Epigenetics in preeclampsia: meta-analysis with meta-regression

Preeklampsija predstavlja jedan od hipertenzivnih poremećaja u trudnoći koji se karakteriše novonastalim povišenim arterijskim pritiskom i proteinurijom nakon 20. nedelje gestacije sa učestalošću javljanja od čak 5-10%. Predstavlja važan uzrok maternalnog i perinatalnog morbiditeta i mortaliteta. Procenjen broj smrtnih slučajeva majki uzrokovanih preeklampsijom na godišnjem nivou iznosi 30000, što čini neverovatnih 15% ukupnog maternalnog mortaliteta. Stanje preeklampsije utiče na razvoj i zdravlje ploda. Intrauterini zastoj u rastu ploda, prevremeno rođenje i smrt su komplikacije trudnoće koje se povezuju sa preeklampsijom. Prevremeni porođaj je, za sada, jedini vid lečenja. Neki od faktora koji su dovedeni u vezu sa nastankom preeklampsije su antifosfolipidni sindrom, prethodna preeklampsija, insulin zavisni dijabetes melitus, višeplodna trudnoća, nuliparitet, pozitivna porodična anamneza za preeklampsiju, gojaznost, starosna dob majke, prethodna hronična hipertenzija i/ili hronična oboljenja bubrega. Nakon prilično dugog perioda istraživanja u ovoj oblasti, patogeneza preeklampsije je delimično rasvetljena. Poznato je da, jednim delom zbog neadekvatne trofoblastne invazije, a drugim delom zbog neadekvatnog remodelovanja spiralnih arterija i aberantne vaskulogeneze u placenti, dolazi do stanja hipoksije koje indukuje angiogene i antiangiogene faktore, sa pokretanjem molekularnog procesa preeklampsije. Prethodna istraživanja su pokazala da ove procese modulišu fini epigenetski mehanizmi, koji predstavljaju nasledne promene genske ekspresije koje nisu praćene promenom DNK sekvence. Ipak, do sada je nedovoljno razjašnjeno učešće epigenetskih markera, kao karike u gotovo svakom ćelijskom procesu, u patogenezi ovog oboljenja. Cilj ove studije je bilo utvrđivanje povezanosti epigenetskih nalaza (metilacija DNK molekula, ekspresija miRNA, izmena histona i genetičko utiskivanje) u različitim tkivima žena sa preeklampsijom u poređenju sa ženama bez preeklampsije. Imajući u vidu da je osnov većine istraživanja u humanoj populaciji, istraživanje na eksperimentalnim modelima, cilj ove studije je takođe bio i ispitivanje navedenih epigenetskih markera u eksperimentalno izazvanoj preeklampsiji na životinjskim modelima u poređenju sa životinjama bez ovog oboljenja. Sa ciljem prikupljanja i sinteze relevantnih rezultata koji se odnose na ovo izuzetno važno istraživačko pitanje, izvedeni su sistematski pregled literature i meta-analiza. Sistematski pregled literature je izveden prema preporukama MOOSE vodiča za opservacione studije. Pretraživanje je obuhvatilo tri elektronske baze podataka: PubMed, EMBASE i Web of Science. Uključene su studije koje su ispitivale epigenetske mehanizme (nivo metilacije DNK molekula, ekspresije miRNK, izmenjenih histona i nivo ekspresije gena koji podležu genetičkom utiskivanju) u populaciji žena i životinja. U cilju dobijanja objedinjene kvantitativne mere veličine razlike nivoa metilacije DNK molekula, ekspresije miRNK, nivoa izmenjenog histona i ekspresije gena koji podležu genetičkom utiskivanju korišćena je standardizovana prosečna razlika (SMD). Analiza je izvedena u softverskom program Review Manager. Od ukupno 2331 uključene publikacije, na osnovu definisanih kriterijuma za uključenje, nakon uklanjanja duplikata i čitanja sažetaka i naslova, preostalo je 436 publikacija. Čitanjem svih radova u punom tekstu i nakon dodatnog isključivanja, identifikovano je 94 odgovarajućih publikacija koje su ispitivale nivo metilacije DNK molekula, 174 publikacija koje su ispitivale nivo ekspresije miRNK, 7 publikcija koje su ispitivale izmenu histona i 7 publikacija koje su ispitivale genetičko utiskivanje u populaciji žena i životinja...Preeclampsia is one of the hypertensive disorders in pregnancy, which is characterized by newly developed high blood pressure and proteinuria after the 20th week of gestation with an incidence of 5-10%. It is an important cause of maternal and perinatal morbidity and mortality. The estimated number of maternal deaths caused by preeclampsia annually is 30,000, which makes an incredible 15% of the total maternal mortality. Preeclampsia influences the development and health of the fetus. Intrauterine growth retardation, premature birth and death are complications of pregnancy associated with preeclampsia. Premature birth is currently the only type of treatment. Some of the factors associated with the development of preeclampsia are antiphospholipid syndrome, previous preeclampsia, insulin-dependent diabetes mellitus, multiple pregnancy, nulliparity, positive family history of preeclampsia, obesity, maternal age, and previous chronic hypertension. After a rather long period of research in this area, the pathogenesis of preeclampsia has been partially elucidated. It is known that, partly due to inadequate trophoblastic invasions, and partly due to inadequate remodeling of spiral arteries and aberrant vasculogenesis in the placenta, hypoxia occurs and induces angiogenic and antiangiogenic factors sectretion, with the initiation of the molecular process of preeclampsia. Previous research has shown that these processes are modulated by fine epigenetic mechanisms, which represent inherited changes in gene expression that are not accompanied by a change in the DNA sequence. However, the participation of epigenetic markers, as part of almost every cellular process, in the pathogenesis of this disease has not been sufficiently explained. The aim of this study was to determine the magnitude of changes in epigenetic markers (DNA methylation, miRNA expression, histone change, and gene imprinting) in different tissue types of women with preeclampsia compared with women without preeclampsia. Bearing in mind that the basic research of the majority investigations in the human population is the research of experimental models, the aim of this study was also to examine the mentioned epigenetic markets in animal models of preeclampsia in comparison with animals without this disease. With the aim of collecting and synthesizing relevant results related to this extremely important research question, a systematic review of the literature and meta-analysis were performed. A systematic review of the literature was performed according to the recommendations of the MOOSE guideline for observational studies. The search included three electronic databases: PubMed, EMBASE and Web of Science. Studies examining epigenetic mechanisms (level of methylation of DNA molecules, expression of miRNA, altered histones, and level of expression of genes subject to genetic imprinting) in women with and without preeclampsia were included. In order to obtain an overall quantitative measure of the magnitude of the difference in the levels of DNA molecule methylation, miRNA expression, altered histone levels, and gene expression subject to genetic imprinting, standardized mean difference (SMD) was used. The analysis was performed in the software program Review Manager 5.3. Out of a total of 2331 included publications, collected based on the defined inclusion criteria, after removing duplicates and reading abstracts and titles, 436 publications remained. After full text reading and further exclusion, 94 relevant publications examining the level of DNA methylation, 174 publications examining the level of miRNA expression, 7 publications examining histone exchanges and 7 publications examining genetic imprinting in the population of women and animals..