Investigation of genetic base in the treatment of age-related macular degeneration

Doctoral Dissertation uoadl:2897135 5 Read counter

Department of Biology
Library of the School of Science
Deposit date:
Gourgouli Kalliopi
Dissertation committee:
Κλεονίκη Λάμνησου – Αν. Καθηγήτρια, Τμήμα Βιολογίας, ΕΚΠΑ
Παναγιώτης Θεοδοσιάδης – Καθηγητής Οφθαλμολογίας, Ιατρική Σχολή, ΕΚΠΑ
Παναγούλα Κόλλια – Καθηγήτρια, Τμήμα Βιολογίας, ΕΚΠΑ
Σπυρίδων Ευθυμιόπουλος – Καθηγητής, Τμήμα Βιολογίας, ΕΚΠΑ
Δημήτριος Στραβοπόδης – Αν. Καθηγητής, Τμήμα Βιολογίας, ΕΚΠΑ
Ειρήνη Χατζηράλλη – Επ. Καθηγήτρια Οφθαλμολογίας, Ιατρική Σχολή, ΕΚΠΑ
Γεώργιος Δεδούσης – Καθηγητής, Χαροκόπειο Πανεπιστήμιο
Original Title:
Διερεύνηση της γενετικής βάσης στην αντιμετώπιση της ηλικιακής εκφύλισης της ωχράς κηλίδας
Translated title:
Investigation of genetic base in the treatment of age-related macular degeneration
Introduction: Age related macular degeneration (AMD) is a primary cause of irreversible vision loss in elderly people worldwide with relatively higher prevalence in the developed world. There are two types of AMD: non-exudative (dry) AMD and exudative or neovascular (wet) AMD. Drusen formation and pigmentation changes in the choroid/retinal pigmented epithelium (RPE) layers in the macula characterize the early stage of AMD. Late AMD may be atrophic or neovascular. Neovascular AMD is characterized by choroidal neovascularization (CNV) beneath the fovea which is influenced mainly by the production of vascular endothelial growth factor (VEGF). The role of nutritional supplements, such as vitamins and antioxidants, in the progression to advanced AMD has been the focus of several studies. Intravitreal injections of anti-VEGF agents is currently the most efficient treatment for neovascular AMD. The pathophysiology of AMD is poorly understood due to the fact that, it is a multifactorial disease which is associated with both genetic and environmental components. Over the last years, several studies have shown substantial genetic contributions to AMD pathogenesis and have demonstrated statistically significant associations between AMD and single nucleotide polymorphisms (SNPs) of some genes. Two major AMD-associated SNPs include the Y402H (rs1061170) variant of complement factor H (CFH) and the A69S (rs10490924) variant of age related maculopathy susceptibility 2 (ARMS2). Carriers of the risk alleles of these variants have a significantly increased risk of the disease. Moreover, SNPs in other genes such as complement component 2 (C2) and complement factor B (CFB) seem to act protectively and decrease the risk of AMD. Some recent data correlate SNPs of the above genes with the disease progression and the clinical response to treatment.
Purpose: To determine whether gene polymorphisms which are associated with AMD influence treatments’ response and specifically the antioxidant supplementation in dry AMD patients, as well as, the anti-VEGF therapy in neovascular AMD patients.
Methods: 170 patients with dry AMD and 52 neovascular AMD patients were genotyped for the following SNPs: rs1061170/Y402H in CFH gene, rs10490924/A69S in ARMS2 gene, rs9332739/E318D and rs547154/IVS10 in C2 gene, rs4151667/L9H and rs2072633/IVS17 in CFB gene. Dry AMD patients received a daily antioxidant supplement (Ocuvite Lutein forte®) for a period of 12 months, while neovascular AMD patients were treated with three monthly intravitreal injections with a dose of 0.5 mg ranibizumab (Lucentis®). Treatment response was evaluated by comparing visual acuity and optical coherence tomography (OCT) between baseline and the end of the treatment. Patients were classified as responders and non-responders based on OCT and visual acuity measurements. Regarding the dry type of AMD, patients with no change or any improvement in visual acuity and also, no observed anatomical change on OCT compared to baseline, were classified as responders and all the other patients as non-responders. Regarding the wet type of AMD, patients with no change or with an improvement on the Snellen eye chart in visual acuity and also, OCT improvement (no fluid, either subretinal or intraretinal, present at least one month after the third injection) compared to baseline, were classified as responders and all the other patients as non-responders. The proportion of treatment responders was statistically compared to patients’ genotypes for each gene. The association between each genotype and the percentage of responders in the two groups of patients was calculated using p-values with corresponding 95% confidence intervals (95%CIs).
Results: A strong association was detected between CFH Y402H variant and response to antioxidants supplements in dry AMD patients. Carriers of one or two CFH risk alleles displayed a lower chance of responding compared to those with no risk allele. However, no association of antioxidants’ response and ARMS2/A69S genotype was identified. The statistical analysis of the genetic variants rs9332739/E318D, rs547154/IVS10, rs4151667/L9H and rs2072633/IVS17 (protective SNPs) revealed a positive association between these SNPs and the use of antioxidants. Of interest is the finding that individuals who carried at least one protective SNP were more likely to respond to antioxidants and stabilize their visual acuity and OCT compared with those who lacked any protective SNP. In neovascular AMD patients, the analysis indicated that Y402H homozygous patients were less likely to respond to anti-VEGF therapy compared to heterozygous. Regarding the ARMS2/A69S genotype, carriers of the risk variant experienced significantly worse treatment outcome compared to wild type patients. The simultaneous presence of both CFH and ARMS2 high-risk SNPs in patients’ genotype appears to play an important role and to negatively affect response to treatment. On the other hand, the statistical analysis of the genetic variants rs9332739/E318D, rs547154/IVS10, rs4151667/L9H and rs2072633/IVS17 showed no significant association between the protective SNPs and the anti-VEGF treatment outcome.
Conclusion: In AMD patients, the efficacy of the antioxidant supplementation and the anti-VEGF therapy appears to differ by genotype. Our findings suggest that genetic variants could be used as predictors of treatment responsiveness in AMD patients. The detection of such genetic variants, in AMD patients, could lead to improved visual outcomes through genotype-directed therapy.
Main subject category:
age-related macular degeneration, antioxidants, ranibizumab, single nucleotide polymorphisms, treatment response
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