Genetic variation as a modulator of susceptibility to female infertility and a source for potential biomarkers
Date
2015-08-17
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
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.
A wise man once said that the reproduction of mankind is a great marvel and mystery, and he was absolutely right, considering how many couples actually tackle with infertility. In Estonia, the majority of female infertility cases are due to tubal infertility (TFI) that is mostly caused by sexually transmitted infections, and polycystic ovary syndrome (PCOS), which is an endocrine disorder characterised by androgen excess and insulin resistance. In vitro fertilisation can help achieve pregnancy in these cases, but unfortunately the pregnancy rate per treatment cycle is only 30% and depends greatly on how the ovaries respond to the treatment. Over the years, great effort has been directed towards elucidating the molecular mechanisms behind the conditions causing infertility and it has been concluded that individual genetic variation is definitely one of the factors to blame. The studies of individual genetic variation form a good basis for finding biomarkers to predict natural reproductive function and perhaps even infertility treatment success. The general objective of the current thesis was to assess the associations between PCOS, TFI and selected candidate genes. In addition, several genetic variants that could be related to ovarian function and infertility treatment parameters were evaluated. Thus, DNA samples were collected from healthy women and infertile women and 47 genetic variants were studied in association with diagnoses of interest and different clinical parameters. In addition, to determine how many TFI cases are caused by a chlamydia infection, the prevalence of chlamydia-specific antibodies was measured in the blood sera of women with TFI. As a result, we found that ~50% of all TFI cases in Estonia might be caused by a previous chlamydia infection and identified genetic variants in the mannose binding lectin gene that modulate immune response and may be associated with susceptibility to TFI. No associations were found between selected variants in genes for insulin and androgen receptor and PCOS. However, we showed that genetic variants related to menopause timing are associated with ovarian function and infertility treatment parameters and could be considered as biomarker candidates if combined with clinical data. In conclusion, this study gave new knowledge about the genetics of female reproduction, but also highlighted the need for further research.
A wise man once said that the reproduction of mankind is a great marvel and mystery, and he was absolutely right, considering how many couples actually tackle with infertility. In Estonia, the majority of female infertility cases are due to tubal infertility (TFI) that is mostly caused by sexually transmitted infections, and polycystic ovary syndrome (PCOS), which is an endocrine disorder characterised by androgen excess and insulin resistance. In vitro fertilisation can help achieve pregnancy in these cases, but unfortunately the pregnancy rate per treatment cycle is only 30% and depends greatly on how the ovaries respond to the treatment. Over the years, great effort has been directed towards elucidating the molecular mechanisms behind the conditions causing infertility and it has been concluded that individual genetic variation is definitely one of the factors to blame. The studies of individual genetic variation form a good basis for finding biomarkers to predict natural reproductive function and perhaps even infertility treatment success. The general objective of the current thesis was to assess the associations between PCOS, TFI and selected candidate genes. In addition, several genetic variants that could be related to ovarian function and infertility treatment parameters were evaluated. Thus, DNA samples were collected from healthy women and infertile women and 47 genetic variants were studied in association with diagnoses of interest and different clinical parameters. In addition, to determine how many TFI cases are caused by a chlamydia infection, the prevalence of chlamydia-specific antibodies was measured in the blood sera of women with TFI. As a result, we found that ~50% of all TFI cases in Estonia might be caused by a previous chlamydia infection and identified genetic variants in the mannose binding lectin gene that modulate immune response and may be associated with susceptibility to TFI. No associations were found between selected variants in genes for insulin and androgen receptor and PCOS. However, we showed that genetic variants related to menopause timing are associated with ovarian function and infertility treatment parameters and could be considered as biomarker candidates if combined with clinical data. In conclusion, this study gave new knowledge about the genetics of female reproduction, but also highlighted the need for further research.
Description
Väitekirja elektrooniline versioon ei sisalda publikatsioone.
Keywords
naised, viljatus, biomarkerid, munasarjade polütsüstiline haigus, munajuhad, geneetiline muutlikkus, immuunvastus, Eesti, women, infertility, biomarkers, polycystic ovary disease, fallopian tubes, genetic variability, immune response, Estonia