In silico study of the spectrum of genetic variants associated with preeclampsia in the Russian population

Background. Preeclampsia (PE) is a serious complication related to high blood pressure during pregnancy, affecting approximately 2-15% of pregnant women. This condition is marked by elevated blood pressure and poses substantial risks to both maternal and fetal health. Identifying early biomarkers for PE is a key focus in the effort to prevent this potentially dangerous condition in a timely manner.

Aim: The aim of this study was to identify potential in silico biomarkers for hypertensive complications during pregnancy by analyzing findings from both international and domestic genome-wide association studies (GWAS).

Methods. The research involved the examination of summary statistics from international GWAS focused on hypertensive complications of pregnancy, which were then cross-validated against data from the Biobank Russia (BBRU) project.

Results. The analysis revealed 44 single nucleotide polymorphisms (SNPs) linked to preeclampsia (PE) and/or other hypertensive complications during pregnancy across both discovery and validating GWAS. Notably, the rs10843404 SNP variant in the PZP gene was statistically significant (p < 0.05) in the domestic GWAS. Additionally, four other SNPs located in the FLT1 and FGF5 genes showed a tendency toward statistical significance (p < 0.1).

Conclusions. The findings from the replication analysis, along with literature data, indicate that the product of the PZP plays a crucial role in the development of hypertensive forms of PE. The limited number of replicated loci in the Russian cohort may reflect genetic differences in PE across populations, highlighting the need for further studies involving larger sample sizes to enhance statistical power and provide a more comprehensive understanding of genetic risk factors for PE in the Russian population.

1. Chang K.J., Seow K.M., Chen K.H. Preeclampsia: Recent Advances in Predicting, Preventing, and Managing the Maternal and Fetal Life Threatening Condition. Int J Environ Res Public Health. 2023;20(4):2994. doi: 10.3390/ijerph20042994.

2. Bokuda K., Ichihara A. Preeclampsia up to date-What’s going on? Hypertens Res. 2023;46(8):1900-1907. doi: 10.1038/s41440-023-01323-w.

3. Giorgione V., Cauldwell M., Thilaganathan B. Pre-eclampsia and Cardiovascular Disease: From Pregnancy to Postpartum. Eur Cardiol. 2023;18:e42. doi: 10.15420/ecr.2022.56.

4. Nakimuli A., Starling J.E., Nakubulwa S., et al. Relative impact of pre-eclampsia on birth weight in a low resource setting: A prospective cohort study. Pregnancy Hypertens. 2020;21:1-6. doi: 10.1016/j.preghy.2020.04.002.

5. Wang M., Wang X., Chen Z., Zhang F. Gestational hypertensive disease and small for gestational age infants in twin pregnancy: A systematic review and meta-analysis. J Obstet Gynaecol Res. 2022;48(11):2677-2685. doi: 10.1111/jog.15401.

6. Goffin S.M., Derraik J.G.B., Groom K.M., Cutfield W.S. Maternal pre-eclampsia and long-term offspring health: Is there a shadow cast? Pregnancy Hypertens. 2018;12:11-15. doi: 10.1016/j.preghy.2018.02.003.

7. Gray K.J., Saxena R., Karumanchi S.A. Genetic predisposition to preeclampsia is conferred by fetal DNA variants near FLT1, a gene involved in the regulation of angiogenesis. Am J Obstet Gynecol. 2018;218(2):211-218. doi: 10.1016/j.ajog.2017.11.562

8. Vashukova E.S. Molekulyarno-geneticheskiye aspekty razvitiya gestoza u zhenshchin Severo-Zapadnogo regiona Rossii: dis. kandidat nauk [Molecular genetic aspects of the development of gestosis in women of the North-West region of Russia: dis. candidate of sciences: 03.02.07]. St. Petersburg State University, St. Petersburg, 2017. 180 p. (In Russ.)

9. Vashukova, E. S., Glotov A. S., Bikmullina D. R., et al. Nasledstvennaya trombofiliya i risk razvitiya gestoza u beremennykh Rossii [Inherited thrombophilia and the risk of pre-eclampsia for Russian pregnant women]. Meditsinskaya genetika [Medical Genetics]. 2010; 9 (10): 39-45. (In Russ.)

10. Semashchenko K.S, Vasilyeva E.V., Molokova N.N., et al. Study of serum procalcitonin and lactate levels in women with preeclampsia. The Journal «Obstetrics and Gynecology» (Moscow).2021;(10): 61-67.

11. Trifonova E.A., Gabidulina T.V., Agarkova T.A., et al. Analiz roli nasledstvennoy trombofilii v razvitii oslozhnennogo techeniya beremennosti [Analysis of the role of hereditary thrombophilia in developing severe gestation course]. Fundamental’nyye issledovaniya [Fundamental Research]. 2012; (10): 337-344. (In Russ.)

12. Churnosov M., Abramova M., Reshetnikov E., et al. Polymorphisms of hypertension susceptibility genes as a risk factors of preeclampsia in the Caucasian population of central Russia. Placenta. 2022;129:51-61. doi: 10.1016/j.placenta.2022.09.010.

