Povezanost perifernih morfoloških promjena mrežnice i genotipskih promjena u bolesnika sa senilnom makularnom degeneracijom [The association of the peripheral morphological retinal changes and genotypic changes in the patients with age-related macular degeneration]

Knežević, Tamara (2016) Povezanost perifernih morfoloških promjena mrežnice i genotipskih promjena u bolesnika sa senilnom makularnom degeneracijom [The association of the peripheral morphological retinal changes and genotypic changes in the patients with age-related macular degeneration]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Age-related macular degeneration (ARMD) is a multifactorial neurodegenerative disease of macular region of the retina and is a leading cause of visual loss of elderly people in developed countries. Early signs of the disease are characterized by the presence of the visible soft drusen, areas of hyperpigmentation or depigmented areas, whereas later stages manifest as either choroidal neovascularization (CNV) or atrophy of photoreceptors and retinal pigment epithelium. In the last decade the risk assessment was based on the clinical examination of the macular region, clinically the easiest one to approach to. Recent clinical data showed that the pathologic changes could be found at the retinal periphery. Likewise, clinical studies confirmed a strong association of the CFH, ARMS2, HtrA1, C2,CFB and C3 susceptibility genes with ARMD. The reports that linked the peripheral retinal changes and nucleotide polymorphisms of the susceptibility genes have analysed peripheral retina with standard fundus camera which can analyze only 30-50 degrees at once. The aim of this study is to determine the association of the peripheral retinal changes and genotypic changes in ARMD and their implications on the course and prognosis of the disease. The inclusion criteria were the age (older than 50) and the presence or absence of the clinical signs of the disease. Depending on those criteria, they were referred either to ARMD or control group. We included 160 participants in ARMD group and 150 participants in the control group. All the participants have undergone the clinical examination, the wide angle fundus photographing, OCT of the macular region and DNA genotyping from extracted peripheral blood. 126 The results showed that there was no statistical significant difference in demographic characteristics (age, sex or habits) between those two groups. The peripheral drusen, peripheral reticular pigment and paving stone degenerations are more prevalent in ARMD group. Likewise, we found statistically significant difference in odd ratio for the association of the nucleotide polymorphisms and ARMD disease: In ARMD group, homozygotes rs10490924 have 17,83 times, rs1061170 2,01 times, rs11200638 16,02 times, rs1410996 8,33 times and heterozygotes rs10490924 2,19 times higher risk for ARMD than in control group. In the control group, we found statistically significant difference in odd ratio for the association of the nucleotide polymorphisms and control group: In the control group, heterozygotes rs4151667 2,70 times, rs641153 5,26 times, rs9332739 2,70 times and rs547154 7,69 times less risk for ARMD than in a disease group. Multivariante analysis of the magnitude of the association of peripheral retinal changes and maculopathy showed that patients with peripheral drusen have almost three times, those with RPP two times and with paving stone degenerations 4,5 times more risk for ARMD macular changes compared to the control group. In ARMD group, there was a strong association of the peripheral drusen and reticular pigment with polymorphism CFHY402H: for peripheral drusen OR=4,5for CC genotype and for RPP OR=4,49 for CC and OR=3,51 for CT genotype. When we analyze peripheral retinal changes and genotypic changes in all participants together with or without signs of maculopathy, we found that peripheral drusen and RPP are statistically significant more present in the participants with polymorphisms of CFH, ARMS2 and HTRA1 genes. We also found that paving stone degenerations are statistically significant more present in the participants with polymorphisms ARMS2 and HtrA1 genes. There was no statistically significant association between hyperpigmentations, hypopigmentations, white without pressure, lattice degenerations, holes, retinoschisis and vitreal opacities with nucleotide polymorphisms in both groups. These results have shown the significance of the peripheral drusen and RPP and potentially paving stone degenerations in the fenotypic features of ARMD and therefore, defining their potential role in the classification of the disease, early detection and follow-up of the patients with ARMD.

