Varijacije odabranih gena u bolesnica sa sindromom policističnih jajnika [Polymorphisms of selected genes in polycystic ovary syndrome]

Škrgatić, Lana (2011) Varijacije odabranih gena u bolesnica sa sindromom policističnih jajnika [Polymorphisms of selected genes in polycystic ovary syndrome]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

INTRODUCTION: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of the reproductive age women. Familial clustering of the PCOS implicates on genetic background. Different phenotypes of the syndrome suggest that PCOS is a complex genetic disorder wherein a variety of predisposing genes interact with environmental factors to produce the disease. Large numbers of association studies are conducted attempting to discover genes that influence the PCOS using candidate gene approach. ----- AIM: The aim of the present study was to investigate the association of (CAG)n AR, (TAAAA)n SHBG, Asp327Asn SHBG, VNTR INS, C/T INSR, Gly792Arg IRS-1 and Pro12Ala PPAR-γ genetic polymorphisms with the presence of the PCOS and different clinical and biochemical traits in Croatian women. ----- STUDY SUBJECTS AND METHODS: The study enrolled 214 women with PCOS and 209 control women. The diagnosis of PCOS was based on Rotterdam consensus criteria. Each subject underwent an evaluation of BMI, WHR, hirsutism, acne and menstrual cycle abnormalities as well as FSH, LH, total and free testosterone, androstendione, DHEAS, SHBG, fasting glucose and fasting insulin. Molecular genetic analyses for the genetic polymorphisms were preformed. ----- RESULTS: There was a significant difference in clinical and biochemical characteristics of the studied groups except for BMI, WHR and fasting glucose levels. (CAG)n AR polymorphism was not identified as a major determinant of the PCOS, but it is a predictor of the serum total testosterone levels variability in women with the PCOS. Longer (TAAAA)n SHBG alleles were found to be significant predictors of the lower serum SHBG levels in both groups studied, thus it probably presents a susceptibility polymorphism for hyperandrogenemia but not PCOS itself. Pro12Ala PPARγ polymorphism was found to have a positive effect on insulin sensitivity in PCOS patients. This polymorphism could present a protective variant for hyperinsulinemia that frequently accompanies the syndrome. The Asp327Asn SHBG, VNTR INS, C/T INSR, Gly792Arg IRS-1 polymorphisms were not identified as susceptibility factors for PCOS. Moreover, no association was found between VNTR INS, C/T INSR and Gly792Arg IRS-1 polymorphism and parameters of insulin resistance in PCOS patients. ----- CONCLUSIONS: The present findings may contribute to systematic efforts to replicate positive results of previously conducted genetic studies since PCOS is a complex disease in which each gene contributes modestly to disease risk.

Abstract in Croatian

UVOD: Sindrom policističnih jajnika najčešća je endokrinopatija žena reproduktivne dobi. Učestala pojavnost unutar obitelji pretpostavlja gensku podlogu sindroma. Velika raznolikost fenotipova govori u prilog tome da je PCOS složena genska bolest koja nastaje međudjelovanjem čimbenika okoliša s genskim čimbenicima u podlozi sindroma. Posljednjih je godina proveden velik broj asocijacijskih studija koje su istraživale gensku podlogu PCOS-a, istražujući pri tomu ulogu pretpostavljenih gena kandidata. ----- CILJ: Cilj ovog istraživanja bio je istražiti povezanost genskih polimorfizama: (CAG)n AR, (TAAAA)n SHBG, Asp327Asn SHBG, VNTR INS, C/T INSR, Gly792Arg IRS-1 i Pro12Ala PPAR-γ s nastankom PCOS-a te s različitim kliničkim i biokemijskim značajkama ovoga sindroma u hrvatskoj populaciji bolesnica. ----- ISPITANICE I METODE: U studiju smo uključili 214 bolesnica s PCOS-om i 209 kontrolnih ispitanica. Dijagnozu smo postavili na temelju konsenzusa u Rotterdamu. Svakoj ispitanici izmjeren je ITM, omjer struka i bokova, stupanj hirzutizma i akni te ocijenjen poremećaj ciklusa. Određene su serumske vrijednosti FSH-a, LH-a, ukupnoga i slobodnoga testosterona, DHEAS-a, androstendiona, SHBG-a te glukoze i inzulina na tašte. Provedene su molekularnogenetičke analize za određivanje genskih polimorfizama. ----- REZULTATI: Našli smo značajnu razliku u većini kliničkih i biokemijskih značajki između istraživanih skupina osim za ITM, omjer struka i bokova i glukoze na tašte. Nismo našli da je (CAG)n AR-polimorfizam ključan za razvoj PCOS-a, ali se pokazao značajnim pretkazateljem serumskih vrijednosti ukupnoga testosterona u bolesnica s PCOS-om. Dulji aleli (TAAAA)n SHBG značajno predviđaju niske serumske razine SHBG-a, ali neovisno o PCOS-statusu pa vjerujemo da je ovaj polimorfizam važan čimbenik za nastanak hiperandrogenemije, a ne samoga PCOS-a. Polimorfizam Pro12Ala PPAR-γ pozitivno utječe na osjetljivost na inzulin u bolesnica s PCOS-om pa je moguće da je to zaštitna varijanta za ublaživanje hiperinzulinemije koja često prati PCOS. Nismo našli povezanost polimorfizama Asp327Asn SHBG, VNTR INS, C/T INSR i Gly792Arg IRS-1 s razvojem PCOS-a kao ni njihov utjecaj na parametre inzulinske rezistencije. ----- ZAKLJUČAK: S obzirom na to da je PCOS složena genska bolest, kod koje pojedinačni gen samo umjereno pridonosi ukupnom riziku za bolest, nalazi ove studije mogli bi pridonijeti sustavnim naporima da se repliciraju pozitivni nalazi prethodno provedenih genetičkih studija.

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