Single nucleotide variants affecting placental gene expression and pregnancy outcome
Date
2021-07-02
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Abstract
Platsenta on unikaalne organ, mis eksisteerib inimkehas ainult raseduse ajal ning kõrvalekalded selle normaalsest arengust ja funktsioonist võivad kaasa tuua rasedustüsistusi, näiteks preeklampsia. Nende üks riskitegureid on nihe oluliste platsenta geenide avaldumise profiilis. Mehhanismid, mis vastutavad platsenta genoomi regulatsiooni eest vastavalt loote vajadustele ja raseduse etapile pole seni detailselt teada. Muude regulaatorite seas on esile tõusnud ka geneetiliste variantide ehk eVariantide mõju geenide avaldumise taseme mõjutajatena. Platsenta koes on neid seni vähe uuritud.
Antud töö eesmärk oli uurida platsenta genoomi variantide mõju geenide avaldumisele ning rasedustüsistuste tekke riskile. Esiteks analüüsin kahe preeklampsia kandidaatgeeni Vaskulaarse endoteeli kasvufaktori retseptor 1 (FLT1) ja Stanniokaltsiin 1 (STC1) varieeruvust. Eesti rasedate valimis (2097 naist) tuvastasin FLT1 geeni lähedal asuva variandi tugeva ning spetsiifilise seose preeklampsia esinemise riskiga. On huvitav, et see variant mõjutas FLT1 geeni avaldumise taset ainult preeklampsia juhtumite platsentades. Leidsin ka STC1 geeniprodukti taset mõjutava geenivariandi, kuid selle seos preeklampsiaga vajab veel täiendavaid uuringuid. Teiseks viisin läbi ülegenoomse analüüsi, et uurida laiemalt platsenta kude mõjutavaid eVariante. Tuvastasin 199 geneetilist seost, mis mõjutasid 63 geeni avaldumist. Neist 13 olid varasemalt platsentas kirjeldamata. Illustreerides platsenta geneetiliste variantide laia fenotüübilist mõju, oli osa leitud geenivariante varasemalt seostatud täiskasvanuea haiguste riskidega või olid minu analüüsitud valimis seotud vastsündinu kasvuparameetritega. Kombineerides tulemusi varasema kirjandusega, koostasin koondnimekirja ~400 platsenta geenist, mille avaldumine on mõjutatud geneetilisest varieeruvusest. See ülevaade on hea lähtepunkt tulevastele platsenta eVariantide uurimustele nii bioloogilises kui meditsiinilises võtmes, e.g., seoses rasedustüsistusetega.
The placenta is a unique transient organ only present during the pregnancy. Deviations from normal placental development can lead to pregnancy complications such as preeclampsia. One of the risk factors for complications is a disruption of important placental gene expression profiles. Mechanisms that regulate the placental genes to provide accurate and dynamic expression in response to fetal needs and pregnancy stage are still not fully understood. Genetic variants modulating gene expression or eVariants are among many possible mechanisms. Still, placental eVariants are underexplored. This thesis project aimed to investigate the effect of placental variants on gene expression and the risk of developing a pregnancy complication. First, the variation near two preeclampsia candidate genes, Vascular endothelial growth factor receptor 1 (FLT1) and stanniocalcin-1 (STC1) were analyzed. I detected a specific association between preeclampsia risk and a FLT1 variant in a sizeable Estonian cohort (2097 pregnant women). Interestingly, the preeclampsia risk variant affected FLT1 gene expression only in the preeclampsia placentas. Another variant near STC1 was shown to affect the gene expression, but its link to preeclampsia risk needs further research. Secondly, I conducted a genome-wide analysis to identify placental eVariants broadly. Overall, I uncovered 199 links that affected the expression of 63 genes, 13 of which were previously unknown for the placenta. Illustrating the broad impact of placental genetic variants, some eVariants were previously associated with adult diseases or pointed to an association with newborn parameters in the analyzed sample set. Combining the results with previous studies, I compiled a list of over 400 robust placental genes affected by genetic variation. This overview is a good starting point for future placenta eVariant research both in biological and medical aspects, e.g., regarding pregnancy complications.
The placenta is a unique transient organ only present during the pregnancy. Deviations from normal placental development can lead to pregnancy complications such as preeclampsia. One of the risk factors for complications is a disruption of important placental gene expression profiles. Mechanisms that regulate the placental genes to provide accurate and dynamic expression in response to fetal needs and pregnancy stage are still not fully understood. Genetic variants modulating gene expression or eVariants are among many possible mechanisms. Still, placental eVariants are underexplored. This thesis project aimed to investigate the effect of placental variants on gene expression and the risk of developing a pregnancy complication. First, the variation near two preeclampsia candidate genes, Vascular endothelial growth factor receptor 1 (FLT1) and stanniocalcin-1 (STC1) were analyzed. I detected a specific association between preeclampsia risk and a FLT1 variant in a sizeable Estonian cohort (2097 pregnant women). Interestingly, the preeclampsia risk variant affected FLT1 gene expression only in the preeclampsia placentas. Another variant near STC1 was shown to affect the gene expression, but its link to preeclampsia risk needs further research. Secondly, I conducted a genome-wide analysis to identify placental eVariants broadly. Overall, I uncovered 199 links that affected the expression of 63 genes, 13 of which were previously unknown for the placenta. Illustrating the broad impact of placental genetic variants, some eVariants were previously associated with adult diseases or pointed to an association with newborn parameters in the analyzed sample set. Combining the results with previous studies, I compiled a list of over 400 robust placental genes affected by genetic variation. This overview is a good starting point for future placenta eVariant research both in biological and medical aspects, e.g., regarding pregnancy complications.
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Keywords
clinical research, pregnancy, placenta, gene expression, genotype, pregnancy complications