Browsing by Author "Laisk-Podar, Triin"

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Challenges in endometriosis miRNA studies - From tissue heterogeneity to disease specific miRNAs.
(2017) Saare, Merli; Rekker, Kadri; Laisk-Podar, Triin; Rahmioglu, Nilufer; Zondervan, Krina; Salumets, Andres; Götte, Martin; Peters, Maire
In order to uncover miRNA changes in endometriosis pathogenesis, both endometriotic lesions and endometrial biopsies, as well as stromal and epithelial cells isolated from these tissues have been investigated and a large number of dysregulated miRNAs have been reported. However, the concordance between the result of different studies has remained small. One potential explanation for limited overlap between the proposed disease-related miRNAs could be the heterogeneity in tissue composition, as some studies have compared highly heterogeneous whole-lesion biopsies with endometrial tissue, some have compared the endometrium from patients and controls, and some have used pure cell fractions isolated from lesions and endometrium. This review focuses on the results of published miRNA studies in endometriosis to reveal the potential impact of tissue heterogeneity on the discovery of disease-specific miRNA alterations in endometriosis. Additionally, functional studies that explore the roles of endometriosis-involved miRNAs are discussed.
Genetic variation as a modulator of susceptibility to female infertility and a source for potential biomarkers
(2015-08-17) Laisk-Podar, Triin
Üks tark mees on öelnud, et lapse saamine on üks ebatõenäoline protsess, ja arvestades seda, kui paljud paarid on viljatusega hädas, oli tal ilmselt õigus. Eestis on enamik naisepoolse viljatuse juhtudest tingitud peamiselt infektsioonide põhjustatud munajuhaviljatusest ja polütsüstiliste munasarjade sündroomist (PCOS), millele on iseloomulik meessuguhormoonide kõrgenenud tase ja insuliinresistentsus. Kunstlik viljastamine võib aidata sellistel juhtudel järglasi saada, kuid kahjuks on ravi tulemuslikkus ~30% ja sõltub suuresti sellest, kuidas munasarjad reageerivad ravi käigus kasutatavatele hormoonidele. Viljatuse molekulaarseid tagamaid on aastate jooksul palju uuritud ja on jõutud järeldusele, et individuaalne geneetiline varieeruvus mängib selle tekkes kindlasti olulist rolli. Geneetilise varieeruvuse uuringud võimaldavad leida ka biomarkereid, mis sobiksid reproduktiivpotentsiaali ja ehk isegi viljatusravi tulemuslikkuse ennustamiseks. Käesoleva töö üldine eesmärk oli hinnata seoseid erinevate geneetiliste variatsioonide ja PCOS-i ning munajuhaviljatuse vahel. Lisaks uurisime mitmeid menopausi algusajaga või munasarja funktsiooniga seotud geneetilisi variante, mis võiksid olla seotud reproduktiivpotentsiaali ja viljatusravi tulemuslikkuse parameetritega. Selle jaoks koguti tervete ja viljakusprobleemidega naiste DNA proovid ning analüüsiti 47 geneetilise variandi seost huvipakkuvate diagnooside ja kliiniliste tunnustega. Et teha kindlaks, kui suur osa munajuhaviljatuse juhtudest on tingitud urogenitaalsest klamüüdiainfektsioonist, määrati munajuhaviljatusega naiste vereseerumist klamüüdia-vastaste antikehade esinemine. Leidsime, et ~50% kõigist munajuhaviljatuse juhtudest võivad olla tingitud eelnevast klamüüdiainfektsioonist ja näitasime, et immuunvastust mõjutav mannoosi siduva lektiini geeni varieeruvus on ilmselt seotud munajuhaviljatuse geneetilise eelsoodumusega. Insuliini ja androgeeni retseptori geenide varieeruvus ei olnud seotud PCOS-iga. Lisaks näitasime, et menopausi algusaega mõjutavad geenivariandid on seotud munasarja funktsiooni ja viljatusravi tulemuslikkuse parameetritega, ja tulevikus võiks neid kombineerituna kliiniliste andmetega kaaluda võimalike biomarkeritena. Antud töö andis uut teavet naise viljakuse ja viljatuse geneetika kohta, kuid ühtlasi rõhutas edasiste uuringute vajalikkust.
Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria
(2018) Day, Felix; Karaderi, Tugce; Jones, Michelle R; Meun, Cindy; He, Chunyan; Drong, Alex; Kraft, Peter; Lin, Nan; Huang, Hongyan; Broer, Linda; Magi, Reedik; Saxena, Richa; Laisk-Podar, Triin; Urbanek, Margrit; Welt, Corrine K; Lindgren, Cecilia M; Franks, Steve; Thorsteinsdottir, Unnur; Stefansson, Kari; Ong, Ken; Anttila, Verneri; Neale, Benjamin M; Jarvelin, Marjo-Riitta; Hayes, Geoffrey M; Thorleifsson, Gudmar; Fernandez-Tajes, Juan; Mahajan, Anubha; Mullin, Benjamin H; Stuckey, Bronwyn G.A; Spector, Timothy D.; Wilson, Scott G; Goodarzi, Mark O; Davis, Lea; Obermeyer-Pietsch, Barbara; Uitterlinden, Andre G; Fauser, Bart; Kowalska, Irina; Visser, Jenny A; Anderson, Marianne; McCarthy, Mark I; Morin-Papunen, Laure; Salumets, Andres; Stener-Victorin, Elisabet; Ehrmann, David; Legro, Richard S; Styrkarsdottir, Unnur; Perry, John; Dunaif, Andrea; Laven, Joop S.E.
Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.
Ovarian Physiology and GWAS: Biobanks, Biology, and Beyond
(2016-05) Laisk-Podar, Triin; Lindgren, Cecilia M.; Peters, Maire; Tapanainen, Juha S.; Lambalk, Cornelis B.; Salumets, Andres; Mägi, Reedik
Ovarian function is central to female fertility, and several genome-wide association studies (GWAS) have been carried out to elucidate the genetic background of traits and disorders that reflect and affect ovarian physiology. While GWAS have been successful in reporting numerous genetic associations and highlighting involved pathways relevant to reproductive aging, for ovarian disorders, such as premature ovarian insufficiency and polycystic ovary syndrome, research has lagged behind due to insufficient study sample size. Novel approaches to study design and analysis methods that help to fit GWAS findings into biological context will improve our knowledge about genetics governing ovarian function in fertility and disease, and provide input for clinical tools and better patient management.
TAC-seq: targeted DNA and RNA sequencing for precise biomarker molecule counting
(2018) Teder, Hindrek; Koel, Mariann; Paluoja, Priit; Jatsenko, Tatjana; Rekker, Kadri; Laisk-Podar, Triin; Kukuškina, Viktorija; Velthut-Meikas, Agne; Fjodorova, Olga; Peters, Maire; Kere, Juha; Salumets, Andres; Palta, Priit; Krjutškov, Kaarel
Targeted next-generation sequencing (NGS) methods have become essential in medical research and diagnostics. In addition to NGS sensitivity and high-throughput capacity, precise biomolecule counting based on unique molecular identifier (UMI) has potential to increase biomolecule detection accuracy. Although UMIs are widely used in basic research its introduction to clinical assays is still in progress. Here, we present a robust and cost-effective TAC-seq (Targeted Allele Counting by sequencing) method that uses UMIs to estimate the original molecule counts of mRNAs, microRNAs, and cell-free DNA. We applied TAC-seq in three different clinical applications and compared the results with standard NGS. RNA samples extracted from human endometrial biopsies were analyzed using previously described 57 mRNA-based receptivity biomarkers and 49 selected microRNAs at different expression levels. Cell-free DNA aneuploidy testing was based on cell line (47,XX, +21) genomic DNA. TAC-seq mRNA profiling showed identical clustering results to transcriptome RNA sequencing, and microRNA detection demonstrated significant reduction in amplification bias, allowing to determine minor expression changes between different samples that remained undetermined by standard NGS. The mimicking experiment for cell-free DNA fetal aneuploidy analysis showed that TAC-seq can be applied to count highly fragmented DNA, detecting significant (p = 7.6 × 10−4) excess of chromosome 21 molecules at 10% fetal fraction level. Based on three proof-of-principle applications we demonstrate that TAC-seq is an accurate and highly potential biomarker profiling method for advanced medical research and diagnostics.