Vpliv polimorfizma rs2277923 v genu za prepisovalni dejavnik NKX2-5 na pojavnost prirojenih srčnih napak v slovenski populaciji

Zupančič, Maruša (author), Karas Kuželički, Nataša (mentor)

Prirojene srčne napake so opredeljene kot prirojene nepravilnosti v strukturnem ali funkcionalnem razvoju srca in predstavljajo eno najpogostejših prirojenih napak z visoko stopnjo smrtnosti novorojenčkov po celem svetu. Razvoj srca je izredno kompleksen večstopenjski proces. Etiologija prirojenih srčnih napak še vedno ni natančno poznana, najverjetnje gre za multifaktorski vzrok, ki združuje genetske in okoljske dejavnike. Potencialni genetski dejavnik tveganja predstavljajo mutacije v genu za prepisovalni dejavnik Nkx2-5. Spremembe v genu nkx2-5 lahko pomembno vplivajo na delovanje prepisovalnega dejavnika, kar poveča tveganje za nastanek prirojenih srčnih napak. Eden izmed preiskovanih polimorfizmov v genu nkx2-5 je polimorfizem rs2277923. Namen magistrske naloge je določiti vpliv polimorfizma rs2277923 na pojavnost prirojenih srčnih napak v slovenski populaciji. S tehnologijo hidrolizirajočih sond Taqman smo genotipizirali 119 otrok s potrjeno obliko nesindromske prirojene srčne napake in 169 zdravih kontrol. Prirojene srčne napake smo za bolj poglobljeno študijo opredelili tudi glede na etiološko klasifikacijo ter izpostavili najpogostejše oblike prirojenih srčnih napak v slovenski populaciji. Kljub temu, da nismo uspeli dokazati statistično značilnih razlik med preiskovano in kontrolno skupino, v študiji izstopajo rezultati prirojenih srčnih napak atrialnega septalnega defekta (ASD), aortne stenoze (AS) in tetralogije Fallot (TOF), kjer se nakazuje morebitna povezava polimorfizma rs2277923 s tveganjem za razvoj posameznih oblik srčnih napak. Predvidevamo, da bi s povečanjem števila preiskovancev v posameznih kategorijah morda dosegli statistično značilne vrednosti. Določili smo tudi pogostost polimorfizma rs2277923 v slovenski populaciji in jo primerjali z drugimi svetovnimi populacijami, saj pogostost alelov med svetovnimi populacijami močno variira. Alelna frekvenca v slovenski populaciji znaša 71 % za alel A ter 29 % za alel G, kar predstavlja skorajšnje popolno ujemanje z evropskim povprečjem. Študije nakazujejo, da je polimorfizem rs2277923 v nastanek prirojenih srčnih napak vpleten preko vpliva na koregulirane prepisovalne dejavnike in tarčne gene, preko vpliva na nivoju mRNA ali preko vpliva na proteinskem nivoju. Sklepamo, da rs2277923 izraziteje vpliva na nastanek le določenih oblik prirojenih srčnih napak, vendar po še neznanem mehanizmu. Za boljše razumevanje vpletenosti polimorfizma rs2277923 v nastanek prirojenih srčnih napak so potrebne dodatne študije.

• Language: Slovenian
• Keywords: razvoj srca, prirojene srčne napake, prepisovalni dejavnik Nkx2-5, polimorfizem rs2277923, pogostost alela
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2021
• PID: 20.500.12556/RUL-127745
• Publication date in RUL: 22.06.2021

Secondary language

• Language: English
• Title: The influence of rs2277923 polymorphism in the NKX2-5 transcription factor gene on the occurrence of congenital heart disease in Slovenian population

Abstract

Congenital heart diseases or congenital heart defects (CHD) are defined as congenital abnormalities in the structural and functional development of the heart and represent one of the most common congenital birth defects with a high mortality rate in newborns worldwide. Cardiac development is an extremely complex multi-stage process. The etiology of congenital heart defects is still not precisely known, most likely it is a multifactorial cause that combines genetic and environmental factors. One of the potential genetic risk factors are mutations in the Nkx2-5 transcription factor gene. Changes in the nkx2-5 gene can significantly affect the function of the transcription factor which greatly increases the risk of congenital heart defects. One of the investigated polymorphisms in the nkx2-5 gene is rs2277923. The purpose of the master's thesis is to determine the influence of the rs2277923 polymorphism on the occurrence of congenital heart defects in the Slovenian population. Using Taqman hydrolysis probe technology, we genotyped 119 children with a confirmed form of nonsyndromic congenital heart defect and 169 healthy controls. For a more in-depth study we defined congenital heart defects according to the etiological classification and pointed out the most common types of congenital heart defects in the Slovenian population. Despite the statistically insignificant results in our study, the results of the analysis of the atrial septal defect (ASD), aortic stenosis (AS) and tetralogy of Fallot (TOF) stand out, indicating rs2277923 association and involvement in the occurrence of heart defects. We assume that by increasing the number of subjects in individual categories, we might achieve statistically significant values. We also determined the frequency of the rs2277923 polymorphism in the Slovenian population and compared it with other world populations as the frequency of alleles varies greatly among world populations. The allele frequency in the Slovenian population is 71 % for the A allele and 29 % for the G allele, which represents an almost perfect fit with the European average. Studies suggest that the rs2277923 polymorphism is involved in the development of congenital heart defects through the influence on co-regulated transcription factors and target genes, through influence at the mRNA level, or at the protein level. We conclude that rs2277923 has a more distinct effect on the development of only particular types of congenital heart defects, but the mechanism remains unknown. In order to better understand involvement of rs2277923 in the development of congenital heart defects further studies are needed.

• Keywords: heart development, congenital heart disease, transcription factor Nkx2-5, polymorphism rs2277923, allele frequency