Genetic susceptibility factors in endometriosis

Endometrioos on sageli esinev krooniline günekoloogiline haigus, mille korral emaka limaskesta sarnane kude esineb kolletena väljaspool emakat, enamasti munasarjadel ja kõhuõõne seinal, harvem ka kuseteedes, sooleseinas jne. Antud kolletest menstruatsiooni ajal erituv veri põhjustab põletikulise reaktsiooni teket ning liidete moodustumist kõhuõõnes. Haigus võib kulgeda kaebusteta, kuid sageli põhjustab see tugevaid alakõhuvalusid ja viljatust, mõjutades seeläbi märkimisväärselt nii haigust põdevate naiste kui nende lähedaste elu. Kuna endometrioosi diagnoosimine põhineb kollete visualiseerimisel operatsiooni käigus, siis võib õige diagnoosini jõudmine hilineda aastaid. Endometrioos on kompleksne haigus, mille tekkepõhjused pole veel täielikult selged. Tõenäoliselt on haiguse kujunemises roll nii geneetilisel eelsoodumusel, immuunsüsteemi häiretel kui ka keskkonnafaktoritel. Endometrioosi riski mõjutavate geenide kindlaks tegemine annab teavet haiguse arengus osalevatest bioloogilistest mehhanismidest ning võimaldab välja töötada efektiivsemaid diagnoosimis- ja ravimeetodeid. Antud töö põhieesmärgiks oli uurida endometrioosi tekke seost erinevate kandidaatgeenidega. Selleks kasutati 199 tervelt ja 150 endometrioosi põdevalt naiselt kogutud DNA proove ning võrreldi erinevate geenivariantide esinemissagedust kahes grupis. Lisaks analüüsiti endometrioosikoes sünteesitava valgu surviviini vastaste autoantikehade esinemist 98 patsiendi ja 47 sarnaste kaebustega endometrioosi mittepõdeva naise seerumis, et selgitada, kas neid saab kasutada haiguse väheinvasiivse biomarkerina. Uuringu tulemused näitasid, et eelsoodumust endometrioosi tekkeks võivad mõjutada kümnest testitud geenist viis, mille poolt kodeeritavad valgud osalevad östrogeenide sünteesis (17β-hüdroksüsteroid dehüdrogenaas 1) ja toimes (östrogeeni retseptor β), koe remodelleerimises (maatriksi metalloproteinaasid 2 ja 9) ja veresoonte kasvus (vaskulaarne endoteliaalne kasvufaktor). Östrogeeni retseptor α kodeeriv geen on aga enam seotud naistel esineva viljatusega. Lisaks selgus, et uuritud antikehi ei saa kasutada endometrioosi diagnostilise markerina, kuna nende sisaldus haigete ja tervete naiste seerumis on sarnane. Antud töö andis uut teavet endometrioosi geneetilise tausta kohta, kuid haigusega seotud geenivariantide täpse toimemehhanismi väljaselgitamiseks on vajalikud edasised uuringud. Endometriosis is a common chronic gynaecological disease defined by the presence of endometrial-like tissue outside the uterus, mainly on the ovaries and peritoneal wall, but sometimes also in the urinary tract, bowel wall, etc. Monthly bleeding from these lesions causes local inflammatory reaction and the formation of adhesions. In some cases the disease may remain asymptomatic, but often it is associated with severe pelvic pain and infertility, thus having a major impact both on women suffering from it as well as on their families. Since the ‘gold standard’ for the diagnosis of endometriosis is laparoscopic visualization of lesions, the right diagnosis is often delayed for years. Endometriosis is a complex disease and its exact aetiology is not clear yet. It is likely that different factors like genetic predisposition, impaired immune function and environmental factors are involved in disease development. Identifying the genes that influence susceptibility to endometriosis could help us understand better various disease mechanisms and thus would aid in the development of more effective diagnostic and therapeutic methods. The aim of the present study was to analyse associations between endometriosis and different candidate genes. Thus, DNA samples from 199 healthy women and 150 endometriosis patients were collected and the frequencies of different genetic variants were compared between the two groups. In addition, to verify whether autoantibodies against survivin, a protein expressed in endometriotic lesions, could be used as a biomarker of endometriosis, their level was measured in the sera of 98 patients and 47 women with similar complaints but without the disease. Out of ten genes that were analysed, five showed an association with endometriosis. These genes encode for proteins involved in oestrogen biosynthesis (17β-hydroxysteroid dehydrogenase type 1) and function (oestrogen receptor β), tissue remodelling (matrix metalloproteinases 2 and 9) and angiogenesis (vascular endothelial growth factor). Instead, the gene encoding for oestrogen receptor α seemed to be more associated with female infertility. It was also found that anti-survivin antibodies cannot be used as a diagnostic marker, since their level is similar in women with and without endometriosis. In conclusion, this study gave new knowledge about the genetics of endometriosis, but further research is needed to clear the exact function of these genetic variants. Endometriosis is a common chronic gynaecological disease defined by the presence of endometrial-like tissue outside the uterus, mainly on the ovaries and peritoneal wall, but sometimes also in the urinary tract, bowel wall, etc. Monthly bleeding from these lesions causes local inflammatory reaction and the formation of adhesions. In some cases the disease may remain asymptomatic, but often it is associated with severe pelvic pain and infertility, thus having a major impact both on women suffering from it as well as on their families. Since the ‘gold standard’ for the diagnosis of endometriosis is laparoscopic visualization of lesions, the right diagnosis is often delayed for years. Endometriosis is a complex disease and its exact aetiology is not clear yet. It is likely that different factors like genetic predisposition, impaired immune function and environmental factors are involved in disease development. Identifying the genes that influence susceptibility to endometriosis could help us understand better various disease mechanisms and thus would aid in the development of more effective diagnostic and therapeutic methods. The aim of the present study was to analyse associations between endometriosis and different candidate genes. Thus, DNA samples from 199 healthy women and 150 endometriosis patients were collected and the frequencies of different genetic variants were compared between the two groups. In addition, to verify whether autoantibodies against survivin, a protein expressed in endometriotic lesions, could be used as a biomarker of endometriosis, their level was measured in the sera of 98 patients and 47 women with similar complaints but without the disease. Out of ten genes that were analysed, five showed an association with endometriosis. These genes encode for proteins involved in oestrogen biosynthesis (17β-hydroxysteroid dehydrogenase type 1) and function (oestrogen receptor β), tissue remodelling (matrix metalloproteinases 2 and 9) and angiogenesis (vascular endothelial growth factor). Instead, the gene encoding for oestrogen receptor α seemed to be more associated with female infertility. It was also found that anti-survivin antibodies cannot be used as a diagnostic marker, since their level is similar in women with and without endometriosis. In conclusion, this study gave new knowledge about the genetics of endometriosis, but further research is needed to clear the exact function of these genetic variants. Description Väitekirja elektrooniline versioon ei sisalda publikatsioone.

endometrioos, pärilikkus, autoantikehad, endometriosis, heredity, autoantibodies