Abstract in Croatian

Senilna makularna degeneracija (SMD) je multifaktorijalna neurodegenerativna bolest mrežnice i vodeći uzrok gubitak vida u razvijenim zemljama. Bolest je u početku karakterizirana pojavom tzv. druza− žućkastih depozita na razini retinalnog pigmentnog epitela (RPE), fokalnih hiper- ili hipopigmentacija, dok su kasniji poznati klinički oblici bolesti geografska atrofija (suhi oblik) na razini fotoreceptora i RPE i eksudativni (vlažni) oblik na razini koriokapilarisa. Njihovo pravodobno otkrivanje je od velikog značaja jer dovode do dramatičnog pada vidne oštrine unutar godinu dana. Do unazad desetak godina procjena rizika se zasnivala na kliničkom izgledu promjena makularnog područja, najlakše dostupnog pregledu. Novija istraživanja ukazuju da se ključne morfološke promjene SMD-a mogu nalaziti i na periferiji mrežnice te da se značajnije pojavljuju u uznapredovaloj SMD. Nadalje utvrđena je snažna povezanost genskih polimorfizama gena za CFH, ARMS2, HtrA1, C2, CFB i C3 i pojave SMD-a. Studije koje su do sada ispitivale povezanost perifernih i genotipskih promjena su snimale i analizirale periferiju mrežnice standardnim fundus kamerama koje mogu snimiti 30-50 stupnjeva mrežnice u jednoj snimci. Stoga je cilj ove studije određivanje povezanosti perifernih morfoloških promjena i nukleotidnih polimorfizama gena za CFH, ARMS2, HTRA1, C2, CFB i C3 u SMD-u i njenu implikaciju na težinu i tijek bolesti. U istraživanje su bili uključeni ispitanici u dobi iznad 50 godina, susljedno redom dolaska na Kliniku, te ovisno o kliničkoj slici, bili su, prema redu dolaska, svrstani u skupinu ispitanika sa SMD-om ili u kontrolnu skupinu sa zdravim ispitanicima. U SMD skupinu uključeno je 160, a u kontrolnu skupinu 150 ispitanika. Nije bilo značajne statističke značajne razlike u dobi, spolu i navikama između obiju skupina ispitanika, čime se ostvario uvjet za valjanu statističku analizu. Svim ispitanicama je nakon zadovoljenih kriterija uključivanja učinjen klinički pregled, snimanje i analiza snimaka makularnog područja i periferije mrežnice širokokutnom kamerom koja snima 200 stupnjeva mrežnice u jednoj snimci, snimanje makularnog područja OCT-om i genotipizacija DNK iz uzorka periferne krvi. Između SMD i kontrolne skupine, nije bilo statistički značajne razlike u dobi, spolu i navikama. Rezultati istraživanja su dokazali statistički značajno češće prisustvo perifernih druza, retikularnih pigmentacija i kaldrmastih degeneracija u SMD skupini. Dokazana je povezanost genotipova s centralnim promjenama u SMD skupini, odnosno da određeni genotip značajno povećava omjer izgleda za prisustvo SMD-a: homozigoti rs10490924 za 17,83 puta, rs1061170 za 2,01 puta, rs11200638 za 16,02 puta i rs1410996 za 8,33 puta; te rs10490924 heterozigot za 2,19 puta. 124 U kontrolnoj skupini u odnosu na normalni genotip, sljedeći genotip značajno smanjuje vjerojatnost prisustva SMD-a: rs4151667 heterozigot za 2,70 puta, rs641153 heterozigot za 5,26 puta, rs9332739 heterozigot za 2,70 puta te rs547154 heterozigot za 7,69 puta. Multivarijantnom analizom razine povezanosti tih istih perifernih promjena s centralnom makulopatijom, vidljivo je da ispitanici koji imaju periferne druze imaju gotovo tri puta, RPP dva puta, a kaldrmaste degeneracije 4,5 puta veće izglede za prisustvo SMD-a u odnosu na kontrolnu skupinu. Dokazana je povezanost perifernih druza i RPP-a s polimorfizmom CFHY402H u ispitanika sa SMD-om: za periferne druze, OR=4,5 za CC genotip, za RPP OR=4,49 za CC i OR=3,51 za CT genotip. Prilikom analize povezanosti perifernih promjena i nukleotidnih polimorfizama na ukupnom broju ispitanika sa ili bez znakova makulopatije, dokazani su veći izgledi prisustva perifernih druza i RPP-a u ispitanika s polimorfizmima CFH, ARMS2 i HtrA1 dok je za kaldrmaste degeneracije dokazan veći izgled za prisustvo u ispitanika s polimorfizmima ARMS2 i HtrA1. Nije nađena povezanost hiperpigmentacija, hipopigmentacija i ostalih perifernih degeneracija (mrežolikih degeneracija, bljedila bez pritiska, ruptura, retinoshiza, vitrealnih opaciteta) s nukleotidnim polimorfizmima. Ovim istraživanjem je dokazano važno mjesto perifernih druza, RPP-a i potencijalno kaldrmastih degeneracija u fenotipu SMD-a, a time i klasifikaciji, pravodobnom otkrivanju i praćenju bolesnika sa SMD-om.

Item Type: Thesis (PhD)
Mentors:
Mentor
Vatavuk, Zoran
Departments: Izvan medicinskog fakulteta
Depositing User: dr.med. Helena Markulin
University: Sveučilište u Zagrebu
Institution: Medicinski fakultet
Number of Pages: 145
Status: Unpublished
Creators:
CreatorsEmail
Knežević, TamaraUNSPECIFIED
Date: 20 July 2016
Date Deposited: 18 Jan 2018 08:59
Last Modified: 18 Jan 2018 08:59
Subjects: /
Related URLs:
    URI: http://medlib.mef.hr/id/eprint/2784

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