13. Barbitoff Y.A., Khmelkova D.N., Pomerantseva E.A., et al. Expanding the Russian allele frequency reference via cross-laboratory data integration: insights from 7452 exome samples. Natl Sci Rev. 2024 Sep 14;11(10):nwae326. doi: 10.1093/nsr/nwae326.

14. Usoltsev, D., Kolosov, N., Rotar, O. et al. Complex trait susceptibilities and population diversity in a sample of 4,145 Russians. Nat Commun. 2024; 15: 6212. https://doi.org/10.1038/s41467-024-50304-1

15. Goławski K., Soczewica R., Kacperczyk-Bartnik J., et al. The Role of Cadherin 12 (CDH12) in the Peritoneal Fluid among Patients with Endometriosis and Endometriosis-Related Infertility. Int J Environ Res Public Health. 2022;19(18):11586. doi: 10.3390/ijerph191811586

16. Steinthorsdottir V., McGinnis R., Williams N.O., et al. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women. Nat Commun. 2020;11(1):5976. doi: 10.1038/s41467-020-19733-6.

17. Gray K.J., Kovacheva V.P., Mirzakhani H., et al. Gene-Centric Analysis of Preeclampsia Identifies Maternal Association at PLEKHG1. Hypertension. 2018;72(2):408-416. doi: 10.1161/HYPERTENSIONAHA.117.10688.

18. Changalidis A.I., Maksiutenko E.M., Barbitoff Y.A., et al. Aggregation of Genome-Wide Association Data from FinnGen and UK Biobank Replicates Multiple Risk Loci for Pregnancy Complications. Genes (Basel). 2022;13(12):2255. doi: 10.3390/genes13122255.

19. Tyrmi J.S., Kaartokallio T., Lokki A.I., et al. Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy. JAMA Cardiol. 2023;8(7):674-683. doi: 10.1001/jamacardio.2023.1312.

20. Barbitoff Y.A., Tsarev A.A., Vashukova E.S., et al. A Data-Driven Review of the Genetic Factors of Pregnancy Complications. Int J Mol Sci. 2020;21(9):3384. doi: 10.3390/ijms21093384.

21. Sollis E., Mosaku A., Abid A., et al. The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource. Nucleic Acids Res. 2023;51(D1):D977-D985. doi: 10.1093/nar/gkac1010.

22. Glotov A.S., Vashukova Y.S., Glotov O.S. et al. Study of the population frequencies of gene polymorphisms, associated with preeclampsia. Russ J Genet Appl Res/ 2014; 4: 388–396. https://doi.org/10.1134/S2079059714050049

23. Löb S., Vattai A., Kuhn C., et al. The Pregnancy Zone Protein (PZP) is significantly downregulated in the placenta of preeclampsia and HELLP syndrome patients. J Reprod Immunol. 2022;153:103663. doi: 10.1016/j.jri.2022.103663.

24. Cater J.H., Kumita J.R., Zeineddine Abdallah R., et al. Human pregnancy zone protein stabilizes misfolded proteins including preeclampsia and Alzheimer’s-associated amyloid beta peptide. Proc Natl Acad Sci U S A. 2019;116(13):6101-6110. doi: 10.1073/pnas.1817298116.

25. McGinnis R., Steinthorsdottir V., Williams N.O., et al. Variants in the fetal genome near FLT1 are associated with risk of preeclampsia. Nat Genet. 2017;49(8):1255-1260. doi: 10.1038/ng.3895.

26. Fan X., Rai A., Kambham N., et al. Endometrial VEGF induces placental sFLT1 and leads to pregnancy complications. J Clin Invest. 2014;124(11):4941-52. doi: 10.1172/JCI76864.

27. Xin Q., Han Y., Jiang W., et al. Genetic susceptibility analysis of FGF5 polymorphism to preeclampsia in Chinese Han population. Mol Genet Genomics. 2022;297(3):791-800. doi: 10.1007/s00438-022-01889-z.

28. Ren Y., Jiao X., Zhang L. Expression level of fibroblast growth factor 5 (FGF5) in the peripheral blood of primary hypertension and its clinical significance. Saudi J Biol Sci. 2018;25(3):469-473. doi: 10.1016/j.sjbs.2017.11.043.

29. Marigorta U.M., Rodríguez J.A., Gibson G., Navarro A. Replicability and Prediction: Lessons and Challenges from GWAS. Trends Genet. 2018;34(7):504-517. doi: 10.1016/j.tig.2018.03.005.

30. Tam V., Patel N., Turcotte M., et al. Benefits and limitations of genome-wide association studies. Nat Rev Genet. 2019;20(8):467-484. doi: 10.1038/s41576-019-0127-1.

31. Luo X., Stavrakakis N., Penninx B.W., et al. Does refining the phenotype improve replication rates? A review and replication of candidate gene studies on Major Depressive Disorder and Chronic Major Depressive Disorder. Am J Med Genet B Neuropsychiatr Genet. 2016;171B(2):215-36. doi: 10.1002/ajmg.b.32396.

32. Korte A., Farlow A. The advantages and limitations of trait analysis with GWAS: a review. Plant Methods. 2013;9:29. doi: 10.1186/1746-4811-9-29.