirnaja L, Laan M. Genetics of recurrent miscarriage: challenges, current knowledge, future directions. Front Genet. 2012; 3:34. PMID: 22457663.
23. Amin-Beidokhti M, Mirfakhraie R, Zare-Karizi S, Karamoddin F. The role of parental microRNA alleles in recurrent pregnancy loss: an association study. Reprod Biomed Online. 2017; 34(3):325–330. PMID: 28012790.
24. Su X, Hu Y, Li Y, Cao JL, Wang XQ, Ma X, et al. The polymorphism of rs6505162 in the MIR423 coding region and recurrent pregnancy loss. Reproduction. 2015; 150(1):65–76. PMID: 25926693.
25. Hu Y, Liu CM, Qi L, He TZ, Shi-Guo L, Hao CJ, et al. Two common SNPs in pri-miR-125a alter the mature miRNA expression and associate with recurrent pregnancy loss in a Han-Chinese population. RNA Biol. 2011; 8(5):861–872. PMID: 21788734.
26. 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(2):168–173. PMID: 22222140.
27. Wang M, Gao Y, Qu P, Qing S, Qiao F, Zhang Y, et al. Sperm-borne miR-449b influences cleavage, epigenetic reprogramming and apoptosis of SCNT embryos in bovine. Sci Rep. 2017; 7(1):13403. PMID: 29042680.
28. Teruel-Montoya R, Rosendaal FR, Martínez C. MicroRNAs in hemostasis. J Thromb Haemost. 2015; 13(2):170–181. PMID: 25400249.
29. Knöfler M, Mösl B, Bauer S, Griesinger G, Husslein P. TNF-α/TNFRI in primary and immortalized first trimester cytotrophoblasts. Placenta. 2000; 21(5-6):525–535. PMID: 10940203.
Full Text Links
  • JKMS
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2023 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr