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(Epi)-Genetycznych W Wysokiej Krótkowzroczności U Polskich Pacjentów

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(Epi)-Genetycznych W Wysokiej Krótkowzroczności U Polskich Pacjentów Joanna Świerkowska Charakterystyka wybranych aspektów (epi)-genetycznych w wysokiej krótkowzroczności u polskich pacjentów MONOGRAFIA Poznań, 2019 Copyright © Joanna Świerkowska Copyright © Instytut Genetyki Człowieka PAN Poznań 2019 Recenzenci naukowi: Prof. dr hab. n. med. Marzena Gajęcka dr inż. n. farm. Justyna A. Karolak Projekt okładki: Mirka Korbańska Zdjęcia i ilustracje pochodzą ze zbiorów autora ISBN: 978-83-950393-4-8 Wydawca Instytut Genetyki Człowieka PAN ul. Strzeszyńska 32, 60-479 Poznań www.igcz.poznan.pl Joanna Świerkowska Charakterystyka wybranych aspektów (epi)-genetycznych w wysokiej krótkowzroczności u polskich pacjentów SPIS TREŚCI 1. WYKAZ SKRÓTÓW STOSOWANYCH W PRACY ................................................ 7 2. STRESZCZENIE PRACY W JĘZYKU POLSKIM .................................................... 8 3. STRESZCZENIE PRACY W JĘZYKU ANGIELSKIM ............................................. 9 4. WSTĘP ....................................................................................................................... 10 4.1. Zasada tworzenia obrazu widzianych przedmiotów ............................................ 10 4.2. Charakterystyka kliniczna wysokiej krótkowzroczności ..................................... 11 4.3. Epidemiologia krótkowzroczności i wysokiej krótkowzroczności ..................... 11 4.4. Czynniki środowiskowe warunkujące powstawanie krótkowzroczności ............ 12 4.5. Czynniki genetyczne w krótkowzroczności ........................................................ 13 4.5.1. Loci krótkowzroczności i wysokiej krótkowzroczności ............................... 13 4.5.2. Geny kandydaci powiązane z wysoką krótkowzrocznością ......................... 14 4.5.3. Czynniki genetyczne warunkujące długość osiową gałki ocznej, ciśnienie wewnątrzgałkowe i krzywiznę rogówki ................................................................. 16 4.6. Czynniki epigenetyczne w krótkowzroczności .................................................... 17 4.7. Uzasadnienie podjęcia tematu rozprawy doktorskiej .......................................... 19 5. CEL NAUKOWY PROWADZONYCH BADAŃ ..................................................... 21 6. MATERIAŁY ............................................................................................................. 22 6.1. Pacjenci i materiał biologiczny ............................................................................ 22 6.2. Charakterystyka badanych grup ........................................................................... 23 6.3. Rodowody rodzin polskich wybranych do analizy fenotypowej i genotypowej . 23 6.4. Odczynniki ........................................................................................................... 27 6.5. Aparatura i oprogramowanie ............................................................................... 28 6.6. Bazy danych i narzędzia bioinformatyczne ......................................................... 28 7. METODY ................................................................................................................... 29 7.1. Badania podmiotowe i okulistyczne .................................................................... 29 7.2. Analiza statystyczna danych klinicznych członków polskich rodzin .................. 29 7.3. Weryfikacja wyników sekwencjonowania eksomowego .................................... 31 7.3.1. Analiza wyników sekwencjonowań eksomowych i wybór wariantów do weryfikacji .............................................................................................................. 32 7.3.2. Projektowanie starterów ............................................................................... 33 7.3.3. Łańcuchowa reakcja polimerazy .................................................................. 33 7.3.4. Rozdział elektroforetyczny ........................................................................... 33 7.3.5. Sekwencjonowanie metodą Sangera ............................................................. 34 7.4. Analiza znanych polimorfizmów pojedynczego nukleotydu powiązanych z długością osiową gałki ocznej, ciśnieniem wewnątrzgałkowym i krzywizną rogówki u pacjentów z HM ....................................................................................................... 34 7.5. Analiza całogenomowej metylacji ....................................................................... 36 8. WYNIKI ..................................................................................................................... 39 8.1. Wyniki badań okulistycznych i podmiotowych u członków polskich rodzin ..... 39 8.1.1. Fenotypy występujące wśród badanych członków rodzin z HM ................. 39 8.1.2. Struktura wieku osób badanych .................................................................... 39 8.1.3. Charakterystyka pacjentów pod względem współistniejących lub przebytych chorób i operacji narządu wzroku oraz chorób ogólnych ....................................... 40 8.1.4. Charakterystyka przedniego odcinka i dna oka ............................................ 43 8.1.5. Dodatkowe informacje .................................................................................. 44 8.1.6. Dane kliniczne pacjentów oraz członków wybranych rodzin ...................... 45 8.1.7. Dane kliniczne dzieci zakwalifikowanych do badania całogenomowej metylacji .................................................................................................................. 55 8.2. Wyniki analiz statystycznych danych klinicznych .............................................. 56 8.2.1. Wyniki statystyki opisowej ........................................................................... 56 8.2.2. Wyniki statystyki testowej ............................................................................ 59 8.2.3. Zależności pomiędzy badanymi parametrami okulistycznymi ..................... 63 8.3. Weryfikacja wyników sekwencjonowania eksomowego .................................... 73 8.3.1. Analiza bioinformatyczna wyników sekwencjonowania eksomowego ....... 73 8.3.2. Weryfikacja wyników sekwencjonowania eksomowego ............................. 73 8.3.3. Dodatkowa analiza bioinformatyczna wyników sekwencjonowania eksomowego ........................................................................................................... 80 8.3.4. Weryfikacja wybranych wyników sekwencjonowania eksomowego .......... 81 8.4. Wyniki analizy wariantów sekwencji powiązanych z długością osiową gałki ocznej, ciśnieniem wewnątrzgałkowym i krzywizną rogówki u pacjentów z HM .... 86 8.4.1. Analizy polimorfizmów związanych z długością osiową gałki ocznej ........ 86 8.4.2. Analiza polimorfizmów związanych z ciśnieniem wewnątrzgałkowym ...... 87 8.4.3. Analizy polimorfizmów związanych z krzywizną rogówki ......................... 87 8.5. Wyniki analiz całogenomowej metylacji DNA ................................................... 88 8.5.1. Wyniki analiz hipermetylacji DNA .............................................................. 88 8.5.2. Wyniki analiz hipometylacji DNA ............................................................... 93 9. DYSKUSJA .............................................................................................................. 100 10. WNIOSKI ............................................................................................................... 116 11. PIŚMIENNICTWO ................................................................................................ 117 12. SPIS RYCIN ........................................................................................................... 135 13. SPIS TABEL ........................................................................................................... 136 14. ZAŁĄCZNIKI ........................................................................................................ 139 1. WYKAZ SKRÓTÓW STOSOWANYCH W PRACY Skrót Rozwinięcie w języku angielskim Rozwinięcie w języku polskim AL axial length długość osiowa gałki ocznej AUC area under the curve pole powierzchni pod krzywą ROC CC corneal curvature krzywizna rogówki CCR corneal curvature radius promień krzywizny rogówki cGMP cyclic guanosine monophosphate cykliczny guanozynomonofosforan CP corneal power moc łamiąca rogówki D dioptre dioptria DNA deoxyribonucleic acid kwas deoksyrybonukleinowy dNTP deoxynucleoside triphosphate trifosforan deoksyrybonukleotydu DMSO dimethyl sulfoxide dimetylosulfotlenek ECM extracellular matrix macierz zewnątrzkomórkowa EDTA ethylenediaminetetraacetic acid kwas etylenodiaminotetraoctowy ES exome sequencing sekwencjonowanie eksomowe FAK focal adhesion kinase kinaza ogniskowo-adhezyjna spodziewany odsetek wyników FDR false discovery rate fałszywie dodatnich GWAS genome-wide association study badania asocjacyjne całego genomu HM high myopia wysoka krótkowzroczność IOP intraocular pressure ciśnienie wewnątrzgałkowe IPA Ingenuity Pathway Analysis - MAF minor allele frequency częstość rzadszego allelu ORF open reading frame otwarta ramka odczytu PCR polymerase chain reaction łańcuchowa reakcja polimerazy PKG GMP-dependent protein kinase kinaza białkowa zależna od GMP RGC retinal ganglion cells komórki zwojowe siatkówki krzywa charakterystyczno-operacyjna ROC receiver operating characteristic odbiornika SE spherical equivalent ekwiwalent sferyczny polimorfizm pojedynczego SNP single nucleotide polymorphism nukleotydu TRIS tris(hydroxymethyl)aminomethane tris(hydroksymetylo)aminometan 7 2. STRESZCZENIE PRACY W JĘZYKU POLSKIM
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