2658-6533Research Results in Biomedicine2658-653310.18413/2313-8955-2018-4-3-0-41513GeneticsEVOLUTIONARY-GENETIC ANALYSIS OF THE ROLE OF REGULATORY REGIONS IN CORO2A GENE IN THE DEVELOPMENT OF HEREDITARY PREDISPOSITION TO PREECLAMPSIA IN RUSSIAN AND YAKUT ETHNIC GROUPSEVOLUTIONARY-GENETIC ANALYSIS OF THE ROLE OF REGULATORY REGIONS IN CORO2A GENE IN THE DEVELOPMENT OF HEREDITARY PREDISPOSITION TO PREECLAMPSIA IN RUSSIAN AND YAKUT ETHNIC GROUPSSerebrovaVictoria N.SerebrovaVictoria N.vika.serebrova@medgenetics.ruTrifonovaEkaterina A.TrifonovaEkaterina A.StepanovВадим A.StepanovВадим A.20184300

Background: Preeclampsia (PE) is one of the most serious pregnancy complications and is the leading cause of maternal and perinatal morbidity and mortality, because there are currently no prognostic biomarkers and effective pharmacological therapy of PE, and the etiopathogenesis of this pathology remains poorly understood. Therefore, studying the genetics components of PE is a promising approach. The aim of the study: To study PE genetics components via the regulatory polymorphic variants (rSNPs) of the new CORO2A candidate gene and to detect the role of natural selection in its formation. Materials and methods: We analyzed 925 DNA samples of women from two ethnic groups: Russian and Yakut (a group of patients with PE, N=412 women and a control group, N=513 women). The search of rSNPs was conducted using the online resource «RegulomeDB». Genotyping was performed using MALDI-TOF mass-spectrometry. Chi-square or Fisher's exact tests were used to compare the frequencies of alleles and genotypes between the analyzed groups. We used the INSIGHT method to detect the signals of natural selection in the evolutionary line of parvorder Catarrhini. Results: In the Russian population, for the allele C of regulatory polymorphism variant rs10985257 has been shown to associate with preeclampsia (p=0.005, OR=2.33, CI:1.32-4.11), while the allele A (p=0.005, OR=0.43, CI:0.24-0.76) and genotype AA (p=0.02, OR=0.45, CI:0.24-0.85) have protective properties. In the evolutionary line of parvorder Catarrhini we demonstrated the effect of weak negative selection for rs10985257, rs2231656 and rs78486797. Conclusions: We demonstrated a significant role of the rs10985257 and adaptive changes of this rSNP at the macroevolutionary level in the formation of hereditary predisposition to PE.

Background: Preeclampsia (PE) is one of the most serious pregnancy complications and is the leading cause of maternal and perinatal morbidity and mortality, because there are currently no prognostic biomarkers and effective pharmacological therapy of PE, and the etiopathogenesis of this pathology remains poorly understood. Therefore, studying the genetics components of PE is a promising approach. The aim of the study: To study PE genetics components via the regulatory polymorphic variants (rSNPs) of the new CORO2A candidate gene and to detect the role of natural selection in its formation. Materials and methods: We analyzed 925 DNA samples of women from two ethnic groups: Russian and Yakut (a group of patients with PE, N=412 women and a control group, N=513 women). The search of rSNPs was conducted using the online resource «RegulomeDB». Genotyping was performed using MALDI-TOF mass-spectrometry. Chi-square or Fisher's exact tests were used to compare the frequencies of alleles and genotypes between the analyzed groups. We used the INSIGHT method to detect the signals of natural selection in the evolutionary line of parvorder Catarrhini. Results: In the Russian population, for the allele C of regulatory polymorphism variant rs10985257 has been shown to associate with preeclampsia (p=0.005, OR=2.33, CI:1.32-4.11), while the allele A (p=0.005, OR=0.43, CI:0.24-0.76) and genotype AA (p=0.02, OR=0.45, CI:0.24-0.85) have protective properties. In the evolutionary line of parvorder Catarrhini we demonstrated the effect of weak negative selection for rs10985257, rs2231656 and rs78486797. Conclusions: We demonstrated a significant role of the rs10985257 and adaptive changes of this rSNP at the macroevolutionary level in the formation of hereditary predisposition to PE.

