GSR (glutathione reductase) gene as a possible candidate gene for predisposition to uterine fibroids

Uterine fibroids (UF), or leiomyoma, is the most common tumor of the reproductive system in female. Oxidative stress is one of the basic pathogenetic mechanisms for uterine fibroids development. Glutathione (GSH) is a non-enzymatic antioxidant that plays a key role in the protection against oxidative stress. The reduction of oxidized glutathione is carried out by the enzyme glutathione reductase, encoded by the GSR gene. The aim of the study was to investigate the association of common single nucleotide polymorphism rs2551715 in gene encoding glutathione reductase with the risk of UF. A total of 978 unrelated individuals from Central Russia were included for this study: 590 patients with uterine fibroids (MM) and 388 age-matched healthy females. Genotyping of the single nucleotide polymorphism rs2551715 GSR was performed using TaqMan-based PCR. To analyze the associations of genotypes with the risk of diseases, a log-additive regression model was used. All calculations were performed relative to the minor allele; corrections for gender and age have been introduced. Allele T rs2551715 GSR (OR = 0.81, 95% CI = 0.67-0.97; P = 0.02) was associated with a decreased risk of UF. Analysis of genotype frequencies showed that rs2551715 GSR was associated with a decreased risk of UF (OR = 0.82, 95% CI = 0.69-0.98 ; P = 0.028). Bioinformatic analysis revealed that the spectrum of transcription factors binding with the protective allele T is involved in the regulation of the of smooth muscle cells signaling pathway, response to growth factor, regulation of cell differentiation, regulation of cell population proliferation. Thus, for the first time, the association of rs2551715 GSR with a predisposition to development of uterine fibroids has been established.

uterine fibroids, GSR, glutathione reductase, rs2551715, glutathione, oxidative stress

1. Wise L.A., Laughlin-Tommaso S.K. Epidemiology of Uterine Fibroids: From Menarche to Menopause. Clin Obstet Gynecol. 2016;59(1):2-24. doi:10.1097/GRF.0000000000000164

2. Aleksandrovych V., Bereza T., Sajewicz M., Walocha J.A., Gil K. Uterine fibroid: common features of widespread tumor (Review article). Folia Med Cracov. 2015;55(1):61-75.

3. Fletcher N.M., Abusamaan M.S., Memaj I., Saed M.G., Al-Hendy A., Diamond M.P., Saed G.M. Oxidative stress: a key regulator of leiomyoma cell survival. Fertil Steril. 2017;107(6):1387-1394.e1. doi:10.1016/j.fertnstert.2017.04.015

4. Toledano M.B., Huang M.E. The Unfinished Puzzle of Glutathione Physiological Functions, an Old Molecule That Still Retains Many Enigmas. Antioxid Redox Signal. 2017;27(15):1127-1129. doi:10.1089/ars.2017.7230

5. Bansal A., Simon M.C. Glutathione metabolism in cancer progression and treatment resistance. J Cell Biol. 2018;217(7):2291-2298. doi:10.1083/jcb.201804161

6. Drozd E., Krzysztoń-Russjan J., Marczewska J., Drozd J., Bubkoa I., Bielak M., Lubelska K., Wiktorska K., Chilmonczyk Z., Anuszewska E., Gruber-Bzura B. Up-regulation of glutathione-related genes, enzyme activities and transport proteins in human cervical cancer cells treated with doxorubicin. Biomed Pharmacother. 2016;83:397-406. doi:10.1016/j.biopha.2016.06.051

7. Кудрявцева О.К., Барышева Е.М., Сорокина М.В., Полшведкина О.Б., Иванова Н.В., Полоников А.В., Бушуева О.Ю. Анализ взаимосвязи полиморфизма A/G (rs1801310) гена GSS с развитием миомы матки: пилотное исследование. Медицинская генетика. 2017;16(2):37-39.

8. Пономаренко И.В. Отбор полиморфных локусов для анализа ассоциаций при генетико-эпидемиологических исследованиях. Научный результат. Медицина и фармация. 2018;4(2):40-54. DOI: 10.18413/2313-8955-2018-4-2-0-5

9. SNPStats of The Catalan Institute of Oncology. URL: https://www.snpstats.net/start.htm

10. atSNP Search. URL: http://atsnp.biostat.wisc.edu/search

11. The Gene Ontology Resource. URL: http://geneontology.org/

12. HaploReg v4.1. URL: https://pubs.broadinstitute.org/mammals/haploreg/haploreg.php

13. The Genotype-Tissue Expression (GTEx) Portal. URL: https://www.gtexportal.org/

14. The GeneCards human gene database. URL: https://www.genecards.org/cgi-bin/carddisp.pl?gene=GTF2E2

15. Gruchała-Niedoszytko M., Niedoszytko M., Sanjabi B., van der Vlies P., Niedoszytko P., Jassem E., Małgorzewicz S. Analysis of the differences in whole-genome expression related to asthma and obesity. Pol Arch Med Wewn. 2015;125(10):722-30. doi: 10.20452/pamw.3109