preeclampsiaregulatory single-nucleotide polymorphisms (rSNPs)association studyCORO2A geneplacentatranscriptomenatural selectionpreeclampsiaregulatory single-nucleotide polymorphisms (rSNPs)association studyCORO2A geneplacentatranscriptomenatural selectionСписок литературыCorbo RM, Gambina G, Scacchi R. How contemporary human reproductive behaviors influence the role of fertility-related genes: the example of the p53 gene. PLoS One. 2012;7(4):e35431.Kirwan JD, Bekaert M, Commins JM, et al. A phylomedicine approach to understanding the evolution of auditory sensory perception and disease in mammals. Evol Appl. 2013;6(3):412-422.Saeb AT, Al-Naqeb D. The impact of evolutionary driving forces on human complex diseases: a population genetics approach. Scientifica (Cairo). 2016;2016:2079704.Scheinfeldt LB, Tishkoff SA. Recent human adaptation: genomic approaches, interpretation and insights. Nat Rev Genet. 2013;14(10):692-702.Boeldt DS, Bird IM. Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. J Endocrinol. 2017;232(1):R27-R44.Tannetta D, Sargent I. Placental disease and the maternal syndrome of preeclampsia: missing links? Curr Hypertens Rep. 2013;15(6):590-599.Trifonova EA, Gabidulina TV, Ershov NI, et al. Analysis of the placental tissue transcriptome of normal and preeclampsia complicated pregnancies. Acta Naturae. 2014.6(2):71-83.Louwen F, Muschol-Steinmetz C, Reinhard J, et al. A lesson for cancer research: placental microarray gene analysis in preeclampsia. Oncotarget. 2012;3(8):759-773.Antontseva EV, Bryizgalov LO, Matveeva MYu, et al. [Search for regulatory SNPs associated with colon cancer in the APC and MLH1 genes]. Vavilovskiy zhurnal genetiki i selektsii. 2011;15(4):644-652. Russian.Jones BL, Swallow DM. The impact of cis-acting polymorphisms on the human phenotype. Hugo J. 2011;5(1-4):13-23.Abrams ET, Rutherford JN. Framing postpartum hemorrhage as a consequence of human placental biology: an evolutionary and comparative perspective. Am Anthropol. 2011;113(3):417-430.Pijnenborg R, Vercruysse L, Hanssens M. Fetal-maternal conflict, trophoblast invasion, preeclampsia, and the red queen. Hypertens Pregnancy. 2008;27(2):183-196.Elliot MG. Oxidative stress and the evolutionary origins of preeclampsia. J Reprod Immunol. 2016;114:75-80.Robillard PY, Hulsey TC, Dekker GA, Chaouat G. Preeclampsia and human reproduction. An essay of a long term reflection. J Reprod Immunol. 2003;59(2):93-100.Løset M, Mundal SB, Johnson MP, et al. A transcriptional profile of the decidua in preeclampsia. Am J Obstet Gynecol. 2011;204(1):e1-27.Meng T, Chen H, Sun M, et al. Identification of differential gene expression profiles in placentas from preeclamptic pregnancies versus normal pregnancies by DNA microarrays. OMICS. 2012;16(6):301-311.Boyle AP, Hong EL, Hariharan M, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22(9):1790-1797.Razin SV, Ulyanov SV, Gavrilov AA. Transcription-controlling regulatory elements of the eukaryotic genome. Molecular Biology. 2015;49(2):185-194.Cheung VG, Spielman RS, Ewens KG, et al. Mapping determinants of human gene expression by regional and genome-wide association. Nature. 2005;437(7063):1365-1369.Stepanov VA, Trifonova EA. Multiplex SNP genotyping by MALDI-TOF mass spectrometry: Frequencies of 56 immune response gene SNPs in human populations. Molecular Biology. 2013;47(6):852-862.Gronau I, Arbiza L, Mohammed J, Siepel A. Inference of natural selection from interspersed genomic elements based on polymorphism and divergence. Mol Biol Evol. 2013;30(5):1159-1171.Arbiza L, Gronau I, Aksoy BA, et al. Genome-wide inference of natural selection on human transcription factor binding sites. Nat Genet. 2013;45(7):723-729.Serebrova VN, Trifonova EA, Stepanov VA. [The role of CORO2A gene regulatory sites in the development of predisposition to preeclampsia]. Meditsinskaya genetika. 206;15(5):32-34. Russian.1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015;526(7571):68-74.Huang W, Ghisletti S, Saijo K, et al. Coronin 2A mediates actin-dependent de-repression of inflammatory response genes. Nature. 2011;470(7334):414-418.Tinel M, Berson A, Elkahwaji J, et al. Downregulation of cytochromes P450 in growth-stimulated rat hepatocytes: role of c-Myc induction and impaired C/EBP binding to DNA. J Hepatol. 2003;39(2):171-178.Gathiram P, Moodley J. Pre-eclampsia: its pathogenesis and pathophysiology. Cardiovasc J Afr. 2016;27(2):71-78.Saito S, Sakai M. Th1/Th2 balance in preeclampsia. J Reprod Immunol. 2003;59(2):161-173.Radde J, Löning T, Bamberger AM. Expression pattern of the CCAAT/enhancer-binding protein C/EBP-beta in gestational trophoblastic disease. Int J Gynecol Pathol. 2004;23(4):373-377.Zhuang B, Luo X, Rao H, et al. Oxidative stress-induced C/EBPβ inhibits β-catenin signaling molecule involving in the pathology of preeclampsia. Placenta. 2015;36(8):839-846.